| Type |
Details |
Score |
| Protein Domain |
| Name: |
Tumour necrosis factor receptor 19 |
| 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 19, also known as toxicity and JNK inducer (TAJ) and TROY, is highly expressed during embryonic development, where it may act as a regulator of cell activation and cell death [
]. In adult tissues, the receptor is expressed in the central nervous system, and may mediate the inhibitory effects of myelin upon axon regeneration []. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 11 |
| 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 []. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 25 |
| 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 25 (alternatively known as death receptor 3 (DR3) and lymphocyte-associated receptor of death (LARD) is expressed primarily on the surface of thymocytes and lymphocytes [
]. The receptor contains a death domain in its C-terminal region, and acts as a key regulator of life/death decisions during thymocyte development []. |
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| Protein Domain |
| Name: |
Ephrin receptor ligand binding domain |
| Type: |
Domain |
| Description: |
The Eph receptors, which bind a group of cell-membrane-anchored ligands known
as ephrins, represent the largest subfamily of receptor tyrosine kinases(RTKs). The Eph receptors and their ephrin ligands control a
diverse array of cell-cell interactions in the nervous and vascular systems.On ephrin binding, the Eph kinase domain is activated, initiating 'forward'
signaling in the receptor-expressing cells. Simultaneously, signals are alsoinduced in the ligand-expressing cells a phenomenon referred to as 'reverse'
signalling. The extracellular Eph receptor region contains a conserved 180-amino-acid N-terminal ligand-binding domain (LBD) which is both necessary and
sufficient for bindings of the receptors to their ephrin ligands. An adjacentcysteine-rich region might be involved in receptor-receptor oligomerization
often observed on ligand binding, whereas the next two fibronectin type IIIrepeats have yet to be assigned a clear biological function.
The cytoplasmic Eph receptor region contains a kinase domain, a sterile alpha motif (SAM) domain, and a PDZ-binding motif. The ligand-binding domain (LBD) of Eph receptors is unique tothis family of RTKs ans shares no significant amino-acid-sequence homology
with other known proteins [,
,
].The Eph LBD domain forms a compact globular structure which folds into ajellyroll β-sandwich composed of 11 antiparallel β-strands. It has two antiparallel β-sheets, with the usual left-handed
twist, packed against each other to form a compact β-sandwich, and a short3(10) helix [
,
,
]. |
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| Protein Domain |
| Name: |
Proteasome subunit alpha6 |
| Type: |
Family |
| Description: |
The proteasome (or macropain) (
) [
,
,
,
,
] is a multicatalytic proteinase complex in eukaryotes and archaea, and in some bacteria, that is involved in an ATP/ubiquitin-dependent non-lysosomal proteolytic pathway. In eukaryotes the 20S proteasome is composed of 28 distinct subunits which form a highly ordered ring-shaped structure (20S ring) of about 700kDa. Proteasome subunits can be classified on the basis of sequence similarities into two groups, alpha (A) and beta (B). The proteasome consists of four stacked rings composed of alpha/beta/beta/alpha subunits. There are seven different alpha subunits and seven different beta subunits []. Three of the seven beta subunits are peptidases, each with a different specificity. Subunit beta1c (MEROPS identifier T01.010) has a preference for cleaving glutaminyl bonds ("peptidyl-glutamyl-like"or "caspase-like"), subunit beta2c (MEROPS identifier T01.011) has a preference for cleaving arginyl and lysyl bonds ("trypsin-like"), and subunit beta5c (MEROPS identifier T01.012) cleaves after hydrophobic amino acids ("chymotrypsin-like") [
]. The proteasome subunits are related to N-terminal nucleophile hydrolases, and the catalytic subunits have an N-terminal threonine nucleophile.This entry includes the non-proteolytic alpha6 subunit of the 19S proteasome (MEROPS identifier T01.971). The equivalent subunit in Saccharomyces cerevisiae is known as alpha1. A single nuclear polymorphism is associated with a higher risk of myocardial infarction in a Japanese population, possibly because of an increased risk of atherosclerosis [
]. |
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| Protein Domain |
| Name: |
Restriction endonuclease, type II, CfrBI |
| Type: |
Family |
| Description: |
Type II restriction endonucleases (
) are components of prokaryotic DNA restriction-modification mechanisms that protect the organism against invading foreign DNA. These site-specific deoxyribonucleases catalyse the endonucleolytic cleavage of DNA to give specific double-stranded fragments with terminal 5'-phosphates. Of the 3000 restriction endonucleases that have been characterised, most are homodimeric or tetrameric enzymes that cleave target DNA at sequence-specific sites close to the recognition site. For homodimeric enzymes, the recognition site is usually a palindromