| Type |
Details |
Score |
| Protein Domain |
| Name: |
Aldo-keto reductase family 3C2/3 |
| Type: |
Family |
| Description: |
This entry represents aldo-keto reductase family 3C2/3 (AKR3C2/3), including YDL124W from Saccharomyces cerevisiae, SPAC19G12.09 from Schizosaccharomyces pombe and CPRC1/2 from Candida parapsilosis [
]. SPAC19G12.09 reductase catalyses the conversion from (Indol-3-yl)ethanol to (indol-3-yl)acetaldehyde in a NAD/NADP-dependent manner []. CPR acts as a NADPH-dependent conjugated polyketone reductase with broad substrate specificity and strict stereospecificity. It reduces ketopantoyl lactone and isatin [,
].In general, the aldo-keto reductase (AKR) protein superfamily members reduce carbonyl substrates such as: sugar aldehydes, keto-steroids, keto-prostaglandins, retinals, quinones, and lipid peroxidation by-products [
,
]. However, there are some exceptions, such as the reduction of steroid double bonds catalysed by AKR1D enzymes (5beta-reductases); and the oxidation of proximate carcinogen trans-dihydrodiol polycyclic aromatic hydrocarbons; while the beta-subunits of potassium gated ion channels (AKR6 family) control Kv channel opening [].Structurally, they contain an (alpha/beta)8-barrel motif, display large loops at the back of the barrel which govern substrate specificity, and have a conserved cofactor binding domain. The binding site is located in a large, deep, elliptical pocket in the C-terminal end of the beta sheet, the substrate being bound in an extended conformation. The hydrophobic nature of the pocket favours aromatic and apolar substrates over highly polar ones [
]. They catalyse an ordered bi bi kinetic mechanism in which NAD(P)H cofactor binds first and leaves last []. Binding of the NADPH coenzyme causes a massive conformational change, reorienting a loop, effectively locking the coenzyme in place. This binding is more similar to FAD- than to NAD(P)-binding oxidoreductases []. |
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| Protein Domain |
| Name: |
Aldo-keto reductase family 1 member A1 |
| Type: |
Family |
| Description: |
This entry represents aldo-keto reductase family 1 member A1 (AKR1A), including aldehyde reductase (ALR) from mammals [
]. The AKR1A family belongs to the aldo-keto reductase (AKR) family. ALR, also known as aldehyde reductase, or ALDR1, catalyses the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols. In vitro substrates include succinic semialdehyde, 4-nitrobenzaldehyde, 1,2-naphthoquinone, methylglyoxal, and D-glucuronic acid [
,
]. In general, the aldo-keto reductase (AKR) protein superfamily members reduce carbonyl substrates such as: sugar aldehydes, keto-steroids, keto-prostaglandins, retinals, quinones, and lipid peroxidation by-products [
,
]. However, there are some exceptions, such as the reduction of steroid double bonds catalysed by AKR1D enzymes (5beta-reductases); and the oxidation of proximate carcinogen trans-dihydrodiol polycyclic aromatic hydrocarbons; while the beta-subunits of potassium gated ion channels (AKR6 family) control Kv channel opening [].Structurally, they contain an (alpha/beta)8-barrel motif, display large loops at the back of the barrel which govern substrate specificity, and have a conserved cofactor binding domain. The binding site is located in a large, deep, elliptical pocket in the C-terminal end of the beta sheet, the substrate being bound in an extended conformation. The hydrophobic nature of the pocket favours aromatic and apolar substrates over highly polar ones [
]. They catalyse an ordered bi bi kinetic mechanism in which NAD(P)H cofactor binds first and leaves last []. Binding of the NADPH coenzyme causes a massive conformational change, reorienting a loop, effectively locking the coenzyme in place. This binding is more similar to FAD- than to NAD(P)-binding oxidoreductases []. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 10 |
| Type: |
Family |
| Description: |
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern [
]. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences [
]. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [,
]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis [
]. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 10 is activated by TNF-related apoptosis-inducing ligand (TRAIL). Four subtypes of the receptor have been identified: TNF receptors 10A and 10B (also known as death receptor 4 and 5, respectively), which contain a death domain within their C-terminal regions, and TNF receptors 10C and 10D, in which the death domain is not present or is truncated. It has been suggested that the function of the latter two receptors may be to inhibit TRAIL cytotoxicity by competing with the other TRAIL receptors for binding of the ligand [
,
]. |
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| Protein Domain |
| Name: |
NADH-ubiquinone/plastoquinone oxidoreductase chain 6, subunit NuoJ |
| Type: |
Homologous_superfamily |
| Description: |
NADH:ubiquinone oxidoreductase (complex I) (
) is a respiratory-chain enzyme that catalyses the transfer of two electrons from NADH to ubiquinone in a reaction that is associated with proton translocation across the membrane (NADH + ubiquinone = NAD+ + ubiquinol) [
]. Complex I is a major source of reactive oxygen species (ROS) that are predominantly formed by electron transfer from FMNH(2). Complex I is found in bacteria, cyanobacteria (as a NADH-plastoquinone oxidoreductase), archaea [], mitochondria, and in the hydrogenosome, a mitochondria-derived organelle. In general, the bacterial complex consists of 14 different subunits, while the mitochondrial complex contains homologues to these subunits in addition to approximately 31 additional proteins [].This entry represents chain 6 from NADH:ubiquinone oxidoreductase and NADH-plastoquinone oxidoreductase. Bacterial proton-translocating NADH-quinone oxidoreductase (NDH-1) is composed of 14 different subunits. The chain belonging to this family is a subunit that constitutes the membrane sector of the complex. It reduces ubiquinone to ubiquinol utilising NADH. Plant chloroplastic NADH-plastoquinone oxidoreductase reduces plastoquinone to plastoquinol. Mitochondrial NADH-ubiquinone oxidoreductase from a variety of sources reduces ubiquinone to ubiquinol.Subunit NuoJ has an unusual non-globular fold: three linearly arranged amino-terminal TM helices border NuoK, and TMs 4 and 5 are separated at the opposite sides of the domain. Thus, NuoJ interweaves between NuoK, A and N, stabilising the complex. TM3 of NuoJ contains in its middle a pi-bulge/kink, so this helix is probably flexible and mechanistically important. TM3 is the most conserved helix in NuoJ and is a hotspot for human mitochondrial disease mutations [
]. |
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| Protein Domain |
| Name: |
Voltage-gated cation channel calcium and sodium |
| Type: |
Family |
| Description: |
Voltage-dependent sodium channels are transmembrane (TM) proteins are responsible for the depolarising phase of the action potential in most electrically excitable cells [
]. Several structural and functional isoforms are found in mammals, coded for by a multigene family, which leads to different types of sodium ion in excitable tissues.Voltage-dependent calcium channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular calcium signalling. The opening and closing of these channels by depolarizing stimuli allows calcium ions to enter neurons down a steep electrochemical gradient, producing transient intracellular calcium signals. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus and the known sites of channel regulation by second messengers, drugs, and toxins [
].T-type calcium channels exhibit unique voltage-dependent kinetics, small single channel conductance, rapid inactivation, slow deactivation and a relatively high permeability to calcium [
]. They are primarily responsible for rebound burst firing in central neurons and are implicated in normal brain functions, such as slow wave sleep, and in diseased states, such as epilepsy []. They also play an important role in hormone secretion [] and smooth muscle excitability [].The structure of sodium channels is based on 4 internal repeats of a 6-helix bundle [
]. The basic structural motif (the 6-helix bundle) is also found in potassium and calcium channel alpha subunits.This entry represents alpha subunits of the voltage-gated sodium channel superfamily and the alpha-1 subunit of T-type calcium channels. |
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| Protein Domain |
| Name: |
Dynein heavy chain, linker, subdomain 3 |
| Type: |
Homologous_superfamily |
| Description: |
Dyneins are described as motor proteins of eukaryotic cells, as they can convert energy derived from the hydrolysis of ATP to force and movement along cytoskeletal polymers, such as microtubules. Dyneins generally contain one to three heavy chains, which belong to the AAA+ superfamily of mechanochemical enzymes [
]. Each heavy chain consists of a flexible N-terminal tail known as the cargo-binding domain [] and a motor domain which consists of an ATP-hydrolysing AAA+ ring, a flexible microtubule-binding stalk, a linker and a C-sequence []. The stalk has an ATP-sensitive microtubule-binding site (MTBD) at its tip [,
], whereas the linker has been suggested to function as a mechanical element for generating dynein's power stroke [,
,
].The two categories of dyneins are the axonemal dyneins, which produce the bending motions that propagate along cilia and flagella, and the cytosolic dyneins, which drive a variety of fundamental cellular processes including nuclear migration, organisation of the mitotic spindle, chromosome separation during mitosis, and the positioning and function of many intracellular organelles. Cytoplasmic dyneins contain several accessory subunits ranging from light to intermediate chains.This superfamily represents the subdomain 3 found in the linker domain of dynein heavy chain. The linker exists as a rod-like structure that comprises nineteen α-helices and eight β-strands and can be divided into five subdomains from 0 to 4. This subdomain interacts with subdomain 2 and 4 and has been suggested to play a role in the interactions between the linker base and the ring [
]. |
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| Protein Domain |
| Name: |
Diphthamide synthesis DPH1/DPH2, domain 2 |
| Type: |
Homologous_superfamily |
| Description: |
Diphthamide is the name given to a unique post-translationally modified histidine residue in archaeal and eukaryotic translation elongation factor 2. This modified histidine is target of diphtheria toxin, which inhibits eukaryotic protein synthesis by ADP-ribosylating diphthamide in EF2 [
].The diphthamide synthesis DPH1/DPH2 enzymes which catalyse the first step in diphthamide biosynthesis. Archaeal DPHs are more similar to eukaryotic DPH1 than to DPH2 [
].Available structural information on PhDph2 reveals that this enzyme is a homodimer and that each monomer comprises three domains which share the same overall fold. The basic domain fold is a four-stranded parallel β-sheet with three flanking α-helices (or two α-helices and one 3(10) helix in the case of domain 2). The two β-sheets in domain 1 and 2 each contain an additional β-strand that is antiparallel to the rest of the β-sheet. Domains 2 and 3 have two additional α-helices. Domain 1 of one monomer and domain 3 of the adjacent monomer form the dimer interface, creating an extended nine-stranded β-sheet. The domain folds and their arrangement resemble the structure of quinolinate synthase but the orientations of the domains with respect to each other are different in the two enzymes. Three conserved cysteine residues (Cys59, Cys163 and Cys287), each coming from a different structural domain, are clustered together in the centre of the PhDph2 monomers. All three cysteine residues are conserved in eukaryotic DPH1s. The first and third cysteine residues are conserved in eukaryotic DPH2s [
].This superfamily represents the domain 2 found in diphthamide synthesis DPH1/DPH2 enzymes. |
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| Protein Domain |
| Name: |
Diphthamide synthesis DPH1/DPH2, domain 1 |
| Type: |
Homologous_superfamily |
| Description: |
Diphthamide is the name given to a unique post-translationally modified histidine residue in archaeal and eukaryotic translation elongation factor 2. This modified histidine is target of diphtheria toxin, which inhibits eukaryotic protein synthesis by ADP-ribosylating diphthamide in EF2 [
].The diphthamide synthesis DPH1/DPH2 enzymes which catalyse the first step in diphthamide biosynthesis. Archaeal DPHs are more similar to eukaryotic DPH1 than to DPH2 [
].Available structural information on PhDph2 reveals that this enzyme is a homodimer and that each monomer comprises three domains which share the same overall fold. The basic domain fold is a four-stranded parallel β-sheet with three flanking α-helices (or two α-helices and one 3(10) helix in the case of domain 2). The two β-sheets in domain 1 and 2 each contain an additional β-strand that is antiparallel to the rest of the β-sheet. Domains 2 and 3 have two additional α-helices. Domain 1 of one monomer and domain 3 of the adjacent monomer form the dimer interface, creating an extended nine-stranded β-sheet. The domain folds and their arrangement resemble the structure of quinolinate synthase but the orientations of the domains with respect to each other are different in the two enzymes. Three conserved cysteine residues (Cys59, Cys163 and Cys287), each coming from a different structural domain, are clustered together in the centre of the PhDph2 monomers. All three cysteine residues are conserved in eukaryotic DPH1s. The first and third cysteine residues are conserved in eukaryotic DPH2s [].This superfamily represents the domain 1 found in diphthamide synthesis DPH1/DPH2 enzymes. |
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| Protein Domain |
| Name: |
Diphthamide synthesis DPH1/DPH2, domain 3 |
| Type: |
Homologous_superfamily |
| Description: |
Diphthamide is the name given to a unique post-translationally modified histidine residue in archaeal and eukaryotic translation elongation factor 2. This modified histidine is target of diphtheria toxin, which inhibits eukaryotic protein synthesis by ADP-ribosylating diphthamide in EF2 [
].The diphthamide synthesis DPH1/DPH2 enzymes which catalyse the first step in diphthamide biosynthesis. Archaeal DPHs are more similar to eukaryotic DPH1 than to DPH2 [
].Available structural information on PhDph2 reveals that this enzyme is a homodimer and that each monomer comprises three domains which share the same overall fold. The basic domain fold is a four-stranded parallel β-sheet with three flanking α-helices (or two α-helices and one 3(10) helix in the case of domain 2). The two β-sheets in domain 1 and 2 each contain an additional β-strand that is antiparallel to the rest of the β-sheet. Domains 2 and 3 have two additional α-helices. Domain 1 of one monomer and domain 3 of the adjacent monomer form the dimer interface, creating an extended nine-stranded β-sheet. The domain folds and their arrangement resemble the structure of quinolinate synthase but the orientations of the domains with respect to each other are different in the two enzymes. Three conserved cysteine residues (Cys59, Cys163 and Cys287), each coming from a different structural domain, are clustered together in the centre of the PhDph2 monomers. All three cysteine residues are conserved in eukaryotic DPH1s. The first and third cysteine residues are conserved in eukaryotic DPH2s [
].This superfamily represents the domain 3 found in diphthamide synthesis DPH1/DPH2 enzymes. |
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| Protein Domain |
| Name: |
DNA gyrase, subunit A |
| Type: |
Family |
| Description: |
DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type II topoisomerases are ATP-dependent enzymes, and can be subdivided according to their structure and reaction mechanisms: type IIA (topoisomerase II or gyrase, and topoisomerase IV) and type IIB (topoisomerase VI). These enzymes are responsible for relaxing supercoiled DNA as well as for introducing both negative and positive supercoils [
].Topoisomerase II (called gyrase in bacteria) primarily introduces negative supercoils into DNA. In bacteria, topoisomerase II consists of two polypeptide subunits, gyrA and gyrB, which form a heterotetramer: (BA)2. In most eukaryotes, topoisomerase II consists of a single polypeptide, where the N- and C-terminal regions correspond to gyrB and gyrA, respectively.This entry represents the A subunit (gyrA) as found predominantly in bacteria, but does not include the topoisomerase II enzymes composed of a single polypeptide, as are found in most eukaryotes. GyrA has two functional domains: an N-terminal that forms the covalent DNA-protein bridge that is responsible for the breaking- and rejoining function, and a C-terminal that can bind DNA non-specifically [
]. |
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| Protein Domain |
| Name: |
Aminoacyl-tRNA synthetase, class Ic |
| Type: |
Family |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases [
]. |
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| Protein Domain |
| Name: |
Transketolase binding site |
| Type: |
Binding_site |
| Description: |
Transketolase
(TK) catalyses the reversible transfer of a
two-carbon ketol unit from xylulose 5-phosphate to an aldose receptor, such asribose 5-phosphate, to form sedoheptulose 7-phosphate and glyceraldehyde 3-
phosphate. This enzyme, together with transaldolase, provides a link betweenthe glycolytic and pentose-phosphate pathways.
TK requires thiamine pyrophosphate as a cofactor. In most sources where TK hasbeen purified, it is a homodimer of approximately 70 Kd subunits. TK sequences
from a variety of eukaryotic and prokaryotic sources [,
] show that theenzyme has been evolutionarily conserved.
In the peroxisomes of methylotrophic yeast Pichia angusta (Yeast) (Hansenula polymorpha), there is ahighly related enzyme, dihydroxy-acetone synthase (DHAS)
(also
known as formaldehyde transketolase), which exhibits a very unusualspecificity by including formaldehyde amongst its substrates.
1-deoxyxylulose-5-phosphate synthase (DXP synthase) [] is an enzyme so farfound in bacteria (gene dxs) and plants (gene CLA1) which catalyses the
thiamine pyrophosphoate-dependent acyloin condensation reaction between carbonatoms 2 and 3 of pyruvate and glyceraldehyde 3-phosphate to yield 1-deoxy-D-xylulose-5-phosphate (dxp), a precursor in the biosynthetic pathway to
isoprenoids, thiamine (vitamin B1), and pyridoxol (vitamin B6). DXP synthaseis evolutionary related to TK.
The N-terminal section, contains a histidine residue which appears to function inproton transfer during catalysis [
]. This entry represents the centralsection there are conserved acidic residues that are part of the active cleft
and may participate in substrate-binding [].This group of proteins includes transketolase enzymes
and 2-oxoisovalerate dehydrogenasebeta subunit
. Both these enzymes
utilise thiamine pyrophosphate as a cofactor, suggestingthere may be common aspects in their mechanism of catalysis.
This entry conserved acidic residues that are located in the central section, which may participate in substrate-binding [
]. |
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| Protein Domain |
| Name: |
Phosphoglycerate kinase, N-terminal |
| Type: |
Homologous_superfamily |
| Description: |
Phosphoglycerate kinase (
) (PGK) is an enzyme that catalyses the formation of ATP to ADP and vice versa. In the second step of the second phase in glycolysis, 1,3-diphosphoglycerate is converted to
3-phosphoglycerate, forming one molecule of ATP. If the reverse were to occur, one molecule of ADP would be formed. This reaction is essential in most cells for the generation of ATP in aerobes, for fermentation in anaerobes and for carbon fixation in plants.PGK is found in all living organisms and its sequence has been highly conserved throughout evolution. The enzyme exists as a monomer containing two nearly equal-sized domains that correspond to the N- and C-termini of the protein (the last 15 C-terminal residues loop back into the N-terminal domain). 3-phosphoglycerate (3-PG) binds to the N-terminal, while the nucleotide substrates, MgATP or MgADP, bind to the C-terminal domain of the enzyme. This extended two-domain structure is associated with large-scale 'hinge-bending' conformational changes, similar to those found in hexokinase [
]. At the core of each domain is a 6-stranded parallel β-sheet surrounded by alpha helices. Domain 1 has a parallel β-sheet of six strands with an order of 342156, while domain 2 has a parallel β-sheet of six strands with an order of 321456. Analysis of the reversible unfolding of yeast phosphoglycerate kinase leads to the conclusion that the two lobes are capable of folding independently, consistent with the presence of intermediates on the folding pathway with a single domain folded []. Phosphoglycerate kinase (PGK) deficiency is associated with haemolytic anaemia and mental disorders in man [
].This superfamily represents the N-terminal domain of PGK. |
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| Protein Domain |
| Name: |
DNA topoisomerase II, eukaryotic-type |
| Type: |
Family |
| Description: |
DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type II topoisomerases are ATP-dependent enzymes, and can be subdivided according to their structure and reaction mechanisms: type IIA (topoisomerase II or gyrase, and topoisomerase IV) and type IIB (topoisomerase VI). These enzymes are responsible for relaxing supercoiled DNA as well as for introducing both negative and positive supercoils [
].This entry represents DNA topoisomerase II enzymes from eukaryotes and viruses. Topoisomerase II primarily functions in introducing negative supercoils into DNA, and is of particular importance during the segregation of chromosomes during mitosis [
,
]. In eukaryotes and viruses, this enzyme occurs as a single polypeptide, with the N-terminal portion (homologous to subunit B of bacterial topoisomerase II, or gyraseB) responsible for ATPase activity and the C-terminal portion (homologous to subunit A of bacterial topoisomerase II, or gyraseA) responsible for the breaking-rejoining function through its capacity to form protein-DNA bridges. In mammals, there are at least two isozymes of this enzyme, topoisomerases II-alpha and II-beta, which are similar in structure and catalytic properties [,
]. The alpha isoform is involved in chromosome condensation and segregation. |
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| Protein Domain |
| Name: |
DNA topoisomerase, type IIA, domain A |
| Type: |
Domain |
| Description: |
Type II topoisomerases are ATP-dependent enzymes, and can be subdivided according to their structure and reaction mechanisms: type IIA (topoisomerase II or gyrase, and topoisomerase IV) and type IIB (topoisomerase VI). These enzymes are responsible for relaxing supercoiled DNA as well as for introducing both negative and positive supercoils [
].This entry represents a domain found in type IIA topoisomerases, such as bacterial DNA topoisomerase IV (C subunit, ParC), bacterial DNA gyrases (A subunit, GyrA), and mammalian DNA toposiomerases II. DNA topoisomerases are essential enzymes that regulate the conformational changes in DNA topology by catalysing the concerted breakage and rejoining of DNA strands during normal cellular growth [].In bacteria, topoisomerase II consists of two polypeptide subunits, gyrA and gyrB, which form a heterotetramer: (BA)2. In most eukaryotes, topoisomerase II consists of a single polypeptide, where the N- and C-terminal regions correspond to gyrB and gyrA, respectively; this topoisomerase II forms a homodimer that is equivalent to the bacterial heterotetramer. There are four functional domains in topoisomerase II: domain 1 (N-terminal of gyrB) is an ATPase, domain 2 (C-terminal of gyrB) is responsible for subunit interactions (differs between eukaryotic and bacterial enzymes), domain 3 (N-terminal of gyrA) is responsible for the breaking-rejoining function through its capacity to form protein-DNA bridges, and domain 4 (C-terminal of gyrA) is able to non-specifically bind DNA [
].Topoisomerase IV primarily decatenates DNA and relaxes positive supercoils, which is important in bacteria, where the circular chromosome becomes catenated, or linked, during replication [
]. Topoisomerase IV consists of two polypeptide subunits, parE and parC, where parC is homologous to gyrA and parE is homologous to gyrB. |
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| Protein Domain |
| Name: |
Phosphoglycerate kinase, conserved site |
| Type: |
Conserved_site |
| Description: |
Phosphoglycerate kinase (
) (PGK) is an enzyme that catalyses the formation of ATP to ADP and vice versa. In the second step of the second phase in glycolysis, 1,3-diphosphoglycerate is converted to
3-phosphoglycerate, forming one molecule of ATP. If the reverse were to occur, one molecule of ADP would be formed. This reaction is essential in most cells for the generation of ATP in aerobes, for fermentation in anaerobes and for carbon fixation in plants.PGK is found in all living organisms and its sequence has been highly conserved throughout evolution. The enzyme exists as a monomer containing two nearly equal-sized domains that correspond to the N- and C-termini of the protein (the last 15 C-terminal residues loop back into the N-terminal domain). 3-phosphoglycerate (3-PG) binds to the N-terminal, while the nucleotide substrates, MgATP or MgADP, bind to the C-terminal domain of the enzyme. This extended two-domain structure is associated with large-scale 'hinge-bending' conformational changes, similar to those found in hexokinase [
]. At the core of each domain is a 6-stranded parallel β-sheet surrounded by alpha helices. Domain 1 has a parallel β-sheet of six strands with an order of 342156, while domain 2 has a parallel β-sheet of six strands with an order of 321456. Analysis of the reversible unfolding of yeast phosphoglycerate kinase leads to the conclusion that the two lobes are capable of folding independently, consistent with the presence of intermediates on the folding pathway with a single domain folded []. Phosphoglycerate kinase (PGK) deficiency is associated with haemolytic anaemia and mental disorders in man [
].This entry represents a conserved motif found in the N-terminal region of PGK. |
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| Protein Domain |
| Name: |
Fumarate lyase family |
| Type: |
Family |
| Description: |
A number of enzymes, belonging to the lyase class, for which fumarate is a substrate, have been shown to share a short conserved sequence around a
methionine which is probably involved in the catalytic activity of this typeof enzymes [
]. The following are examples of members of this family:: 3-carboxymuconate lactonizing enzyme,
(3-carboxy-cis,cis-muconate cycloisomerase), an enzyme involved in aromatic acids catabolism [
]. : Delta-crystallin shares around 90% sequence identity with arginosuccinate lyase, showing that it is an example of a 'hijacked' enzyme - accumulated mutations have, however, rendered the protein enzymatically inactive.: Class I Fumarase enzyme,
(fumarate hydratase), which catalyses the reversible hydration of fumarate to L-malate. Class I enzymes are thermolabile dimeric enzymes (as for example: Escherichia coli fumC).
: Arginosuccinase,
(argininosuccinate lyase), which catalyses the formation of arginine and fumarate from argininosuccinate, the last step in the biosynthesis of arginine.
: Aspartate ammonia-lyase,
(aspartase), which catalyses the reversible conversion of aspartate to fumarate and ammonia. This reaction is analogous to that catalyzed by fumarase, except that ammonia rather than water is involved in the trans-elimination reaction.
: class II Fumarase enzyme,
, are thermostable and tetrameric and are found in prokaryotes (as for example: E. coli fumA and fumB) as well as in eukaryotes. The sequence of the two classes of fumarases are not closely related.
: Adenylosuccinase,
(adenylosuccinate lyase) [
], which catalyses the eighth step in the de novo biosynthesis of purines, the formation of 5'-phosphoribosyl-5-amino-4-imidazolecarboxamide and fumarate from 1-(5-phosphoribosyl)-4-(N-succino-carboxamide). That enzyme can also catalyse the formation of fumarate and AMP from adenylosuccinate. : Trans-aconitate decarboxylase 1, which decarboxylates trans-aconitate, an intermediate in the biosynthesis of itaconic acid and 2-hydroxyparaconate [
,
]. |
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| Protein Domain |
| Name: |
Cysteine-tRNA ligase |
| Type: |
Family |
| Description: |
Cysteine-tRNA ligase (also known as Cysteinyl-tRNA synthetase) (
) is an alpha monomer and belongs to class Ia [
]. It is highly specific despite not possessing the amino acid editing activity characteristic of many other tRNA ligases [].The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c []. |
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| Protein Domain |
| Name: |
Glutaminyl-tRNA synthetase, class Ib, non-specific RNA-binding domain, N-terminal |
| Type: |
Domain |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].This is a domain found N-terminal to the catalytic domain of glutaminyl-tRNA synthetase (
) in eukaryotes but not in Escherichia coli. This domain is thought to bind RNA in a non-specific manner, enhancing interactions between the tRNA and enzyme, but is not essential for enzyme function [
]. |
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| Protein Domain |
| Name: |
Glutaminyl-tRNA synthetase, class Ib, non-specific RNA-binding domain 2 |
| Type: |
Domain |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].This is a region found N-terminal to the catalytic domain of glutaminyl-tRNA synthetase (
) in eukaryotes but not in Escherichia coli. This region is thought to bind RNA in a non-specific manner, enhancing interactions between the tRNA and enzyme, but is not essential for enzyme function [
]. |
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| Protein Domain |
| Name: |
Cytochrome c oxidase subunit II-like C-terminal |
| Type: |
Domain |
| Description: |
Cytochrome c oxidase (
) [
,
] is an oligomeric enzymatic complex which is a component of the respiratory chain and is involved in the transfer of electrons from cytochrome c to oxygen. In eukaryotes this enzyme complex is located in the mitochondrial inner membrane; in aerobic prokaryotes it is found in the plasma membrane. The number of polypeptides in the complex ranges from 3-4 (prokaryotes), up to 13(mammals). In Archaea, a cytochrome-c-type oxidase from Natronobacterium (cytochrome ba3) has been shown to consists of four subunits []. Subunit 2 (CO II) transfers the electrons from cytochrome c to the catalytic subunit 1. It contains two adjacent transmembrane regions in its N terminus and the major part of the protein is exposed to the periplasmic or to the mitochondrial intermembrane space, respectively. CO II provides the substrate-binding site and contains a copper centre called Cu(A), probably the primary acceptor in cytochrome c oxidase. An exception is the corresponding subunit of the cbb3-type oxidase which lacks the copper A redox-centre. Several bacterial CO II have a C-terminal extension that contains a covalently bound haem c.It has been shown [
,
] that nitrous oxide reductase (gene nosZ) of Pseudomonas has sequence similarity in its C terminus to CO II. This enzyme is part of the bacterial respiratory system which is activated under anaerobic conditions in the presence of nitrate or nitrous oxide. NosZ is a periplasmic homodimer that contains a dinuclear copper centre, probably located in a 3-dimensional fold similar to the cupredoxin-like fold that has been suggested for the copper-binding site of CO II []. |
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| Protein Domain |
| Name: |
Arginyl tRNA synthetase N-terminal domain |
| Type: |
Domain |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].This domain is found at the N terminus of Arginyl tRNA synthetase, also called additional domain 1 (Add-1). It is about 140 residues long and it has been suggested to be involved in tRNA recognition [
]. |
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| Protein Domain |
| Name: |
DNA breaking-rejoining enzyme, catalytic core |
| Type: |
Homologous_superfamily |
| Description: |
Phage integrases are enzymes that mediate unidirectional site-specific recombination between two DNA recognition sequences, the phage attachment site, attP, and the bacterial attachment site, attB []. Integrases may be grouped into two major families, the tyrosine recombinases and the serine recombinases, based on their mode of catalysis. Tyrosine family integrases, such as Bacteriophage lambda integrase, utilise a catalytic tyrosine to mediate strand cleavage, tend to recognise longer attP sequences, and require other proteins encoded by the phage or the host bacteria.The 356 amino acid lambda integrase consists of two domains: an N-terminal domain that includes residues 1-64 and is responsible for binding the arm-type sites of attP, and a C-terminal domain (CTD) that binds the lower affinity core-type sites and contains the catalytic site. The CTD can be further divided into the core-type binding domain (residues 65-169) and the catalytic core domain (170-356), the later representing this entry. The catalytic core adopts an alpha3-beta3-alpha4 fold, where one side of the beta sheet is exposed.The recombinases Cre from phage P1, XerD from Escherichia coli and Flp from yeast are members of the tyrosine recombinase family, and have a two-domain motif resembling that of lambda integrase, as well as sharing a conserved binding mechanism [
]. The structural fold of their catalytic core domains resemble that of Lambda integrase.The catalytic core of the eukaryotic DNA topoisomerase I shares significant structural similarity with the bacteriophage family of DNA integrases [
]. Topoisomerases I promote the relaxation of DNA superhelical tension by introducing a transient single-stranded break in duplex DNA and are vital for the processes of replication, transcription and recombination. |
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| Protein Domain |
| Name: |
Aspartyl/glutamyl-tRNA(Asn/Gln) amidotransferase, subunit B /E |
| Type: |
Family |
| Description: |
Glutamyl-tRNA(Gln) amidotransferase (Gat;
) provides a means of producing correctly charged Gln-tRNA(Gln) through the transamidation of mis-acylated Glu-tRNA(Gln) in organisms which lack glutaminyl-tRNA synthetase [
,
]. The reaction takes place in the presence of glutamine and ATP through an activated gamma-phospho-Glu-tRNA(Gln). The enzyme is composed of three subunits: A (an amidase), B and C. It also exists in eukaryotes as a protein targeted to the mitochondria.The heterotrimer GatABC is involved in converting Glu to Gln and/or Asp to Asn, when the amino acid is attached to the appropriate tRNA. In Lactobacillus, GatABC is responsible for producing tRNA(Gln). In Archaea, GatABC is responsible for producing tRNA(Asn), while GatDE is responsible for producing tRNA(Gln). In lineages that include Thermus, Chlamydia, or Acidithiobacillus, the GatABC complex catalyses both tRNA(Gln) and tRNA(Asn).Glutamyl-tRNA(Gln) amidotransferase, subunit E (GatE) is found only in the Archaea. It is part of a heterodimer, with GatD (
), that acts as an amidotransferase on misacylated Glu-tRNA(Gln) to produce Gln-tRNA(Gln) [
]. The reaction takes place in the presence of glutamine and ATP through an activated gamma-phospho-Glu-tRNA(Gln). The GatDE system is specific for glutamate and does not act on aspartate. This function is carried out in bacteria by the GatABC system, which acts both on Asp-tRNA(Asn) and Glu-tRNA(Gln). GatABC orthologues also exist in some archaea, where it coexist with GatDE (GatE being paralogous to GatB); while other archaea only posses GatED and use an asparaginyl-tRNA synthetase to produce Asn-tRNA by direct acylation of the tRNA []. The crystal structure of GatED showed tRNA(Gln) recognition by indirect readout based on shape complementarity []. This entry represents aspartyl/glutamyl-tRNA(Asn/Gln) amidotransferase subunit B and glutamyl-tRNA(Gln) amidotransferase subunit E. |
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| Protein Domain |
| Name: |
3-phosphoshikimate 1-carboxyvinyltransferase |
| Type: |
Family |
| Description: |
This entry represents 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase (also known as 3-phosphoshikimate 1-carboxyvinyltransferase), catalyses the sixth step in the biosynthesis from chorismate of the aromatic amino acids (the shikimate pathway) in bacteria (gene aroA), plants and fungi (where it is part of a multifunctional enzyme which catalyses five consecutive steps in this pathway) [
]. The sixth step is the formation of EPSP and inorganic phosphate from shikimate-3-phosphate (S3P) and phosphoenolpyruvate (PEP).EPSP can use shikimate or shikimate-3-phosphate as a substrate. By binding shikimate, the backbone of the active site is changed, which affects the binding of glyphosate and renders the reaction insensitive to inhibition by glyphosate [
]. On isolation of the discontinuous C-terminal domain, it was found that it binds neither its substrate nor its inhibitor but maintains structural integrity [].Earlier studies suggested that the active site of the enzyme is in the cleft between its two globular domains. When the enzyme binds S3P, there is a conformational change in the isolated N-terminal domain [
]. The sequence of EPSP from various biological sources shows that the structure of the enzyme has been well conserved throughout evolution. Two strongly conserved regions are well defined. The first one corresponds to a region that is part of the active site and which is also important for the resistance to glyphosate []. The second second one is located in the C-terminal part of the protein and contains a conserved lysine which seems to be important for the activity of the enzyme.Since the shikimate pathway is not present in vertebrates but is essential for the life of plants, fungi and bacteria, it is commonly viewed as a target for antimicrobial drug development. |
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| Protein Domain |
| Name: |
Aminoacyl-tRNA synthetase, class Ia |
| Type: |
Domain |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases [
]. |
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| Protein Domain |
| Name: |
Serine-tRNA synthetase, type1, N-terminal |
| Type: |
Domain |
| Description: |
This entry represents the N-terminal domain of Serine-tRNA synthetase, which consists of two helices in a long alpha-hairpin and corresponds to the tRNA binding domain. Serine-tRNA synthetase (
) exists as monomer and belongs to class IIa aminoacyl-tRNA synthetase [
].The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c []. |
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| Protein Domain |
| Name: |
NUDIX hydrolase domain |
| Type: |
Domain |
| Description: |
The Nudix superfamily is widespread among eukaryotes, bacteria, archaea and viruses and consists mainly of pyrophosphohydrolases that act upon substrates of general structure NUcleoside DIphosphate linked to another moiety, X (NDP-X) to yield NMP plus P-X. Such substrates include (d)NTPs (both canonical and oxidised derivatives), nucleotide sugars and alcohols, dinucleoside polyphosphates (NpnN), dinucleotide coenzymes and capped RNAs. However, phosphohydrolase activity, including activity towards NDPs themselves, and non-nucleotide substrates such as diphosphoinositol polyphosphates (DIPs), 5-phosphoribosyl 1-pyrophosphate (PRPP), thiamine pyrophosphate (TPP) and dihydroneopterin triphosphate (DHNTP) have also been described. Some superfamily members, such as Escherichia coli mutT, have the ability to degrade potentially mutagenic, oxidised nucleotides while others control the levels of metabolic intermediates and signalling compounds. In procaryotes and simple eucaryotes, the number of Nudix genes varies from 0 to over 30, reflecting the metabolic complexity and adaptability of the organism. Nudix hydrolases are typically small proteins, larger ones having additional domains with interactive or other catalytic functions []. The Nudix domain formed by two β-sheets packed between α-helices [
,
]. It can accomodate sequences of different lengths in the connecting loops and in the antiparallel β-sheet. Catalysis depends on the conserved 23-amino acid Nudix motif (Nudix box), G-x(5)-E-x(5)-[UA]-x-R-E-x(2)-E-E-x-G-U, where U is an aliphatic, hydrophobic residue. This sequence is located in a loop-helix-loop structural motif and the Glu residues in the core of the motif, R-E-x(2)-E-E, play an important role in binding essential divalent cations [
]. The substrate specificity is determined by other residues outside the Nudix box. For example, CoA pyrophosphatases share the NuCoA motif L-L-T-x-R-[SA]-x(3)-R-x(3)-G-x(3)-F-P-G-G that is located N-terminal of the Nudix box and is involved in CoA recognition [
]. |
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| Protein Domain |
| Name: |
Peptidase S9A, prolyl oligopeptidase |
| Type: |
Family |
| Description: |
Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes [
]. They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence []. Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases [
].Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base [
]. The geometric orientations of the catalytic residues are similar between families, despite different protein folds []. The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) [,
].This group of serine peptidases belong to MEROPS peptidase family S9 (clan SC), subfamily S9A (prolyl oligopeptidase). The active site of members of this clan consists of a linear
arrangement of serine, histidine and threonine catalytic residues []. Prolyl oligopeptidases are either located in the cytosol or they are membrane bound, where they cleave peptide bonds with prolyl P1 specificities (but cleavage of alanyl bonds has been detected). The proline must adopt a trans configuration within the chain. Peptides of up to 30 residues are cleaved []. |
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| Protein Domain |
| Name: |
Aldehyde dehydrogenase domain |
| Type: |
Domain |
| Description: |
Aldehyde dehydrogenases (
and
) are enzymes that oxidize a wide variety of aliphatic and aromatic aldehydes using NADP as a cofactor. In mammals at least four different forms of the enzyme are known [
]: class-1 (or Ald C) a tetrameric cytosolic enzyme, class-2 (or Ald M) a tetrameric mitochondrial enzyme, class- 3 (or Ald D) a dimeric cytosolic enzyme, and class IV a microsomal enzyme. Aldehyde dehydrogenases have also been sequenced from fungal and bacterial species. A number of enzymes are known to be evolutionary related to aldehyde dehydrogenases. A glutamic acid and a cysteine residue have been implicated in the catalytic activity of mammalian aldehyde dehydrogenase. These residues are conserved in all the enzymes of this entry.Some of the proteins in this entry are allergens. Allergies are hypersensitivity reactions of the immune system to specific substances called allergens (such as pollen, stings, drugs, or food) that, in most people, result in no symptoms. A nomenclature system has been established for antigens (allergens) that cause IgE-mediated atopic allergies in humans [WHO/IUIS Allergen Nomenclature Subcommittee
King T.P., Hoffmann D., Loewenstein H., Marsh D.G., Platts-Mills T.A.E.,Thomas W. Bull. World Health Organ. 72:797-806(1994)]. This nomenclature system is defined by a designation that is composed ofthe first three letters of the genus; a space; the first letter of the
species name; a space and an arabic number. In the event that two speciesnames have identical designations, they are discriminated from one another
by adding one or more letters (as necessary) to each species designation.The allergens in this family include allergens with the following designations: Alt a 10 and Cla h 3. |
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| Protein Domain |
| Name: |
Glutamate/phenylalanine/leucine/valine/L-tryptophan dehydrogenase, C-terminal |
| Type: |
Domain |
| Description: |
Glutamate, leucine, phenylalanine, valine and tryptophan dehydrogenases are structurally and functionally related. They contain a Gly-rich region containing a conserved Lys residue, which has been implicated in the catalytic activity, in each case a reversible oxidative deamination reaction.Glutamate dehydrogenases (
,
, and
) (GluDH) are enzymes that catalyse the NAD- and/or NADP-dependent reversible deamination of L-glutamate into alpha-ketoglutarate [
,
]. GluDH isozymes are generally involved with either ammonia assimilation or glutamate catabolism. Two separate enzymes are present in yeasts: the NADP-dependent enzyme, which catalyses the amination of alpha-ketoglutarate to L-glutamate; and the NAD-dependent enzyme, which catalyses the reverse reaction [] - this form links the L-amino acids with the Krebs cycle, which provides a major pathway for metabolic interconversion of alpha-amino acids and alpha- keto acids []. In rice, glutamate dehydrogenase 3 is mitochondrial.Leucine dehydrogenase (
) (LeuDH) is a NAD-dependent enzyme that catalyses the reversible deamination of leucine and several other aliphatic amino acids to their keto analogues [
]. Each subunit of this octameric enzyme from Bacillus sphaericus contains 364 amino acids and folds into two domains, separated by a deep cleft. The nicotinamide ring of the NAD+ cofactor binds deep in this cleft, which is thought to close during the hydride transfer step of the catalytic cycle.Phenylalanine dehydrogenase (
) (PheDH) is na NAD-dependent enzyme that catalyses the reversible deamidation of L-phenylalanine into phenyl-pyruvate [
].Valine dehydrogenase (
) (ValDH) is an NADP-dependent enzyme that catalyses the reversible deamidation of L-valine into 3-methyl-2-oxobutanoate [
].L-tryptophan dehydrogenase catalyses the reversible oxidative deamination of L-tryptophan to indole-3-pyruvate in the presence of NAD+ [
,
].This entry represents the C-terminal domain of these proteins. |
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| Protein Domain |
| Name: |
Ferrochelatase |
| Type: |
Family |
| Description: |
Synonym(s): Protohaem ferro-lyase, Iron chelatase, etc.
Ferrochelatase is the terminal enzyme of the heme biosynthetic pathway. It catalyzes the insertion of ferrous iron into the protoporphyrin IX ring yielding protoheme. This enzyme is ubiquitous in nature and widely distributed in bacteria and eukaryotes. Recently, some archaeal members have been identified. The oligomeric state of these enzymes varies depending on the presence of a dimerization motif at the C terminus [
,
,
,
,
,
,
,
,
,
,
,
]. In eukaryotic cells, it binds to the mitochondrial inner membrane with its active site on the matrix side of the membrane.The X-ray structure of
Bacillus subtilisand human ferrochelatase have been solved [
,
].The human enzyme exists as a homodimer. Each
subunit contains one [2Fe-2S]cluster. The monomer is folded into two
similar domains, each with a four-stranded parallelβ-sheet flanked by an α-helix in a beta-α-β motif that is
reminiscent of the fold found in the periplasmic bindingproteins. The topological similarity between the domains suggests that
they have arisen from a gene duplication event. However,significant differences exist between the two domains, including an
N-terminal section (residues 80-130) that forms part of theactive site pocket, and a C-terminal extension (residues 390-423) that
is involved in coordination of the [2Fe-2S]cluster and in
stabilisation of the homodimer. Ferrochelatase seems to have a structurally conserved core region that is common to the enzyme from bacteria, plants and mammals. Porphyrin binds in the identified cleft; this cleft also includes the metal-binding site of the enzyme. It is likely that the structure of the cleft region will have different conformations upon substrate binding and release [
]. |
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| Protein Domain |
| Name: |
Prolyl-tRNA synthetase, class IIa, bacterial-type |
| Type: |
Family |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].Prolyl-tRNA synthetase belongs to class IIa. Prolyl-tRNA synthetase (
) exists in two forms, which are loosely related. The first form is present in the majority of eubacteria species. The second one, present in some eubacteria, is essentially present in archaea and eukaryota. This entry contains the first form of prolyl-tRNA synthetase.
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| Protein Domain |
| Name: |
Nitric oxide synthase, N-terminal domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
This entry represents the N-terminal domain superfamily of the nitric oxide synthases. Nitric oxide synthase (
) (NOS) enzymes produce nitric oxide (NO) by catalysing a five-electron oxidation of a guanidino nitrogen of L-arginine (L-Arg). Oxidation of L-Arg to L-citrulline occurs via two successive monooxygenation reactions producing N(omega)-hydroxy-L-arginine as an intermediate. 2 mol of O(2) and 1.5 mol of NADPH are consumed per mole of NO formed [
].Arginine-derived NO synthesis has been identified in mammals, fish, birds, invertebrates, plants, and bacteria [
]. Best studied are mammals, where three distinct genes encode NOS isozymes: neuronal (nNOS or NOS-1), cytokine-inducible (iNOS or NOS-2) and endothelial (eNOS or NOS-3) []. iNOS and nNOS are soluble and found predominantly in the cytosol, while eNOS is membrane associated. The enzymes exist as homodimers, each monomer consisting of two major domains: an N-terminal oxygenase domain, whichbelongs to the class of haem-thiolate proteins, and a C-terminal reductase domain, which is homologous to NADPH:P450 reductase (
). The interdomain linker between the oxygenase and reductase domains contains a calmodulin (CaM)-binding sequence. NOSs are the only enzymes known to simultaneously require five bound cofactors animal NOS isozymes are catalytically self-sufficient. The electron flow in the NO synthase reaction is: NADPH -->FAD -->FMN -->haem -->O(2).
eNOS localisation to endothelial membranes is mediated by cotranslational N-terminal myristoylation and post-translational palmitoylation [
]. The subcellular localisation of nNOS in skeletal muscle ismediated by anchoring of nNOS to dystrophin. nNOS contains an additional
N-terminal domain, the PDZ domain []. Some bacteria, like Bacillus halodurans, Bacillus subtilis or Deinococcus radiodurans, contain homologues of NOS oxygenase domain. |
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| Protein Domain |
| Name: |
Nicotinate-nucleotide-dimethylbenzimidazole phosphoribosyltransferase, bacterial type |
| Type: |
Family |
| Description: |
This entry represents bacterial-type nicotinate-nucleotide-dimethylbenzimidazole phosphoribosyltransferase enzymes involved in dimethylbenzimidazole synthesis [
]. This enzyme catalyses the synthesis of alpha-ribazole-5'-phosphate from nicotinate mononucleotide (NAMN) and 5,6-dimethylbenzimidazole (DMB). This function is essential to de novocobalamin (vitamin B12) production in bacteria.
Nicotinate mononucleotide (NaMN):5,6-dimethylbenzimidazole (DMB) phosphoribosyltransferase (CobT) plays a central role in the synthesis of alpha-ribazole-5'-phosphate, an intermediate for the lower ligand of cobalamin [
]. It is one of the enzymes of the anaerobic pathway of cobalamin biosynthesis, and one of the four proteins (CobU, CobT, CobC, and CobS) involved in the synthesis of the lower ligand and the assembly of the nucleotide loop [,
]. Vitamin B
12(cobalamin) is used as a cofactor in a number of enzyme-catalysed reactions in bacteria, archaea and eukaryotes [
]. The biosynthetic pathway to adenosylcobalamin from its five-carbon precursor, 5-aminolaevulinic acid, can be divided into three sections: (1) the biosynthesis of uroporphyrinogen III from 5-aminolaevulinic acid; (2) the conversion of uroporphyrinogen III into the ring-contracted, deacylated intermediate precorrin 6 or cobalt-precorrin 6; and (3) the transformation of this intermediate to form adenosylcobalamin []. Cobalamin is synthesised by bacteria and archaea via two alternative routes that differ primarily in the steps of section 2 that lead to the contraction of the macrocycle and excision of the extruded carbon molecule (and its attached methyl group) []. One pathway (exemplified by Pseudomonas denitrificans) incorporates molecular oxygen into the macrocycle as a prerequisite to ring contraction, and has consequently been termed the aerobic pathway. The alternative, anaerobic, route (exemplified by Salmonella typhimurium) takes advantage of a chelated cobalt ion, in the absence of oxygen, to set the stage for ring contraction []. |
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| Protein Domain |
| Name: |
Bacteriocin, class IIa |
| Type: |
Family |
| Description: |
Many Gram-positive bacteria produce ribosomally synthesized antimicrobial peptides, often termed bacteriocins. One important and well studied class of bacteriocins is the class IIa or pediocin-like bacteriocins produced by lactic acid bacteria. All class IIa bacteriocins are produced by food-associated strains, isolated from a variety of food products of industrial and natural origins, including meat products, dairy products and vegetables. Class IIa bacteriocins are all cationic, display anti-Listeria activity, and kill target cells by permeabilizing the cell membrane [
,
,
]. Class IIa bacteriocins contain between 37 and 48 residues. Based on their primary structures, the peptide chains of class IIa bacteriocins may be divided roughly into two regions: a hydrophilic, cationic and highly conserved N-terminal region, and a less conserved hydrophobic/amphiphilic C-terminal region. The N-terminal region contains the conserved Y-G-N-G-V/L 'pediocin box' motif and two conserved cysteine residues joined by a disulphide bridge. It forms a three-stranded antiparallel β-sheet supported by the conserved disulphide bridge. This cationic N-terminal β-sheet domain mediates binding of the class IIa bacteriocin to the target cell membrane. The C-terminal region forms a hairpin-like domain that penetrates into the hydrophobic part of the target cell membrane, thereby mediating leakage through the membrane. The two domains are joined by a hinge, which enables movement of the domains relative to each other [
,
]. Some proteins known to belong to the class IIa bacteriocin family are listed below: Pediococcus acidilactici pediocin PA-1. Leuconostoc mesenteroides mesentericin Y105. Carnobacterium piscicola carnobacteriocin B2. Lactobacillus sakei sakacin P. Enterococcus faecium (Streptococcus faecium) enterocin A. E. faecium enterocin P. Leuconostoc gelidum leucocin A. Lactobacillus curvatus curvacin A. Listeria innocua listeriocin 743A. Streptococcus mutans mutacin F-59.1. |
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| Protein Domain |
| Name: |
Integrin beta tail domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [
,
]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits [
]. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.This entry represents the tail domain of the integrin beta subunit. It forms a four-stranded β-sheet that contains parallel and antiparallel strands and faces an alpha helix found at the N terminus of this domain [
]. Interactions between the α-helix and the β-sheet are mostly hydrophobic and involve a disulphide bond. The rear of the beta sheet is covered with a long A-B loop. |
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| Protein Domain |
| Name: |
Galanin receptor 3 |
| Type: |
Family |
| Description: |
Galanin is involved in a variety of physiological mechanisms and disease states, from appetite and neuroregeneration to seizures and pain [
,
]. The actions of galanin are mediated through interaction with specific membrane receptors. Three receptor subtypes have been identified; Galanin receptor 1 (GALR1), Galanin receptor 2 (GALR2) and Galanin receptor 3 (GAL3), all of which are rhodopsin-like GPCRs. They differ from one another in terms of their expression patterns, affinity for various peptide analogues and G protein-coupling specificity [,
,
]. In signaling, all can act via the Gi/o class [], whilst GAL2 also has Gq/11 as a major signaling route []. Galanin receptors are widely distributed in a wide range of central nervous system (CNS), peripheral tissues and in the endocrine, mirroring the distribution of galanin [
,
]. Galanin receptors mediate a variety of physiological functions including inhibition of glucose-induced insulin secretion [], stimulation of growth hormone release [] and modulation of gastrointestinal motility []. These receptors also modulate neuronal functions including memory, nociception, spinal reflexes and feeding [,
]. Disruption of galanin expression or galanin receptor signaling is seen in many multifactoral conditions, suggesting a role in the development and/or pathology of certain diseases. These include Alzheimer's disease, epilepsy, diabetes, alcoholism, neuropathic pain and cancer [,
,
]. This entry represents galanin receptor 3 subtype, which is expressed abundantly in the periphery and at lower levels in the CNS. In the brain, the highest levels have been found in the hypothalamus and pituitary [
]. Expression has also been detected in peripheral tissues, including the pancreas, liver, kidney, stomach, adrenal gland, lung and spleen []. |
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| Protein Domain |
| Name: |
Photosynthetic reaction centre, M subunit |
| Type: |
Family |
| Description: |
The photosynthetic apparatus in non-oxygenic bacteria consists of light-harvesting (LH) protein-pigment complexes LH1 and LH2, which use carotenoid and bacteriochlorophyll as primary donors [
]. LH1 acts as the energy collection hub, temporarily storing it before its transfer to the photosynthetic reaction centre (RC) []. Electrons are transferred from the primary donor via an intermediate acceptor (bacteriopheophytin) to the primary acceptor (quinine Qa), and finally to the secondary acceptor (quinone Qb), resulting in the formation of ubiquinol QbH2. RC uses the excitation energy to shuffle electrons across the membrane, transferring them via ubiquinol to the cytochrome bc1 complex in order to establish a proton gradient across the membrane, which is used by ATP synthetase to form ATP [,
,
]. The core complex is anchored in the cell membrane, consisting of one unit of RC surrounded by LH1; in some species there may be additional subunits [
]. RC consists of three subunits: L (light), M (medium), and H (heavy). Subunits L and M provide the scaffolding for the chromophore, while subunit H contains a cytoplasmic domain []. In Rhodopseudomonas viridis, there is also a non-membranous tetrahaem cytochrome (4Hcyt) subunit on the periplasmic surface. This entry describes the photosynthetic reaction centre M subunit. The L and M subunits are arranged around an axis of 2-fold rotational symmetry perpendicular to the membrane, forming a scaffold that maintains the cofactors in a precise configuration. The L and M subunits have both sequence and structural similarity, suggesting a common evolutionary origin. The L and M subunits bind noncovalently to the nine cofactors in 2-fold symmetric branches: four bacteriochlorophylls, two bacteriopheophytins, two ubiquinone molecules (QA and QB), and a non-heme iron. |
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| Protein Domain |
| Name: |
Quinohemoprotein amine dehydrogenase, gamma subunit structural domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Quinohemoprotein amine dehydrogenases (QHNDH)
) are enzymes produced in the periplasmic space of certain Gram-negative bacteria, such as Paracoccus denitrificans and Pseudomonas putida, in response to primary amines, including n-butylamine and benzylamine. QHNDH catalyses the oxidative deamination of a wide range of aliphatic and aromatic amines through formation of a Schiff-base intermediate involving one of the quinone O atoms [
]. Catalysis requires the presence of a novel redox cofactor, cysteine tryptophylquinone (CTQ). CTQ is derived from the post-translational modification of specific residues, which involves the oxidation of the indole ring of a tryptophan residue to form tryptophylquinone, followed by covalent cross-linking with a cysteine residue []. There is one CTQ per subunit in QHNDH. In addition to CTQ, two haem c cofactors are present in QHNDH that mediate the transfer of the substrate-derived electrons from CTQ to an external electron acceptor, cytochrome c-550 [,
].QHNDH is a heterotrimer of alpha, beta and gamma subunits. The alpha and beta subunits contain signal peptides necessary for the translocation of QHNDH to the periplasm. The alpha subunit is composed of four domains - domain 1 forming a dihaem cytochrome, and domains 2-4 forming antiparallel β-barrel structures; the beta subunit is a 7-bladed β-propeller that provides part of the active site; and the small, catalytic gamma subunit contains the novel cross-linked CTQ cofactor, in addition to additional thioester cross-links between Cys and Asp/Glu residues that encage CTQ. The gamma subunit assumes a globular secondary structure with two short α-helices having many turns and bends [
]. This entry represents the main structural domain of the QHNDH gamma subunit. |
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| Protein Domain |
| Name: |
Quinohemoprotein amine dehydrogenase alpha subunit, domain 2 superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Quinohemoprotein amine dehydrogenases (QHNDH)
) are enzymes produced in the periplasmic space of certain Gram-negative bacteria, such as Paracoccus denitrificans and Pseudomonas putida, in response to primary amines, including n-butylamine and benzylamine. QHNDH catalyses the oxidative deamination of a wide range of aliphatic and aromatic amines through formation of a Schiff-base intermediate involving one of the quinone O atoms []. Catalysis requires the presence of a novel redox cofactor, cysteine tryptophylquinone (CTQ). CTQ is derived from the post-translational modification of specific residues, which involves the oxidation of the indole ring of a tryptophan residue to form tryptophylquinone, followed by covalent cross-linking with a cysteine residue []. There is one CTQ per subunit in QHNDH. In addition to CTQ, two haem c cofactors are present in QHNDH that mediate the transfer of the substrate-derived electrons from CTQ to an external electron acceptor, cytochrome c-550 [,
].QHNDH is a heterotrimer of alpha, beta and gamma subunits. The alpha and beta subunits contain signal peptides necessary for the translocation of QHNDH to the periplasm. The alpha subunit is composed of four domains - domain 1 forming a dihaem cytochrome, and domains 2-4 forming antiparallel β-barrel structures; the beta subunit is a 7-bladed β-propeller that provides part of the active site; and the small, catalytic gamma subunit contains the novel cross-linked CTQ cofactor, in addition to additional thioester cross-links between Cys and Asp/Glu residues that encage CTQ. The gamma subunit assumes a globular secondary structure with two short α-helices having many turns and bends [
]. This entry represents the second domain found in the QHNDH alpha subunit. |
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| Protein Domain |
| Name: |
Quinohemoprotein amine dehydrogenase, alpha subunit, domain 2 |
| Type: |
Domain |
| Description: |
Quinohemoprotein amine dehydrogenases (QHNDH)
) are enzymes produced in the periplasmic space of certain Gram-negative bacteria, such as Paracoccus denitrificans and Pseudomonas putida, in response to primary amines, including n-butylamine and benzylamine. QHNDH catalyses the oxidative deamination of a wide range of aliphatic and aromatic amines through formation of a Schiff-base intermediate involving one of the quinone O atoms [
]. Catalysis requires the presence of a novel redox cofactor, cysteine tryptophylquinone (CTQ). CTQ is derived from the post-translational modification of specific residues, which involves the oxidation of the indole ring of a tryptophan residue to form tryptophylquinone, followed by covalent cross-linking with a cysteine residue []. There is one CTQ per subunit in QHNDH. In addition to CTQ, two haem c cofactors are present in QHNDH that mediate the transfer of the substrate-derived electrons from CTQ to an external electron acceptor, cytochrome c-550 [,
].QHNDH is a heterotrimer of alpha, beta and gamma subunits. The alpha and beta subunits contain signal peptides necessary for the translocation of QHNDH to the periplasm. The alpha subunit is composed of four domains - domain 1 forming a dihaem cytochrome, and domains 2-4 forming antiparallel β-barrel structures; the beta subunit is a 7-bladed β-propeller that provides part of the active site; and the small, catalytic gamma subunit contains the novel cross-linked CTQ cofactor, in addition to additional thioester cross-links between Cys and Asp/Glu residues that encage CTQ. The gamma subunit assumes a globular secondary structure with two short α-helices having many turns and bends [
]. This entry represents the second domain found in the QHNDH alpha subunit. |
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| Protein Domain |
| Name: |
Arginyl tRNA synthetase N-terminal domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].This domain superfamily is found at the N terminus of Arginyl tRNA synthetase, also called additional domain 1 (Add-1). It is about 140 residues long and it has been suggested to be involved in tRNA recognition [
]. |
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| Protein Domain |
| Name: |
Acetylcholinesterase, fish/snake |
| Type: |
Family |
| Description: |
Cholinesterase enzymes are members of the broader alpha/beta hydrolase family and can be dividied into two distinct groups: those that catalyse the hydrolysis of acetylcholine to choline and acetate (acetylcholinesterases
)
acetylcholine + H2O ->choline + acetate
and those that catalyse the conversion of other acylcholines to a choline and a weak acid (cholinesterases )
an acylcholine + H2O ->choline + a carboxylate
Acetylcholinesterase also acts on a variety of acetic esters and catalyses transacetylations. It is the most intensively studied of the cholinesterase enzymes due to its key physiological role in the turnover of the neurotransmitter acylcholine [
]. This enzyme is found in, or attached to, cellular or basement membranes of presynaptic cholinergic neurons and postsynaptic cholinoceptive cells within the neuromuscular junction. Signal transmission at the neuromuscular junction involves the release of acylcholine, its interaction with the acycholine receptor and hydrolysis, all occuring in a period of a few milliseconds. Rapid hydrolysis of the newly released aceytlcholine is vital in order to prevent continuous firing of the nerve impulses []. Consistent with its role in this process, acetylcholinesterase has an unusually high turnover number, ensuring that acetylcholine is broken down quickly. There is evidence to suggest that acetylcholinesterase has additional important roles including involvement in neuronal adhesion, the formation of Alzheimer fibrils, and neurite growth [,
,
]. The 3D structure of acetylcholinesterase and a cholinesterase have been determined [
,
]. These proteins share the 3-layer α-β-alpha sandwich fold common to members of the alpha/beta hydrolase family. Surprisingly, given the high turnover number of acetylcholinesterase, the active site of these enzymes is located at the bottom of a deep and narrow cleft, named the active-site gorge. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 11A |
| Type: |
Family |
| Description: |
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern [
]. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences [
]. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [,
]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis [
]. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptors 11A and 11B mediate the effects of receptor activator for NF-kappa-B ligand (RANKL), an essential osteoclast regulatory factor. The receptors have opposing effects - activation of TNF receptor 11A by RANKL promotes osteoclast differentiation [
], while TNF receptor 11B acts as a soluble decoy receptor for the ligand, thus inhibiting differentiation []. Mutations in the TNF receptor 11A gene have been implicated in a range of bone disorders, such as expansile osteolysis, osteopetrosis, and Paget disease of bone. The receptor also has a role in immune function, vascular disease and mammary gland development [
]. |
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| Protein Domain |
| Name: |
Bacteriophytochrome, CheY-like |
| Type: |
Family |
| Description: |
This entry contains bacteriophytochromes, or BphPs (light-regulated signal transduction histidine kinases) with the receiver (CheY-like) domain fused at the C terminus.Phytochrome dimeric photoreceptors regulate growth and development by sensing ambient light [
]. Apart from phytochromes in photosynthetic organisms, phytochrome-like photoreceptors have been found in several nonphotosynthetic organisms, including in the heterotrophic eubacteria Deinococcus radiodurans and Pseudomonas aeruginosa, ]. These homodimeric photoreceptors sense red light (R) and far-red light (FR) through photointerconversion between two stable conformations, a R-absorbing Pr form and a FR-absorbing Pfr form [].Phytochromes in general contain a signature N-terminal chromophore-binding region (CBD) that includes GAF and PHY domains, both of which are essential for autocatalytically binding bilin chromophores. A C-terminal module is involved in signal transduction and homodimerisation, and is different in different groups of phytochromes. Phytochromes are divided into three groups: plant phys, cyanobacterial phys (Cphs), and bacteriophytochrome photoreceptors (BphPs) [
].The BphPs are common among photosynthetic and nonphotosynthetic Eubacteria and present in some fungi [
]. They act as photoregulated kinases that presumably initiate the phosphorelay cascade by phosphotransfer to an associated response regulator (RR). In some cases, the receiver (CheY-like) domain of this RR is fused to the C-terminal end of the BphP (such hybrid proteins are in this entry).Like Cphs, BphPs often contain the canonical two-component histidine kinase motif and act as histidine kinases in vitro. The main distinction is that they use the bilin biliverdin (BV) as the chromophore [
]. Included in the CBD are the positionally conserved cysteine (Cys-20 and Cys-13) and histidine (His-250 and His-248) residues that could serve as the chromophore-binding site, by using either a thiolether or Schiff-base-type linkage, respectively [,
,
,
]. |
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| Protein Domain |
| Name: |
Integrin beta subunit, tail |
| Type: |
Domain |
| Description: |
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [
,
]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits [
]. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.This entry represents the tail domain of the integrin beta subunit. It forms a four-stranded β-sheet that contains parallel and antiparallel strands and faces an alpha helix found at the N terminus of this domain [
]. Interactions between the α-helix and the β-sheet are mostly hydrophobic and involve a disulphide bond. The rear of the beta sheet is covered with a long A-B loop. |
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| Protein Domain |
| Name: |
Signal transduction response regulator, propionate catabolism activator, N-terminal |
| Type: |
Domain |
| Description: |
Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions [
]. Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk []. These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more []. Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) []. The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response [
,
].This entry represents a domain found at the N terminus of several sigma54- dependent transcriptional activators including PrpR, which activates catabolism of propionate. In Salmonella enterica subsp. enterica serovar Typhimurium, PrpR acts as a sensor of 2-methylcitrate (2-MC), an intermediate of the 2-methylcitric acid cycle used by this bacterium to convert propionate to pyruvate [
]. |
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| Protein Domain |
| Name: |
DNA (cytosine-5)-methyltransferase 3A, ADD domain |
| Type: |
Domain |
| Description: |
In mammals, DNA methylation patterns are thought to be established during embryonic development by de novo DNA methyltransferases 3A and 3B (DNMT3A/3B) [
]. DNMT3A/3B work synergistically to propagate methylation patterns with DNMT3B stimulating DNMT3A activity by promoting its association with nucleosomes []. DNMT3A exists in an autoinhibitory form that can be activated by the histone H3 tail in a DNMT3L-independent manner []. DNMT3A has been linked to cancers [,
,
].This entry represents the ADDz domain found in DNA (cytosine-5)-methyltransferase 3A (DNMT3A). The ADD domain is composed of three clearly distinguishable modules that pack together through extensive hydrophobic interactions to form a single globular domain. Packed against this GATA-like finger is a second subdomain, which binds two zinc ions and closely resembles the structure reported for several PHD fingers. Finally, there is a long C-terminal α-helix that runs out from the PHD finger and makes extensive hydrophobic contacts with the N-terminal GATA finger, bringing the N- and C-termini of the ADD domain close together. This combination of fused GATA-like and PHD fingers within a single domain is thus far unique [
,
].The ADD domains of the DNMT3 family have a decisive role in blocking DNMT activity in the areas of the genome with chromatin containing methylated H3K4. Furthermore, the ADD domain of DNMMT3A (ADD-3A) competes with the chromodomain (CD) of heterochromatin protein 1 alpha (HP1alpha, CDHP1alpha) for binding to the H3 tail. The DNA methyltransferase (DNMT) 3 family members DNMT3A and DNMT3B and the DNMT3-like non-enzymatic regulatory factor DNMT3L, are involved in de-novo establishment of DNA methylation patterns in early mammalian development [
,
]. |
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| Protein Domain |
| Name: |
SWR1 chromatin-remodelling complex, subunit Swc7 |
| Type: |
Family |
| Description: |
Th SWR1 complex is involved in chromatin-remodelling by promoting the the ATP-dependent exchange of histone H2A for the H2A variant HZT1 in Saccharomyces cerevisiae (Baker's yeast) or H2AZ in mammals. The SWR1 chromatin-remodelling complex is composed of at least 14 subunits and has a molecular mass of about 1.2 to 1.5 MDa. In S. cerevisiae the core conserved subunits are: ATPase; Swr1.RuvB-like; Rvb1 and Rvb2.Actin; Act1.Actin-related: Arp4 and Arp6.YEATS protein [
]; Yaf9.The non-conserved subunits are: Vps71 (Swc6), Vps72 (Swc2), Swc3, Swc4, Swc5, Swc7, Bdf1 [
].Seven of the SWR1 subunits are involved in maintaining complex integrity and H2AZ histone replacement activity: Swr1, Swc2, Swc3, Arp6, Swc5, Yaf9 and Swc6. Arp4 is required for the association of Bdf1, Yaf9, and Swc4 and Arp4 is also required for SWR1 H2AZ histone replacement activity in vitro. Furthermore the N-terminal region of the ATPase Swr1 provides the platform upon which Bdf1, Swc7, Arp4, Act1, Yaf9 and Swc4 associate [
]; it also contains an additional H2AZ-H2B specific binding site, distinct from the binding site of the Swc2 subunit []. In eukaryotes the deposition of variant histones into nucleosomes by the chromatin-remodelling complexes such as the SWR1 and INO80 complexes have many crucial functions including the control of gene regulation and expression, checkpoint regulation, DNA replication and repair, telomer maintenance and chromosomal segregation and as such represent critical components of pathways that maintain genomic integrity. This entry represents the subunit Swc7; the smallest subunit of the SWR1 complex. Swc7 is not required for H2AZ binding. Swc7 associates with the N terminus of Swr1, and the association of Bdf1 requires Swc7, Yaf9, and Arp4 [
]. |
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| Protein Domain |
| Name: |
INO80 complex subunit Ies5 |
| Type: |
Family |
| Description: |
The INO80 complex is involved in chromatin-remodelling by promoting the repositioning (sliding) or eviction of nucleosomes from the DNA in an ATP-dependent process. The INO80 chromatin-remodelling complex of Saccharomyces cerevisiae (Baker's yeast) is composed of at least 15 subunits and has a molecular mass of about 1.2 to 1.5 MDa. In S. cerevisiae the core conserved subunits are: ATPase; Ino80.RuvB-like; Rvb1 and Rvb2.Actin; Act1.Actin-related: Arp4, Arp5 and Arp8.YEATS protein [
]; Taf14.The non-conserved subunits are: Ies1, Ies2, Ies3, Ies4, Ies5, Ies6 and Nhp10 [
]. The Ino80 ATPase is a member of the SNF2 family of ATPases and functions as an integral component of a multisubunit ATP-dependent chromatin remodelling complex that is conserved from yeast to mammals. Although INO80 complexes from yeast and higher eukaryotes share a common core of conserved subunits, the complexes have diverged substantially during evolution and have acquired new subunits with apparently species-specific functions. Studies in S. cerevisiae have shown that the conserved HSA (helicase) domain of the ATPase subunit, Ino80, is required for the binding of the Arp's and Act1, and this conserved module links the chromatin-remodelling complex to its substrate, the nucleosome [
,
]. In eukaryotes the chromatin-remodelling complexes such as the SWR1 and INO80 complexes have many crucial functions including the control of gene regulation and expression, checkpoint regulation, DNA replication and repair, telomer maintenance and chromosomal segregation and as such represent critical components of pathways that maintain genomic integrity [
,
,
].This entry represents the INO80 subunit 5 or Ies5, which has been shown to associate with the INO80 chromatin-remodelling complex under low-salt conditions [
], though its function is unknown. |
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| Protein Domain |
| Name: |
Nerve growth factor, beta subunit |
| Type: |
Family |
| Description: |
During the development of the vertebrate nervous system, many neurons become redundant (because they have died, failed to connect to target cells, etc.) and are eliminated. At the same time, developing neurons send out axon outgrowths that contact their target cells [
]. Such cells control their degree of innervation (the number of axon connections) by the secretion of various specific neurotrophic factors that are essential for neuron survival. One of these is nerve growth factor (NGF), which is involved in the survival of some classes of embryonic neuron (e.g., peripheral sympathetic neurons) []. NGF is mostly found outside the central nervous system (CNS), but slight traces have been detected in adult CNS tissues, although a physiological role for this is unknown []; it has also been found in several snake venoms [,
]. Proteins similar to NGF include brain-derived neurotrophic factor (BDNF) and neurotrophins 3 to 7, all of which demonstrate neuron survival and outgrowth activities. Although NGF was originally identified in snake venom, its most abundant and best studied source is the submaxillary gland of adult male mice [
]. Mouse NGF is a high molecular weight hexamer, composed of 2 subunits each of alpha, beta and gamma polypeptides. The beta subunit (NGF-beta) is responsible for the physiological activity of the complex []. NGF-beta induces its cell survival effects through activation of neurotrophic tyrosine kinase receptor type 1 (NTRK1; also called TrkA), and can induce cell death by binding to the low affinity nerve growth factor receptor, p75NTR [
]. The neurotrophin has been shown to be involved in sympathetic axon growth and innervation of target fields []. |
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| Protein Domain |
| Name: |
Conotoxin I2 |
| Type: |
Family |
| Description: |
Members of this family display a XI cysteine pattern (C-C-CC-CC-C-C) and belong to the I2- superfamily conotoxins. Family members such as Kappa-conotoxin ViTx (
) and Kappa-conotoxin SrXIA (
) inhibit voltage gated potassium channels (Kv) [
].Cone snail toxins, conotoxins, are small peptides with disulphide connectivity, that target ion-channels or G-protein coupled receptors. Based on the number and pattern of disulphide bonds and biological activities, conotoxins can be classified into several families [
]. Omega, delta and kappa families of conotoxins have a knottin or inhibitor cystine knot scaffold. The knottin scaffold is a very special disulphide through disulphide knot, in which the III-VI disulphide bond crosses the macrocycle formed by two other disulphide bonds (I-IV and II-V) and the interconnecting backbone segments, where I-VI indicates the six cysteine residues starting from the N terminus; for further information see the KNOTTIN database (https://www.dsimb.inserm.fr/KNOTTIN/).Conotoxins represent a unique arsenal of neuropharmacologically active peptides that have been evolutionarily tailored to afford unprecedented and exquisite selectivity for a wide variety of ion-channel subtypes. The toxins derived from cone snails are currently being investigated for the treatment of chronic pain, epilepsy, cardiovascular diseases, psychiatric and movement disorders, spasticity, cancer, stroke as well as an anesthetic agent. Several potential analgesic and anti-inflammatory peptides from conotoxin families have been identified and patented [,
], e.g. Conus magus (Magus cone) (Magician's cone snail) omega-conotoxin MVIIa (Ziconotide), which is used for the treatment of chronic pain, Conus catus (Cat cone) omega-conotoxin CVID, which is tested for treating severe morphine-resistant pain stress, and Conus geographus (Geography cone) (Nubecula geographus) omega-conotoxin GVIA, which may exert antagonistic effects against beta-endorphin induced anti-nociception.
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| Protein Domain |
| Name: |
Voltage-gated sodium channel alpha subunit, inactivation gate |
| Type: |
Domain |
| Description: |
Voltage-dependent sodium channels are transmembrane (TM) proteins responsible for the depolarising phase of the action potential in most
electrically excitable cells []. They may exist in 3 states []: the resting state, where the channel is closed; the activated state, where the channel is open; and the inactivated state, where the channel is closed and refractory to opening. Several different structurally and functionally distinct isoforms are found in mammals, coded for by a multigene family, these being responsible for the different types of sodium ion currents found in excitable tissues.There are nine pore-forming alpha subunit of voltage-gated sodium channels consisting of four membrane-embedded homologous domains (I-IV), each consisting of six α-helical segments (S1-S6), three cytoplasmic loops connecting the domains, and a cytoplasmic C-terminal tail. The S6 segments of the four domains form the inner surface of the pore, while the S4 segments bear clusters of basic residues that constitute the channel's voltage sensors [
,
,
].This domain represents the cytoplasmic loop connecting domains III and IV of the alpha subunits of voltage-gated sodium channels. It forms the channel inactivation gate, acting through a hinged lid mechanism, which is responsible for fast inactivation of the channel and it is essential for proper physiological function [
,
]. This domain contains the highly conserved hydrophobic isoleucine-phenylalanine-methionine (IFM) triad, essential for the fast inactivation mechanism. In particular the phenylalanine residue is suggested to bind to an inactivation gate receptor that causes the loop to occlude the channel pore during the inactivation process. Mutation of this residue causes a severe impairment of the inactivation process, while full mutation of the triad abolishes completely inactivation [
]. |
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| Protein Domain |
| Name: |
P2X purinoreceptor |
| Type: |
Family |
| Description: |
P2X purinoceptors are cell membrane ion channels, gated by adenosine 5'-triphosphate (ATP) and other nucleotides; they have been found to be widely expressed on mammalian cells, and, by means of their functional properties, can be differentiated into three sub-groups. The first group is almost equally well activated by ATP and its analogue alpha,betamethylene-ATP, whereas, the second group is not activated by the latter compound. A third type of receptor (also called P2Z) is distinguished by the fact that repeated or prolonged agonist application leads to the opening of much larger pores, allowing large molecules to traverse the cell membrane. This increased permeability rapidly leads to cell death, and lysis.Molecular cloning studies have identified seven P2X receptor subtypes, designated P2XR1-P2XR7, however, P2X1R, P2X2R, P2X3R, P2X4R, and P2X7R are functional [
]. These receptors are proteins that share 35-48% amino acid identity, and possess two putative transmembrane (TM) domains, separated by a long (~270 residues) intervening sequence, which is thought to form an extracellular loop. Around 1/4 of the residues within the loop are invariant between the cloned subtypes, including 10 characteristic cysteines.Studies of the functional properties of heterologously expressed P2X receptors, together with the examination of their distribution in native tissues, suggests they likely occur as both homo- and hetero multimers in vivo [
,
]. Stimulation of these receptors induces changes in intracellular ion homeostasis leading to multiple key responses crucial for initiation, propagation, and resolution of inflammation []. The P2X7 subtype has an important role in the activation of lymphocyte, granulocyte, macrophage and dendritic cell responses and, therefor, it may be a promising target for anti-inflammatory therapies.This entry represents all P2X purinoreceptor subtypes. |
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| Protein Domain |
| Name: |
Putative phosphonoacetaldehyde dehydrogenase |
| Type: |
Family |
| Description: |
This family of genes are members of the
NAD-dependent aldehyde dehydrogenase family. These genes are observed in Ralstonia eutropha (strain JMP134) (Alcaligenes eutrophus), Sinorhizobium meliloti 1021, Burkholderia mallei ATCC 23344, Burkholderia thailandensis (strain E264/ATCC 700388/DSM 13276/CIP 106301), Burkholderia cenocepacia (strain AU 1054), Burkholderia pseudomallei K96243 and Burkholderia pseudomallei (strain 1710b), Burkholderia xenovorans (strain LB400), Burkholderia sp. (strain 383) (Burkholderia cepacia (strain ATCC 17760/NCIB
9086/R18194)) and Polaromonas sp. (strain JS666/ATCC BAA-500) in close proximity to the PhnW gene () encoding 2-aminoethyl phosphonate aminotransferase (which generates phosphonoacetaldehyde) and PhnA (
) encoding phosphonoacetate hydrolase (not to be confused with the alkylphosphonate utilization operon protein PhnA modelled by
). Additionally, transporters believed to be specific for 2-aminoethyl phosphonate are often present. PhnW is, in other organisms, coupled with PhnX (
) for the degradation of phosphonoacetaldehyde (
), but PhnX is apparently absent in each of the organisms containing this aldehyde reductase. PhnA, characterised in a strain of Pseudomonas fluorescens that has not yet had its genome sequenced, is only rarely found outside of the PhnW and aldehyde dehydrogenase context. For instance in Rhodopseudomonas and Bordetella bronchiseptica, where it is adjacent to transporters presumably specific for the import of phosphonoacetate. It seems reasonably certain then, that this enzyme catalyses the NAD-dependent oxidation of phosphonoacetaldehyde to phosphonoacetate, bridging the metabolic gap between PhnW and PhnA. We propose the name phosphonoacetaldehyde dehydrogenase and the gene symbol PhnY for this enzyme. The structure of PhnY has been solved [
].Putative phosphonoformaldehyde dehydrogenase (PhpJ), an aldehyde dehydrogenase homologue reportedly involved in the biosynthesis of phosphinothricin tripeptides in Streptomyces viridochromogenes DSM 40736, is also included in this entry [
]. |
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| Protein Domain |
| Name: |
Prolyl-tRNA synthetase, class II, C-terminal, archaeal-type |
| Type: |
Domain |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [
,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].This domain is found predominantly found in prolyl-tRNA synthetases from archaeal Methanococci species. It contains a zinc binding site, and adopts a structure consisting of alpha helices and antiparallel beta sheets arranged in 2 layers, in a beta-α-β-α-β motif [
]. |
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| Protein Domain |
| Name: |
Quinohemoprotein amine dehydrogenase, gamma subunit, structural domain |
| Type: |
Domain |
| Description: |
Quinohemoprotein amine dehydrogenases (QHNDH)
) are enzymes produced in the periplasmic space of certain Gram-negative bacteria, such as Paracoccus denitrificans and Pseudomonas putida, in response to primary amines, including n-butylamine and benzylamine. QHNDH catalyses the oxidative deamination of a wide range of aliphatic and aromatic amines through formation of a Schiff-base intermediate involving one of the quinone O atoms [
]. Catalysis requires the presence of a novel redox cofactor, cysteine tryptophylquinone (CTQ). CTQ is derived from the post-translational modification of specific residues, which involves the oxidation of the indole ring of a tryptophan residue to form tryptophylquinone, followed by covalent cross-linking with a cysteine residue []. There is one CTQ per subunit in QHNDH. In addition to CTQ, two haem c cofactors are present in QHNDH that mediate the transfer of the substrate-derived electrons from CTQ to an external electron acceptor, cytochrome c-550 [,
].QHNDH is a heterotrimer of alpha, beta and gamma subunits. The alpha and beta subunits contain signal peptides necessary for the translocation of QHNDH to the periplasm. The alpha subunit is composed of four domains - domain 1 forming a dihaem cytochrome, and domains 2-4 forming antiparallel β-barrel structures; the beta subunit is a 7-bladed β-propeller that provides part of the active site; and the small, catalytic gamma subunit contains the novel cross-linked CTQ cofactor, in addition to additional thioester cross-links between Cys and Asp/Glu residues that encage CTQ. The gamma subunit assumes a globular secondary structure with two short α-helices having many turns and bends [
]. This entry represents the main structural domain of the QHNDH gamma subunit. |
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| Protein Domain |
| Name: |
DNA nucleotidylexotransferase (TdT) |
| Type: |
Family |
| Description: |
DNA carries the biological information that instructs cells how to exist
in an ordered fashion: accurate replication is thus one of the mostimportant events in the cell life cycle. This function is mediated by
DNA-directed DNA-polymerases, which add nucleotide triphosphate (dNTP)residues to the 5'-end of the growing DNA chain, using a complementary
DNA as template. Small RNA molecules are generally used as primers forchain elongation, although terminal proteins may also be used. Three motifs, A, B and C [
], are seen to be conserved across all DNA-polymerases, with motifs A and C also seen in RNA- polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenlow (Escherichia coli) structure: motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-beta secondary structure [].DNA polymerases (
) can be classified, on the basis of sequence
similarity [,
], into at least four different groups: A, B, C and X. Members of family X are small (about 40 Kd) compared with other polymerases and encompass two distinct polymerase enzymes that have similar functionality: vertebrate polymerase beta (same as Saccharomyces cerevisiae pol 4), and terminal deoxynucleotidyl-transferase (TdT) (). The former functions in DNA repair, while
the latter terminally adds single nucleotides to polydeoxynucleotide chains.Both enzymes catalyse addition of nucleotides in a distributive manner, i.e. they
dissociate from the template-primer after addition of each nucleotide.DNA-polymerases show a degree of structural similarity with RNA-polymerases.
This entry represents terminal deoxynucleotidyl-transferase (TdT). |
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| Protein Domain |
| Name: |
Gastrin/cholecystokinin, conserved site |
| Type: |
Conserved_site |
| Description: |
Gastrin and cholecystokinin (CCK) are structurally and functionally related peptide hormones that function as hormonal regulators of various digestive processes and feeding behaviours. They are known to induce gastric secretion, stimulate pancreatic secretion, increase blood circulation and water secretion in the stomach and intestine, and stimulate smooth muscle contraction. Originally found in the gut, these hormones have since been shown to be present in various parts of the nervous system. Like many other active peptides they are synthesized as larger protein precursors that are enzymatically converted to their mature forms. They are found in several molecular forms due to tissue-specific post-translational processing. A number of other peptides are known to belong to the same family: Caerulein, an amphibian skin peptide, with a biological activity similar to that of CCK or gastrin. There are different types of caerulein [
] in which a single or up to four copies of the peptide are present. Leukosulfakinin I and II (LSK) [
,
] are peptides, isolated from cockroach, that change the frequency and amplitude of contractions of the hindgut. Drosulfakinins I and II [
] are putative CCK-homologues from Drosophila. Those two peptides are part of a precursor sequence that was isolated using a probe based on the sequence of CCK and LSK. A chicken antrum peptide [
] which is a potent stimulus of avian gastric acid but not of pancreatic secretion. Cionin [
], a neuropeptide from the protochordate Ciona intestinalis (Transparent sea squirt). The biological activity of gastrin and CCK is associated with the last five C-terminal residues. One or two positions downstream, there is a conserved sulphated tyrosine residue. |
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| Protein Domain |
| Name: |
Chloride channel, voltage-gated, ClcB |
| Type: |
Family |
| Description: |
Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport [
].The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata [
], and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl- channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl- channels is that some of the isoforms may function as Cl- channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains []. Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N- and C-termini residing in the cytoplasm [].This entry represents bacterial voltage-gated chloride channel of the ClcB type. ClcB probably acts as an electrical shunt for an outwardly-directed proton pump that is linked to amino acid decarboxylation, as part of the extreme acid resistance (XAR) response [
]. |
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| Protein Domain |
| Name: |
Ketol-acid reductoisomerase, C-terminal |
| Type: |
Domain |
| Description: |
Ketol-acid reductoisomerase (KARI; (
)), also known as acetohydroxy
acid isomeroreductase (AHIR or AHAIR), catalyzes the conversion ofacetohydroxy acids into dihydroxy valerates in the second step of thebiosynthetic pathway for the essential branched-chain amino acids valine,
leucine, and isoleucine. KARI catalyzes an unusual two-step reactionconsisting of an alkyl migration in which the substrate, either 2-acetolactate
(AL) or 2-aceto-2-hydroxybutarate (AHB), is converted to 3-hydoxy-3-methyl-2-oxobutyrate or 3-hydoxy-3-methyl-2-pentatonate, followed by a NADPH-dependent
reduction to give 2,3-dihydroxy-3-isovalerate or 2,3-dihydroxy-3-methylvalerate respectively [
,
,
,
,
,
].KARI is present only in bacteria, fungi, and plants, but not in animals. KARIs
are divided into two classes on the basis of sequence length andoligomerization state. Class I KARIs are ~340 amino acid residues in length
and include all fungal KARIs, whereas class II KARIs are ~490 residues longand include all plant KARIs. Bacterial KARIs can be either class I or class
II. KARIs are composed of two types of domains, an N-terminal Rossmann folddomain and one or two C-terminal knotted domains. Two intertwinned knotted
domains are required for function, and in the short-chain or class I KARIs,each polypeptide chain has one knotted domain. As a result, dimerization of
two monomers forms two complete KARI active sites. In the long-chain or classII KARIs, a duplication of the knotted domain has occurred and, as a result,
the protein does not require dimerization to complete its active site[
,
,
,
,
,
].The α-helical KARI C-terminal knotted domain can be described as a six-
helix core in which helices coil like cable threads around each other, thusforming a bundle [
,
,
,
,
]. |
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| Protein Domain |
| Name: |
P-type ATPase, subfamily IB |
| Type: |
Family |
| Description: |
P-ATPases (also known as E1-E2 ATPases) ([intenz:3.6.3.-]) are found in bacteria and in a number of eukaryotic plasma membranes and organelles []. P-ATPases function to transport a variety of different compounds, including ions and phospholipids, across a membrane using ATP hydrolysis for energy. There are many different classes of P-ATPases, which transport specific types of ion: H+, Na
+, K
+, Mg
2+, Ca
2+, Ag
+and Ag
2+, Zn
2+, Co
2+, Pb
2+, Ni
2+, Cd
2+, Cu
+and Cu
2+. P-ATPases can be composed of one or two polypeptides, and can usually assume two main conformations called E1 and E2.
This entry represents the copper and cadmium-type heavy metal transporting P-type ATPases, and other related sequences that belong to the IB subfamily of P-type ATPases. Type IB ATPases are involved in transport of the soft Lewis acids: Cu
+, Ag
+, Cu
2+, Zn
2+, Cd
2+, Pb
2+and Co
2+. These proteins are involved in a variety of processes in both prokaryotes and eukaryotes.
In Arabidopsis, the copper-ATPase RAN1 delivers copper to create functional hormone receptors involved in ethylene signalling []. In humans, ATP7A supplies copper to copper-dependent enzymes in the secretory pathway, while ATP7B exports copper out of the cells. Defects in ATP7B are the cause of Wilson disease (WD), an autosomal recessive disorder in which copper cannot be incorporated into ceruloplasmin in liver and cannot be excreted from the liver into the bile []. Defects in ATP7A are the cause of Menkes disease (MNKD), also known as kinky hair disease. MNKD is an X-linked recessive disorder of copper metabolism characterised by generalised copper deficiency []. |
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| Protein Domain |
| Name: |
Phenylalanine ammonia-lyase, shielding domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
The ubiquitous higher plant enzyme phenylalanine ammonia-lyase (PAL;
) is a key biosynthetic catalyst in phenylpropanoid assembly. PAL catalyses the non-oxidative deamination of L-phenylalanine to trans-cinnamic acid. PAL contains a catalytic Ala-Ser-Gly triad that is post-translationally cyclised. PAL is structurally similar to the mechanistically related histidine ammonia lyase (HAL;
), with PAL having an additional approximately 160 residues extending from the common fold [
]. Catalysis in PAL may be governed by the dipole moments of seven α-helices associated with the PAL active site. The cofactor 3,5-dihydro-5-methylidene-4H-imidazol-4-one (MIO) resides atop the positive poles of three helices, for increasing its electrophillicity. Plant and fungal PAL enzymes contain aa approximately 100-residue long C-terminal multi-helix domain, which might play a role in the rapid response of PAL in the regulation of phenylpropanoid biosynthesis by destabilising the enzyme []. This entry also includes fungal proteins such as Phenylalanine ammonia-lyase CLZ10 which mediates the biosynthesis of squalestatin S1 with potent cholesterol lowering activity by targeting squalene synthase (SS) [], and Phenylalanine ammonia-lyase hkm12 involved in the biosynthesis of hancockiamides, an unusual new family of N-cinnamoylated piperazines [].This superfamily represents the shielding domain at the C-terminal of PAL which is tightly connected to the core domain through the exceptionally long 55-residue helix α-17. The shielding domain restricts the access to the active centre so that the risk of inactivation by nucleophiles in conjunction with dioxygen is minimised. This may help PAL to function, for instance, in stressed plant tissue. It should be noted that PAL forms its electrophilic prosthetic group autocatalytically from its own polypeptide, rendering it independent of any cofactor and thus facilitating its upregulation [
]. |
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| Protein Domain |
| Name: |
Endonuclease III-like, iron-sulphur cluster loop motif |
| Type: |
Conserved_site |
| Description: |
Endonuclease III (
) is a DNA repair enzyme which removes a number of damaged pyrimidines from DNA via its glycosylase activity and also cleaves the phosphodiester backbone at apurinic / apyrimidinic sites via a beta-elimination mechanism [
,
]. The structurally related DNA glycosylase MutYrecognises and excises the mutational intermediate 8-oxoguanine-adenine mispair [
]. The 3-D structures of Escherichia coli endonuclease III [] and catalytic domain of MutY [] have been determined. Thestructures contain two all-alpha domains: a sequence-continuous, six-helix domain (residues 22-132) and a Greek-key,
four-helix domain formed by one N-terminal and three C-terminal helices (residues 1-21 and 133-211) together with theFe4S4 cluster. The cluster is bound entirely within the C-terminal loop by four cysteine residues with a ligation pattern
Cys-(Xaa)6-Cys-(Xaa)2-Cys-(Xaa)5-Cys which is distinct from all other known Fe4S4 proteins. This structural motif isreferred to as a Fe4S4 cluster loop (FCL) [
]. Two DNA-binding motifs have been proposed, one at either end of theinterdomain groove: the helix-hairpin-helix (HhH) and FCL motifs. The primary role of the iron-sulphur cluster appears to
involve positioning conserved basic residues for interaction with the DNA phosphate backbone by forming the loop ofthe FCL motif [
,
]. The iron-sulphur cluster loop (FCL) is also found in DNA-(apurinic or apyrimidinic site) lyase, a subfamily of endonuclease III. The enzyme has both apurinic and apyrimidinic endonuclease activity and a DNA N-glycosylase activity. It cuts damaged DNA at cytosines, thymines and guanines, and acts on the damaged strand 5' of the damaged site. The enzyme binds a 4Fe-4S cluster which is not important for the catalytic activity, but is probably involved in the alignment of the enzyme along the DNA strand. |
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| Protein Domain |
| Name: |
Anti-sigma factor CnrY |
| Type: |
Family |
| Description: |
This family is found in alpha and beta proteobacteria. Family members include anti-sigma factor CnrY from Cupriavidus metallidurans.Sigma factors are multi-domain subunits of bacterial RNA polymerase (RNAP) that play critical roles in transcription initiation, including the recognition and opening of promoters as well as the initial steps in RNA synthesis. They also control a wide variety of adaptive responses such as morphological development and the management of stress. A recurring theme in sigma factor control is their sequestration by anti-sigma factors that occlude their RNAP-binding determinants [
]. CnrH controls cobalt and nickel resistance in Cupriavidus metallidurans. CnrH is regulated by a complex of two transmembrane proteins: the periplasmic sensor CnrX and the anti-sigma CnrY. At rest, CnrH is sequestered by CnrY whose 45-residue-long cytosolic domain is one of the shortest anti-sigma domains. Upon Ni(II) or Co(II) ions detection by CnrX in the periplasm, CnrH is released between CnrH and the cytosolic domain of CnrY (CnrYc). The CnrH/CnrYC complex displays an unexpected structural similarity to the anti-sigma NepR in complex with its antagonist PhyR, whereas NepR shares no sequence similarity with CnrY. Crystal structure of CnrH/CnrY shows that CnrYC residues 3-19 are folded as a well-defined α-helix. The peptide further extends along the hydrophobic groove of sigma 2 with no canonical structure except for a short helical turn spanning residues 24-28. CnrY has a hydrophobic knob made of V4, W7 and L8 side chains protruding into sigma 4 hydrophobic pocket and contributing to the interface. In vivo investigation of CnrY function pinpoints part of the hydrophobic knob as a hotspot in CnrH inhibitory binding []. |
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| Protein Domain |
| Name: |
RAG nonamer-binding domain |
| Type: |
Domain |
| Description: |
The variable portions of immunoglobulin and T cell receptor genes are assembled in developing lymphocytes from variable (V), joining (J), and in some cases diversity (D) gene segments, which are widely separated in the genome. These segments are brought together in a highly regulated manner by a somatic site-specific recombination reaction known as V(D)J recombination. Each gene segment is flanked by a signal sequence consisting of a conserved heptamer (consensus sequence 5'-CACAGTG-3') and nonamer (consensus sequence 5'-ACAAAAACC-3') separated by a relatively nonconserved 12 or 23 base pair (bp) spacer (12 signal or 23 signal, respectively). A segment flanked by a 12 signal can only be joined efficiently to one flanked by a 23 signal, a restriction referred to as the 12/23 rule [
].The V(D)J recombinase subunits Rag-1 and Rag-2 (recombination activating gene) mediate assembly of antigen receptor gene segments. The critical step for signal recognition is binding of Rag-1 to the nonamer [
]. The Rag-1 nonamer binding domain (NBD) forms a tightly interwoven dimer that binds and synapses two nonamer elements, with each NBD making contact with both DNA molecules. Each NBD monomer is composed of three helices: H1, H2 and H3. Helix 1 contains a kink that separates it into two smaller helices: H1a and H1b. Helices H2 and H3 from each subunit form a four-helix bundle through extensive hydrophobic interactions and constitute the bulk of the dimer interface, whereas the H1 helices from the two subunits wrap around one side of the four-helix bundle with the N-terminal GGRPR motifs protruding from opposite sides of the dimer. The GGRPR motif is an example of an AT-hook, a structural element found in various DNA binding proteins []. |
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| Protein Domain |
| Name: |
Ferrochelatase, N-terminal |
| Type: |
Domain |
| Description: |
Synonym(s): Protohaem ferro-lyase, Iron chelatase, etc.
Ferrochelatase is the terminal enzyme of the heme biosynthetic pathway. It catalyzes the insertion of ferrous iron into the protoporphyrin IX ring yielding protoheme. This enzyme is ubiquitous in nature and widely distributed in bacteria and eukaryotes. Recently, some archaeal members have been identified. The oligomeric state of these enzymes varies depending on the presence of a dimerization motif at the C terminus [
,
,
,
,
,
,
,
,
,
,
,
]. In eukaryotic cells, it binds to the mitochondrial inner membrane with its active site on the matrix side of the membrane.The X-ray structure of
Bacillus subtilisand human ferrochelatase have been solved [
,
].The human enzyme exists as a homodimer. Each
subunit contains one [2Fe-2S]cluster. The monomer is folded into two
similar domains, each with a four-stranded parallelβ-sheet flanked by an α-helix in a beta-α-β motif that is
reminiscent of the fold found in the periplasmic bindingproteins. The topological similarity between the domains suggests that
they have arisen from a gene duplication event. However,significant differences exist between the two domains, including an
N-terminal section (residues 80-130) that forms part of theactive site pocket, and a C-terminal extension (residues 390-423) that
is involved in coordination of the [2Fe-2S]cluster and in
stabilisation of the homodimer. Ferrochelatase seems to have a structurally conserved core region that is common to the enzyme from bacteria, plants and mammals. Porphyrin binds in the identified cleft; this cleft also includes the metal-binding site of the enzyme. It is likely that the structure of the cleft region will have different conformations upon substrate binding and release [
].This entry represents the N-terminal domain of ferrochelatase. |
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| Protein Domain |
| Name: |
Transforming growth factor beta-3 |
| Type: |
Family |
| Description: |
The transforming growth factors-beta (TGF-beta 1-5) constitute of a family of multi-functional cytokines that regulate cell growth and differentiation [
]. Many cells synthesise TGF-beta, and essentially all have specific receptors for this peptide [
]. TGF-beta regulates the actions of many other peptide growth factors and determines a positive or negative direction of their effects. The protein functions as a disulphide-linked homodimer. Its sequence is characterised by the presence of several C-terminal cysteine residues, which form interlocking disulphide links arranged in a knot-like topology. A similar cystine-knot arrangement has been noted in the structures of some enzyme inhibitors and neurotoxins that bind to voltage-gated Ca2+ channels, although the precise topology differs.TGF-beta genes are expressed differentially, suggesting that the various TGF- beta species may have distinct physiological roles
in vivo. Examination of TGF-beta 3 mRNA levels in adult murine tissues indicated that expression is predominant in brain, heart, adipose tissue and testis [
]. TGF beta-3 mRNA is also observed in adult mouse lung and placenta. Research on rat foetal lung fibroblasts has shown that exposure to cortisol increases TGF-beta 3 mRNA expression in a time- and dose-dependent manner, suggesting that glucocorticoids may mediate their stimulatory effect on lung maturation by inducing TGF-beta 3 expression in foetal lung fibroblasts [].The three-dimensional structures of several members of the TGF-beta super-family have been deduced. The crystal structure of TGF-beta 3 reveals a near identical central core to that of TGF-beta 2 [
]. The principal differences are witnessed in the conformations of the N-terminal α-helix and in the β-sheet loops, which could account for the individual cellular responses, if these differences are recognised by the TGF-beta receptors. |
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| Protein Domain |
| Name: |
Formylmethanofuran dehydrogenase, subunit B |
| Type: |
Family |
| Description: |
Formylmethanofuran dehydrogenase (
) is found in methanogenic and sulphate-reducing archaea. The enzyme contains molybdenum or tungsten, a molybdopterin guanine dinuceotide cofactor (MGD) and iron-sulphur clusters [
]. It catalyses the reversible reduction of CO2and methanofuran via N-carboxymethanofuran (carbamate) to N-formylmethanofuran, the first and second steps in methanogenesis from CO
2[
,
]. This reaction is important for the reduction of CO2to methane, in autotrophic CO
2fixation, and in CO
2formation from reduced C
1units [
]. The synthesis of formylmethanofuran is crucial for the energy metabolism of archaea. Methanogenic archaea derives the energy for autrophic growth from the reduction of CO2with molecular hydrogen as the electron donor [
]. The process of methanogenesis consists of a series of reduction reactions at which the one-carbon unit derived from CO2is bound to C
1carriers.
There are two isoenzymes of formylmethanofuran dehydrogenase: a tungsten-containing isoenzyme (Fwd) and a molybdenum-containing isoenzyme (Fmd). The tungsten isoenzyme is constitutively transcribed, whereas transcription of the molybdenum operon is induced by molybdate [
]. The archaean Methanobacterium thermoautotrophicum contains a 4-subunit (FwdA, FwdB, FwdC, FwdD) tungsten formylmethanofuran dehydrogenase and a 3-subunit (FmdA, FmdB, FmdC) molybdenum formylmethanofuran dehydrogenase [].This entry represents subunit B (FmdB and FwdB) of formylmethanofuran dehydrogenase. The other subunits are subunit A (
), subunit C (
), subunit D (
), subunit E (
) and subunit F. Some organisms also encode a fusion of the C and D subunits (
). Formylmethanofuran dehydrogenase catalyzes the first step in methane formation from CO2 in methanogenic archaea and some eubacteria. Members in this entry belong to the molybdopterin_binding (MopB) superfamily of proteins [
]. |
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| Protein Domain |
| Name: |
S-adenosyl-L-methionine-dependent methyltransferase superfamily |
| Type: |
Homologous_superfamily |
| Description: |
This entry represents S-adenosyl-L-methionine-dependent methyltransferases (SAM MTase). Methyltransferases transfer a methyl group from a donor to an acceptor. SAM-binding methyltransferases utilise the ubiquitous methyl donor SAM as a cofactor to methylate proteins, small molecules, lipids, and nucleic acids. All SAM MTases contain a structurally conserved SAM-binding domain consisting of a central seven-stranded β-sheet that is flanked by three α-helices per side of the sheet [
].A review published in 2003 [
] divides all methyltransferases into 5 classes based on the structure of their catalytic domain (fold):class I: Rossmann-like α/βclass II: TIM β/α-barrel α/βclass III: tetrapyrrole methylase α/βclass IV: SPOUT α/β class V: SET domain all β Another paper [
] based on a study of the Saccharomyces cerevisiae methyltransferome argues for four more folds:class VI: transmembrane all-α class VII: DNA/RNA-binding 3-helical bundle all-αclass VIII: SSo0622-like α+βclass IX: thymidylate synthetase α+βThe vast majority of methyltransferases belong to the Rossmann-like fold (Class I) which consists in a seven-stranded β-sheet adjoined by α-helices. The β-sheet contains a central topological switch-point resulting in a deep cleft in which SAM binds. Class I methyltransferases display two conserved positions, the first one is a GxGxG motif (or at least a GxG motif) at the end of the first β-strand which is characteristic of a nucleotide-binding site and is hence used to bind the adenosyl part of SAM, the second conserved position is an acidic residue at the end of the second β-strand that forms one hydrogen bond to each hydroxyl of the SAM ribose part. The core of these enzymes is composed by about 150 amino acids that show very strong spatial conservation [
]. |
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| Protein Domain |
| Name: |
Peptidase family M49 |
| Type: |
Family |
| Description: |
Peptidase family M49 contains exopeptidases that remove dipeptides from the N terminus of peptides and proteins and are known as dipeptidyl-peptidases (DPP). The best characterized of these is dipeptidyl-peptidase III and represents the prototype for the M49 family of metallopeptidases. It consists of two domains that form a wide cleft containing the catalytic metal ion (DPPIII;
; MEROPS identifier M49.001) [
]. The exopeptidases in M49 are metal-dependent, and bind a single zinc ion via the histidines in an HEXXXH motif, in which the distance between the histidines in one residue longer than in the HEXXH zinc-binding motif found in endopeptidases of clan MA. The importance of the histidines and the glutamic acid was identified by site-directed mutagenesis []. Some members of family M49, notably from bacteria such as Colweliaand plants possess the more usual HEXXH motif [
]. A third zinc ligand occurs within a motif that has been described as EECRAE []. DPPIII releases N-terminal dipeptides sequentially from peptides such as angiotensins II and III, Leu-enkephalin, prolactin and alpha-melanocyte-stimulating hormone, but tripeptides are poor substrates and polypeptides of more than ten residues are not cleaved [,
]. DPPIII is a soluble, cytosolic enzyme with a housekeeping role, but is elevated in retroplacental serum may participate in the increased angiotensin hydrolysis seen during pregnancy [].This family also includes Nudix hydrolase 3 (NUDT3) from plants, which is thought to hydrolyse nucleoside diphosphate derivatives because of the presence of a Nudix box. Isopentenyl diphosphate (IPP), a universal precursor for the biosynthesis of isoprenoid compounds, is hydrolysed; purine nucleotides such as 8-oxo-dATP are dephosphorylated; and the enzyme acts as a dipeptidyl-peptidase against dipeptidyl-2-arylamide substrates [
]. |
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| Protein Domain |
| Name: |
Peptidase S51, cyanophycinase |
| Type: |
Family |
| Description: |
Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes [
]. They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence []. Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases [].Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base [
]. The geometric orientations of the catalytic residues are similar between families, despite different protein folds []. The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) [,
].This entry describes both cytosolic and extracellular cyanophycinases. These are serine exopeptidases that hydrolyse alpha-aspartyl bonds and belonging to MEROPS peptidase family S51, clan PC. They are part of a system in many Cyanobacteria and a few other species of generating and later utilizing a storage polymer for nitrogen, carbon, and energy, called cyanophycin. The latter are found in species such as Pseudomonas anguilliseptica that can use external cyanophycin. The polymer has a backbone of L-aspartic acid, with most Asp side chain carboxyl groups attached to L-arginine. |
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| Protein Domain |
| Name: |
Peptidase S51, dipeptidase E |
| Type: |
Family |
| Description: |
Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes [
]. They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence []. Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases [].Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base [
]. The geometric orientations of the catalytic residues are similar between families, despite different protein folds []. The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) [,
].This entry represents serine peptidases belonging to MEROPS peptidase family S51 (dipeptidase E, clan PC). They hydrolyse peptides bond in dipeptides where the first amino acid is aspartate [
]. The three-dimensional structure of Salmonella typhimurium aspartyl dipeptidase, peptidase E, has been reported at 1.2A resolution. The structure of this 25kDa enzyme consists of two mixed b-sheets forming a V, flanked by six a-helices. The active site contains a Ser-His-Glu catalytic triad []. |
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| Protein Domain |
| Name: |
PD-(D/E)XK endonuclease-like domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
This entry represent a PD-(D/E)XK endonuclease-like domain superfamily [
]. PD-(D/E)XK nucleases constitute a large and highly diverse superfamily of enzymes that display little sequence similarity. However, they share a common core fold and a few critical active site residues []. This domain can be found at the C terminus of nuclease/helicase AddA, AddB, and RecB.There are two classes of helicase-nuclease complex involved in the initiation step for recombinational repair. AddAB-type enzymes (also called RexAB) are found mainly in Gram-positive bacteria, whereas heterotrimeric RecBCD-type enzymes are found mainly in Gram-negative bacteria [
]. The RecBCD holoenzyme has a single nuclease domain found in RecB []. Exodeoxyribonuclease V, or RecBCD holoenzyme, is a multifunctional nuclease with potent ATP-dependent exodeoxyribonuclease activity. Ejection of RecD, as occurs at chi recombinational hotspots, cripples exonuclease activity in favor of recombinagenic helicase activity. All proteins in this family for which functions are known are DNA-DNA helicases that are used as part of an exonuclease-helicase complex (made up of RecBCD homologues) that function to generate substrates for the initiation of recombination and recombinational repair. The complex catalyses exonucleolytic cleavage in either the 5' to 3' or 3' to 5' direction to yield 5-phosphooligonucleotides in the presence of ATP [].This superfamily includes phage-type exonucleases (
) and the C-terminal domain of RecB exodeoxyribonuclease V exonuclease (
), which are closely related in sequence and structure, containing a restriction enzyme-like core fold.
Exonuclease from Bacteriophage lambda facilitates phage DNA recombination through the double-strand break repair (DSBR) and single-strand annealing pathways; it is also important for the late, rolling-circle mode of lambda DNA replication. This magnesium-dependent enzyme catalyses the exonucleolytic cleavage of DNA in the 5'- to 3'-direction to yield nucleoside 5'-phosphates. Lambda exonuclease is a trimer of three subunits that form a toroid structure with a tapered channel passing through the middle [
]. |
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| Protein Domain |
| Name: |
NADH:ubiquinone oxidoreductase, subunit 1/F420H2 oxidoreductase subunit H |
| Type: |
Family |
| Description: |
NADH:ubiquinone oxidoreductase (complex I) (
) is a respiratory-chain enzyme that catalyses the transfer of two electrons from NADH to ubiquinone in a reaction that is associated with proton translocation across the membrane (NADH + ubiquinone = NAD+ + ubiquinol) [
]. Complex I is a major source of reactive oxygen species (ROS) that are predominantly formed by electron transfer from FMNH(2). Complex I is found in bacteria, cyanobacteria (as a NADH-plastoquinone oxidoreductase), archaea [], mitochondria, and in the hydrogenosome, a mitochondria-derived organelle. In general, the bacterial complex consists of 14 different subunits, while the mitochondrial complex contains homologues to these subunits in addition to approximately 31 additional proteins [].This entry represents subunit 1 NADH:ubiquinone oxidoreductase [
]. Among the many polypeptide subunits that make up complex I, there are fifteen which are located in the membrane part, seven of which are encoded by the mitochondrial and chloroplast genomes of most species. The most conserved of these organelle-encoded subunits is known as subunit 1 (gene ND1 in mitochondrion, and NDH1 in chloroplast) and seems to contain the ubiquinone binding site.The ND1 subunit is highly similar to subunit 4 of Escherichia coli formate hydrogenlyase (gene hycD), subunit C of hydrogenase-4 (gene hyfC). Paracoccus denitrificans NQO8 and Escherichia coli nuoH NADH-ubiquinone oxidoreductase subunits also belong to this family [
].This entry also includes the archaeal F420H2 oxidoreductase subunit H (FPO). FPO shuttles electrons from F420H2, via FAD and iron-sulphur (Fe-S) centres, to quinones in the F420H2:heterodisulphide oxidoreduction chain. The immediate electron acceptor for the enzyme in this species is believed to be methanophenazine. Couples the redox reaction to proton translocation (for every two electrons transferred, 0.9 hydrogen ions are translocated across the cytoplasmic membrane), and thus conserves the redox energy in a proton gradient. |
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| Protein Domain |
| Name: |
Isochorismate synthase |
| Type: |
Family |
| Description: |
Isochorismate synthase (
) catalyses the conversion of chorismate to isochorismate, the first step in the biosynthesis of both the respiratory chain component menaquinone (MK, vitamin K2) and phylloquinone (vitamin K1). In bacteria, isochorismate is a precursor of siderophores enterobactin (via the 2,3-dihydroxybenzoate (DHB) precursor) [
], amonabactins [] and salicylic acid []. Most aerobic bacteria secrete siderophores to facilitate iron acquisition []. Siderophores are iron-chelating agents which are low molecular weight compounds that specifically bind ferric iron and mediate iron uptake into the cell by recognition of specific membrane receptor proteins and transport systems. In plants, isochorismate synthase is required for defence against pathogens. Salicylic acid synthesised via the pathway using isochorismate synthase is responsible for both local and systemic acquired resistance in plants [].In Escherichia coli and Bacillus subtilis, two distinct isochorismate synthase isoenzymes, MenF [
] and EntC []/DhbC [], are known to be involved in MK and siderophore biosynthesis pathways, respectively []. MenF and EntC are differentially regulated and isochorismate synthesised by EntC is mainly channelled into enterobactin synthesis, whereas isochorismate synthesised by MenF is mainly channelled into menaquinone synthesis [].The catalytic/chorismate binding domain characteristic of members of this group is related to other chorismate binding enzymes [
]: component I of anthranilate synthase, para-aminobenzoate synthase, and aminodeoxychorismate synthase (please see ).
There is a significant heterogeneity in the length and sequence of the N-terminal region of members of this group. Partially on the basis of the N-terminal region, the group can be divided into subfamilies, with the enzymes involved in DHB (enterobactin precursor) biosynthesis (EntC/DhbC/VibC) forming a distinct subfamily, and the enzymes involved in MK biosynthesis (MenF) forming two groups (E. coli and B. subtilis types). |
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| Protein Domain |
| Name: |
Aspartyl/Asparaginyl-tRNA synthetase, class IIb |
| Type: |
Family |
| Description: |
Aspartyl tRNA synthetase
is an alpha2 dimer that belongs to class IIb. Structural analysis combined with mutagenesis and enzymology data on the yeast enzyme point to a tRNA binding process that starts by a recognition event between the tRNA anticodon loop and the synthetase anticodon binding module [
]. Asparagine tRNA ligase (
) is also an alpha2 dimer that belongs to class IIb. There are remarkable similarities between the tertiary structures of asparaginyl-tRNA synthetase and aspartyl-tRNA synthetase [
].The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c []. |
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| Protein Domain |
| Name: |
Asparagine-tRNA ligase |
| Type: |
Family |
| Description: |
Asparagine tRNA ligase (
) is an alpha2 dimer that belongs to class IIb.
There is a striking similarity between asparagine-tRNA ligases and archaeal/eukaryotic type aspartyl-tRNA ligases () and a striking divergence of bacterial type aspartyl-tRNA ligases (
). This family, AsnS, represents asparagine-tRNA ligases from the three domains of life. Some species lack this enzyme and charge tRNA(asn) by misacylation with Asp, followed by transamidation of Asp to Asn.
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c []. |
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| Protein Domain |
| Name: |
Lambda repressor-like, DNA-binding domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Bacteriophage lambda C1 repressor controls the expression of viral genes as part of the lysogeny/lytic growth switch. C1 is essential for maintaining lysogeny, where the phage replicates non-disruptively along with the host. If the host cell is threatened, then lytic growth is induced. The Lambda C1 repressor consists of two domains connected by a linker: an N-terminal DNA-binding domain that also mediates interactions with RNA polymerase, and a C-terminal dimerisation domain [
]. The DNA-binding domain consists of four helices in a closed folded leaf motif. Several different phage repressors from different helix-turn-helix families contain DNA-binding domains that adopt a similar topology. These include the Lambda Cro repressor, Bacteriophage 434 C1 and Cro repressors, P22 C2 repressor, and Bacteriophage Mu Ner protein.The DNA-binding domain of Bacillus subtilis spore inhibition repressor SinR is identical to that of phage repressors [
]. SinR represses sporulation, which only occurs in response to adverse conditions. This provides a possible evolutionary link between the two adaptive responses of bacterial sporulation and prophage induction.Other DNA-binding domains also display similar structural folds to that of Lambda C1. These include bacterial regulators such as the purine repressor (PurR), the lactose repressor (Lacr) and the fructose repressor (FruR), each of which has an N-terminal DNA-binding domain that exhibits a fold similar to that of lambda C1, except that they lack the first helix [
,
,
]. POU-specific domains found in transcription factors such as in Oct-1, Pit-1 and Hepatocyte nuclear factor 1a (LFB1/HNF1) display four-helical fold DNA-binding domains similar to that of Lambda C1 [,
,
]. The N-terminal domain of cyanase has an α-helix bundle motif similar to Lambda C1, but it probably does not bind DNA. Cyanase is an enzyme found in bacteria and plants that catalyses the reaction of cyanate with bicarbonate to produce ammonia and carbon dioxide in response to extracellular cyanate []. |
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| Protein Domain |
| Name: |
Cytochrome c oxidase-like, subunit I domain |
| Type: |
Domain |
| Description: |
Cytochrome c oxidase (
) is a key enzyme in aerobic metabolism. Proton pumping haem-copper oxidases represent the terminal, energy-transfer enzymes of respiratory chains in prokaryotes and eukaryotes. The CuB-haem a3 (or haem o) binuclear centre, associated with the largest subunit I of cytochrome c and ubiquinol oxidases (
), is directly involved in the coupling between dioxygen reduction and proton pumping [
,
].Some terminal oxidases generate a transmembrane proton gradient across the plasma membrane (prokaryotes) or the mitochondrial inner membrane (eukaryotes).
The enzyme complex consists of 3-4 subunits (prokaryotes) up to 13 polypeptides (mammals) of which only the catalytic subunit (equivalent to mammalian subunit I (CO I) is found in all haem-copper respiratory oxidases. The presence of a bimetallic centre (formed by a high-spin haem and copper B) as well as a low-spin haem, both ligated to six conserved histidine residues near the outer side of four transmembrane spans within CO I is common to all family members [
,
,
]. In contrast to eukaryotes the respiratory chain of prokaryotes is branched to multiple terminal oxidases. The enzyme complexes vary in haem and copper composition, substrate type and substrate affinity. The different respiratory oxidases allow the cells to customize their respiratory systems according to a variety of environmental growth conditions [
]. It has been shown that eubacterial quinol oxidase was derived from cytochrome c oxidase in Gram-positive bacteria and that archaebacterial quinol oxidase has an independent origin. A considerable amount of evidence suggests that proteobacteria (Purple bacteria) acquired quinol oxidase through a lateral gene transfer from Gram-positive bacteria [
].This entry represents a structural domain found in subunit I of cytochrome c oxidase as well as related proteins, including quinol oxidase. |
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| Protein Domain |
| Name: |
Cytochrome c oxidase subunit I |
| Type: |
Family |
| Description: |
Cytochrome c oxidase (
) is a key enzyme in aerobic metabolism. Proton pumping haem-copper oxidases represent the terminal, energy-transfer enzymes of respiratory chains in prokaryotes and eukaryotes. The CuB-haem a3 (or haem o) binuclear centre, associated with the largest subunit I of cytochrome c and ubiquinol oxidases (
), is directly involved in the coupling between dioxygen reduction and proton pumping [
,
].Some terminal oxidases generate a transmembrane proton gradient across the plasma membrane (prokaryotes) or the mitochondrial inner membrane (eukaryotes).
The enzyme complex consists of 3-4 subunits (prokaryotes) up to 13 polypeptides (mammals) of which only the catalytic subunit (equivalent to mammalian subunit I (CO I) is found in all haem-copper respiratory oxidases. The presence of a bimetallic centre (formed by a high-spin haem and copper B) as well as a low-spin haem, both ligated to six conserved histidine residues near the outer side of four transmembrane spans within CO I is common to all family members [
,
,
]. In contrast to eukaryotes the respiratory chain of prokaryotes is branched to multiple terminal oxidases. The enzyme complexes vary in haem and copper composition, substrate type and substrate affinity. The different respiratory oxidases allow the cells to customize their respiratory systems according to a variety of environmental growth conditions [
]. It has been shown that eubacterial quinol oxidase was derived from cytochrome c oxidase in Gram-positive bacteria and that archaebacterial quinol oxidase has an independent origin. A considerable amount of evidence suggests that proteobacteria (Purple bacteria) acquired quinol oxidase through a lateral gene transfer from Gram-positive bacteria [
].Please note, this entry also identifies a number of proteins that are cleaved into two chains - a truncated non-functional cytochrome oxidase 1 and an intron-encoded endonuclease. |
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| Protein Domain |
| Name: |
Fumarate lyase, conserved site |
| Type: |
Conserved_site |
| Description: |
A number of enzymes, belonging to the lyase class, for which fumarate is a substrate, have been shown to share a short conserved sequence around a
methionine which is probably involved in the catalytic activity of this typeof enzymes [
]. The following are examples of members of this family:: 3-carboxymuconate lactonizing enzyme,
(3-carboxy-cis,cis-muconate cycloisomerase), an enzyme involved in aromatic acids catabolism [
]. : Delta-crystallin shares around 90% sequence identity with arginosuccinate lyase, showing that it is an example of a 'hijacked' enzyme - accumulated mutations have, however, rendered the protein enzymatically inactive.
: Class I Fumarase enzyme,
(fumarate hydratase), which catalyses the reversible hydration of fumarate to L-malate. Class I enzymes are thermolabile dimeric enzymes (as for example: Escherichia coli fumC).
: Arginosuccinase,
(argininosuccinate lyase), which catalyses the formation of arginine and fumarate from argininosuccinate, the last step in the biosynthesis of arginine.
: Aspartate ammonia-lyase,
(aspartase), which catalyses the reversible conversion of aspartate to fumarate and ammonia. This reaction is analogous to that catalyzed by fumarase, except that ammonia rather than water is involved in the trans-elimination reaction.
: class II Fumarase enzyme,
, are thermostable and tetrameric and are found in prokaryotes (as for example: E. coli fumA and fumB) as well as in eukaryotes. The sequence of the two classes of fumarases are not closely related.
: Adenylosuccinase,
(adenylosuccinate lyase) [
], which catalyses the eighth step in the de novo biosynthesis of purines, the formation of 5'-phosphoribosyl-5-amino-4-imidazolecarboxamide and fumarate from 1-(5-phosphoribosyl)-4-(N-succino-carboxamide). That enzyme can also catalyse the formation of fumarate and AMP from adenylosuccinate. : Trans-aconitate decarboxylase 1, which decarboxylates trans-aconitate, an intermediate in the biosynthesis of itaconic acid and 2-hydroxyparaconate [,
].This signature contains the conserved methionine which is probably involved in the catalytic activity. |
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| Protein Domain |
| Name: |
Leucine-tRNA ligase |
| Type: |
Family |
| Description: |
Leucine-tRNA ligase (
) is an alpha monomer that belongs to class Ia. The crystal structure of leucine-tRNA ligase from the hyperthermophile Thermus thermophilus has an overall architecture that is similar to that of isoleucine-tRNA ligase, except that the putative editing domain is inserted at a different position in the primary structure. This feature is unique to prokaryote-like leucine-tRNA ligases, as is the presence of a novel additional flexibly inserted domain [
]. The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c []. |
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| Protein Domain |
| Name: |
F1F0 ATP synthase OSCP/delta subunit, N-terminal domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (
) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the alpha(3)beta(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis [
]. These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.The subunits called delta in bacterial and chloroplast ATPase, or OSCP (oligomycin sensitivity conferral protein) in mitochondrial ATPase (note that in mitochondria there is a different delta subunit,
). The OSCP/delta subunit appears to be part of the peripheral stalk that holds the F1 complex alpha3beta3 catalytic core stationary against the torque of the rotating central stalk, and links subunit A of the F0 complex with the F1 complex. In mitochondria, the peripheral stalk consists of OSCP, as well as F0 components F6, B and D. In bacteria and chloroplasts the peripheral stalks have different subunit compositions: delta and two copies of F0 component B (bacteria), or delta and F0 components B and B' (chloroplasts) [
,
].This superfamily represents the N-terminal six α-helix bundle domain of the OSCP/delta subunit [
]. |
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| Protein Domain |
| Name: |
DNA polymerase family X, binding site |
| Type: |
Binding_site |
| Description: |
DNA carries the biological information that instructs cells how to exist
in an ordered fashion: accurate replication is thus one of the mostimportant events in the cell life cycle. This function is mediated byDNA-directed DNA-polymerases, which add nucleotide triphosphate (dNTP)
residues to the 3'-end of the growing DNA chain, using a complementary DNA as template. Small RNA molecules are generally used as primers for
chain elongation, although terminal proteins may also be used. Three motifs, A, B and C [], are seen to be conserved across all DNA-polymerases, with motifs A and C also seen in RNA- polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenow (Escherichia coli) structure: motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-beta secondary structure [].DNA polymerases (
) can be classified, on the basis of sequence
similarity [,
], into at least four different groups: A, B, C and X. Members of family X are small (about 40kDa) compared with other polymerases and encompass two distinct polymerase enzymes that have similar functionality: vertebrate polymerase beta (same as yeast pol 4), and terminal deoxynucleotidyl-transferase (TdT) (). The former functions in DNA repair, while
the latter terminally adds single nucleotides to polydeoxynucleotide chains.Both enzymes catalyse addition of nucleotides in a distributive manner, i.e. they
dissociate from the template-primer after addition of each nucleotide.DNA-polymerases show a degree of structural similarity with RNA-polymerases.
This entry includes a highly conserved region that contains a conserved arginine and two conserved aspartic acid residues. These residues have been shown to be involved in primer binding in polymerase beta [
]. |
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| Protein Domain |
| Name: |
CYTH domain |
| Type: |
Domain |
| Description: |
The entry represents the CYTH domain. The bacterial CyaB like adenylyl cyclase and the mammalian thiamine triphosphatases (ThTPases) define a superfamily of catalytic domains called the CYTH (CyaB, thiamine triphosphatase) domain that is present in all three superkingdoms of life [
]. Proteins containing this domain act on triphosphorylated substrates and require at least one divalent metal cation for catalysis []. The catalytic core of the CYTH domain is predicted to contain an alpha+beta
scaffold with 6 conserved β-strands and 6 conserved α-helices. The CYTHdomains contains several nearly universally conserved charged residues that
are likely to form the active site. The most prominent of these are an EXEXKmotif associated with strand-1 of the domain, two basic residues in helix-2, a
K at the end of strand 3, an E in strand 4, a basic residue in helix-4, a D atthe end of strand 5 and two acidic residues (typically glutamates) in strand
6. The presence of around 6 conserved acidic positions in the majority of theCYTH domains suggests that it coordinates two divalent metal ions. Both CyaB
and ThTPase have been shown to require Mg(2+) ions for their nucleotidecyclase and phosphatase activities. The four conserved basic residues in the
CYTH domain are most probably involved in the binding of acidic phosphatemoieties of their substrates. The conservation of these two sets of residues
in the majority of CYTH domains suggests that most members of this group arelikely to possess an activity dependent on two metal ions, with a preference
for nucleotides or related phosphate-moiety -bearing substrates. The proposedbiochemical activity, and the arrangement of predicted strands in the primary
structure of the CYTH domain imply that they may adopt a barrel or sandwich-like configuration, with metal ions and the substrates bound in the central
cavity []. |
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| Protein Domain |
| Name: |
Citrate synthase, eukaryotic-type |
| Type: |
Family |
| Description: |
Citrate synthase
is a member of a small family of enzymes that can directly form a carbon-carbon bond without the presence of metal ion cofactors. It catalyses the first reaction in the Krebs' cycle, namely the conversion of oxaloacetate and acetyl-coenzyme A into citrate and coenzyme A. This reaction is important for energy generation and for carbon assimilation. The reaction proceeds via a non-covalently bound citryl-coenzyme A intermediate in a 2-step process (aldol-Claisen condensation followed by the hydrolysis of citryl-CoA).
Citrate synthase enzymes are found in two distinct structural types: type I enzymes (found in eukaryotes, Gram-positive bacteria and archaea) form homodimers and have shorter sequences than type II enzymes, which are found in Gram-negative bacteria and are hexameric in structure. In both types, the monomer is composed of two domains: a large α-helical domain consisting of two structural repeats, where the second repeat is interrupted by a small α-helical domain. The cleft between these domains forms the active site, where both citrate and acetyl-coenzyme A bind. The enzyme undergoes a conformational change upon binding of the oxaloacetate ligand, whereby the active site cleft closes over in order to form the acetyl-CoA binding site [
]. The energy required for domain closure comes from the interaction of the enzyme with the substrate. Type II enzymes possess an extra N-terminal β-sheet domain, and some type II enzymes are allosterically inhibited by NADH [].This entry includes both mitochondrial and peroxisomal forms of citrate synthase. Peroxisomal forms of the enzyme, recognised by the C-terminal targeting motif SKL, act in the glyoxylate cycle. Eukaryotic homologues include a Tetrahymena thermophila citrate synthase that doubles as a filament protein, a putative citrate synthase from Plasmodium falciparum (no TCA cycle), and a methylcitrate synthase from Emericella nidulans (Aspergillus nidulans). |
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| Protein Domain |
| Name: |
Methionyl-tRNA synthetase |
| Type: |
Family |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].Methionine-tRNA ligase (
) is an alpha 2 dimer. In some species (archaea, eubacteria and eukaryotes) a coding sequence, similar to the C-terminal end of MetRS, is present as an independent gene which is a tRNA binding domain as a dimer. In eubacteria, MetRS can also be split in two sub-classes corresponding to the presence of one or two CXXC domains specific to zinc binding. The crystal structures of a number of methionine-tRNA ligases are known [
,
,
]. |
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| Protein Domain |
| Name: |
Aminoacyl-tRNA synthetase, class I, anticodon-binding domain, subdomain 2 |
| Type: |
Homologous_superfamily |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].Structurally, an α-helix-bundle anticodon-binding domain characterises the class Ia synthetases, whereas the class Ib synthetases, GlnRS and GluRS have distinct anticodon-binding domains. The anticodon-binding domain has a multi-helical structure, consisting of two all-alpha subdomains. The Rossmann-fold, made up of alternate α-helices and β-sheets involved in ATP binding in the extended conformation, and the anticodon-binding domains are connected by a beta-α-α-beta-alpha topology ('SC fold') domain that contains the class I specific KMSKS motif [
,
]. |
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| Protein Domain |
| Name: |
Aminoacyl-tRNA synthetase, class I, anticodon-binding superfamily |
| Type: |
Homologous_superfamily |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].Structurally, an α-helix-bundle anticodon-binding domain characterises the class Ia synthetases, whereas the class Ib synthetases, GlnRS and GluRS have distinct anticodon-binding domains. The anticodon-binding domain has a multi-helical structure, consisting of two all-alpha subdomains. The Rossmann-fold, made up of alternate α-helices and β-sheets involved in ATP binding in the extended conformation, and the anticodon-binding domains are connected by a beta-α-α-beta-alpha topology ('SC fold') domain that contains the class I specific KMSKS motif [
,
]. |
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| Protein Domain |
| Name: |
3-phosphoshikimate 1-carboxyvinyltransferase, conserved site |
| Type: |
Conserved_site |
| Description: |
This entry represents 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase (also known as 3-phosphoshikimate 1-carboxyvinyltransferase), catalyses the sixth step in the biosynthesis from chorismate of the aromatic amino acids (the shikimate pathway) in bacteria (gene aroA), plants and fungi (where it is part of a multifunctional enzyme which catalyses five consecutive steps in this pathway) [
]. The sixth step is the formation of EPSP and inorganic phosphate from shikimate-3-phosphate (S3P) and phosphoenolpyruvate (PEP).EPSP can use shikimate or shikimate-3-phosphate as a substrate. By binding shikimate, the backbone of the active site is changed, which affects the binding of glyphosate and renders the reaction insensitive to inhibition by glyphosate [
]. On isolation of the discontinuous C-terminal domain, it was found that it binds neither its substrate nor its inhibitor but maintains structural integrity [
].Earlier studies suggested that the active site of the enzyme is in the cleft between its two globular domains. When the enzyme binds S3P, there is a conformational change in the isolated N-terminal domain [
]. The sequence of EPSP from various biological sources shows that the structure of the enzyme has been well conserved throughout evolution and since the shikimate pathway is not present in vertebrates but is essential for the life of plants, fungi and bacteria; it is commonly viewed as a target for weed killers and antimicrobial drug development.This entry represents two conserved regions as signature patterns. The first pattern corresponds to a region that is part of the active site and which is also important for the resistance to glyphosate [
]. The second pattern is located in the C-terminal part of the protein and contains a conserved lysine which seems to be important for the activity of the enzyme. |
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| Protein Domain |
| Name: |
Pyruvate kinase, barrel |
| Type: |
Domain |
| Description: |
Pyruvate kinase (
) (PK) catalyses the final step in glycolysis [
,
], the conversion of phosphoenolpyruvate to pyruvate with concomitant phosphorylation of ADP to ATP:ADP + phosphoenolpyruvate = ATP + pyruvate The enzyme, which is found in all living organisms, requires both magnesium and potassium ions for its activity. In vertebrates, there are four tissue-specific isozymes: L (liver), R (red cells), M1 (muscle, heart and brain), and M2 (early foetal tissue). In plants, PK exists as cytoplasmic and plastid isozymes, while most bacteria and lower eukaryotes have one form, except in certain bacteria, such as Escherichia coli, that have two isozymes. All isozymes appear to be tetramers of identical subunits of ~500 residues.PK helps control the rate of glycolysis, along with phosphofructokinase (
) and hexokinase (
). PK possesses allosteric sites for numerous effectors, yet the isozymes respond differently, in keeping with their different tissue distributions [
]. The activity of L-type (liver) PK is increased by fructose-1,6-bisphosphate (F1,6BP) and lowered by ATP and alanine (gluconeogenic precursor), therefore when glucose levels are high, glycolysis is promoted, and when levels are low, gluconeogenesis is promoted. L-type PK is also hormonally regulated, being activated by insulin and inhibited by glucagon, which covalently modifies the PK enzyme. M1-type (muscle, brain) PK is inhibited by ATP, but F1,6BP and alanine have no effect, which correlates with the function of muscle and brain, as opposed to the liver.The structure of several pyruvate kinases from various organisms have been determined [
,
,
]. The protein comprises three-four domains: a small N-terminal helical domain (absent in bacterial PK), a β/α-barrel domain, a β-barrel domain (inserted within the β/α-barrel domain), and a 3-layer α/β/α sandwich domain.This entry represents the two barrel domains, the β/α-barrel, and the β-barrel inserted within it. |
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| Protein Domain |
| Name: |
Pyruvate kinase |
| Type: |
Family |
| Description: |
Pyruvate kinase (
) (PK) catalyses the final step in glycolysis [
,
], the conversion of phosphoenolpyruvate to pyruvate with concomitant phosphorylation of ADP to ATP:ADP + phosphoenolpyruvate = ATP + pyruvate The enzyme, which is found in all living organisms, requires both magnesium and potassium ions for its activity. In vertebrates, there are four tissue-specific isozymes: L (liver), R (red cells), M1 (muscle, heart and brain), and M2 (early foetal tissue). In plants, PK exists as cytoplasmic and plastid isozymes, while most bacteria and lower eukaryotes have one form, except in certain bacteria, such as Escherichia coli, that have two isozymes. All isozymes appear to be tetramers of identical subunits of ~500 residues.PK helps control the rate of glycolysis, along with phosphofructokinase (
) and hexokinase (
). PK possesses allosteric sites for numerous effectors, yet the isozymes respond differently, in keeping with their different tissue distributions [
]. The activity of L-type (liver) PK is increased by fructose-1,6-bisphosphate (F1,6BP) and lowered by ATP and alanine (gluconeogenic precursor), therefore when glucose levels are high, glycolysis is promoted, and when levels are low, gluconeogenesis is promoted. L-type PK is also hormonally regulated, being activated by insulin and inhibited by glucagon, which covalently modifies the PK enzyme. M1-type (muscle, brain) PK is inhibited by ATP, but F1,6BP and alanine have no effect, which correlates with the function of muscle and brain, as opposed to the liver.The structure of several pyruvate kinases from various organisms have been determined [
,
,
]. The protein comprises three-four domains: a small N-terminal helical domain (absent in bacterial PK), a β/α-barrel domain, a β-barrel domain (inserted within the β/α-barrel domain), and a 3-layer α/β/α sandwich domain. |
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| Protein Domain |
| Name: |
Pyruvate kinase, insert domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Pyruvate kinase (
) (PK) catalyses the final step in glycolysis [
,
], the conversion of phosphoenolpyruvate to pyruvate with concomitant phosphorylation of ADP to ATP:ADP + phosphoenolpyruvate = ATP + pyruvate The enzyme, which is found in all living organisms, requires both magnesium and potassium ions for its activity. In vertebrates, there are four tissue-specific isozymes: L (liver), R (red cells), M1 (muscle, heart and brain), and M2 (early foetal tissue). In plants, PK exists as cytoplasmic and plastid isozymes, while most bacteria and lower eukaryotes have one form, except in certain bacteria, such as Escherichia coli, that have two isozymes. All isozymes appear to be tetramers of identical subunits of ~500 residues.PK helps control the rate of glycolysis, along with phosphofructokinase (
) and hexokinase (
). PK possesses allosteric sites for numerous effectors, yet the isozymes respond differently, in keeping with their different tissue distributions [
]. The activity of L-type (liver) PK is increased by fructose-1,6-bisphosphate (F1,6BP) and lowered by ATP and alanine (gluconeogenic precursor), therefore when glucose levels are high, glycolysis is promoted, and when levels are low, gluconeogenesis is promoted. L-type PK is also hormonally regulated, being activated by insulin and inhibited by glucagon, which covalently modifies the PK enzyme. M1-type (muscle, brain) PK is inhibited by ATP, but F1,6BP and alanine have no effect, which correlates with the function of muscle and brain, as opposed to the liver.The structure of several pyruvate kinases from various organisms have been determined [
,
,
]. The protein comprises three-four domains: a small N-terminal helical domain (absent in bacterial PK), a β/α-barrel domain, a β-barrel domain (inserted within the β/α-barrel domain), and a 3-layer α/β/α sandwich domain.This superfamily represents the β-barrel domain (note: it does not include the β/α-barrel it is inserted into). |
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| Protein Domain |
| Name: |
DNA topoisomerase VI, subunit A |
| Type: |
Family |
| Description: |
DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type II topoisomerases are ATP-dependent enzymes, and can be subdivided according to their structure and reaction mechanisms: type IIA (topoisomerase II or gyrase, and topoisomerase IV) and type IIB (topoisomerase VI). These enzymes are responsible for relaxing supercoiled DNA as well as for introducing both negative and positive supercoils [
].This entry represents subunit A of topoisomerase VI, a type IIB topoisomerase found predominantly in archaea, but also in a few eukayotes, such as the plant Arabidopsis thaliana [
]. This enzyme assembles as a heterotetramer, consisting of two A subunits required for DNA cleavage and two B subunits required for ATP hydrolysis. The B subunit is structurally similar to the ATPase domain of type IIA topoisomerases, but the A subunit is distinct, and instead shares homology with the Spo11 protein that mediates double-strand DNA breaks during meiotic recombination in eukaryotes []. The core of subunit A is a dimer, with a deep groove in which the DNA molecule is thought to bind, with the monomers separating during DNA transport. Therefore, though related to type IIA topoisomerases, topoisomerase VI may have a distinctive mechanism of action. |
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| Protein Domain |
| Name: |
DNA-directed DNA polymerase, family B, multifunctional domain |
| Type: |
Domain |
| Description: |
DNA is the biological information that instructs cells how to exist in an ordered fashion: accurate replication is thus one of the most important events in the life cycle of a cell. This function is performed by DNA- directed DNA-polymerases
) by adding nucleotide triphosphate (dNTP) residues to the 5'-end of the growing chain of DNA, using a complementary DNA chain as a template. Small RNA molecules are generally used as primers for chain elongation, although terminal proteins may also be used for the de novo synthesis of a DNA chain. Even though there are 2 different methods of priming, these are mediated by 2 very similar polymerases classes, A and B, with similar methods of chain elongation.
A number of DNA polymerases have been grouped under the designation of DNA polymerase family B. Six regions of similarity (numbered from I to VI) are found in all or a subset of the B family polymerases. The most conserved region (I) includes a conserved tetrapeptide with two aspartate residues. Its function is not yet known, however, it has been suggested that it may be involved in binding a magnesium ion. All sequences in the B family contain a characteristic DTDS motif, and possess many functional domains, including a 5'-3' elongation domain, a 3'-5' exonuclease domain [], a DNA binding domain, and binding domains for both dNTP's and pyrophosphate []. The DNA polymerase structure resembles a right hand with fingers, palm, and thumb, with an active site formed by a palm holding the catalytic residues, a thumb that binds the primer:template DNA and fingers interacting with incoming nucleotide, and the N and Exo domains extend from the finger toward the thumb [
,
,
].This domain of DNA polymerase B appears to consist of more than one activities, possibly including elongation, DNA-binding and dNTP binding [
]. |
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| Protein Domain |
| Name: |
Prolyl-tRNA synthetase, class II |
| Type: |
Homologous_superfamily |
| Description: |
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].Proline tRNA ligase (also known as Prolyl tRNA synthetase) (
) exists in two forms, which are loosely related. The first form is present in the majority of eubacteria species. The second one, present in some eubacteria, is essentially present in archaea and eukaryota. Proline-tRNA ligase belongs to class IIa.
This superfamily represents a domain found at the C-terminal in archaeal and eukaryotic enzymes, as well as in certain bacterial ones. |
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| Protein Domain |
| Name: |
Proline-tRNA ligase, class II, C-terminal |
| Type: |
Domain |
| Description: |
Proline tRNA ligase (also known as Prolyl tRNA synthetase) (
) exists in two forms, which are loosely related. The first form is present in the majority of eubacteria species. The second one, present in some eubacteria, is essentially present in archaea and eukaryota. Proline-tRNA ligase belongs to class IIa.
This domain is found at the C-terminal in archaeal and eukaryotic enzymes, as well as in certain bacterial ones.The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [
]. |
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| Protein Domain |
| Name: |
LacI-type HTH domain |
| Type: |
Domain |
| Description: |
The lacI-type HTH domain is a DNA-binding, helix-turn-helix (HTH) domain of
about 50-60 residues present in the lacI/galR family of transcriptionalregulators involved in metabolic regulation in prokaryotes. Most of these
bacterial regulators recognize sugar-inducers. The family is named after theEscherichia coli lactose operon repressor lacI and galactose operon repressor
galR. LacI-type regulators are present in diverse bacterial genera, in thecytoplasm. The 'helix-turn-helix' DNA-binding motif is located in the
N-terminal extremity of these transcriptional regulators. The C-terminal partof lacI-type regulators contains several regions that can be involved in (1)
binding of inducers, which are sugars and their analogues and (2)oligomerization. The lac repressor is a tetramer, whilst the gal and cyt
repressors are dimers. LacI-type transcriptional regulators are important inthe coordination of catabolic, metabolic and transport operons [
,
].Several structures of lacI-type transcriptional regulators have been resolved
and their DNA-binding domain encompasses a headpiece, formed by a fold ofthree helices, followed by a hinge region, which can form a fourth α-helix
or hinge-helix. The helix-turn-helix motif comprises thefirst and second helices, the second being called the recognition helix. The
HTH is involved in DNA-binding into the major groove, while the hinge-helixfits into the minor groove and the complete domain specifically recognizes the
operator DNA [].Some proteins known to contain a lacI-type HTH domain:Bacillus subtilis ccpA and ccpB, transcriptional regulators involved in
the catabolic repression of several operons.Salmonella typhimurium fruR, the fructose repressor, involved in the
regulation of a large number of operons encoding enzymes which take part incentral pathways of carbon metabolism.Escherichia coli lacI, the lactose operon repressor, serving as a model for
gene regulation.Escherichia coli purF and purR, repressors involved in the regulation of
enzymes for purine nucleotide synthesis.Haemophilus influenzae galR, a repressor of the galactose operon. |
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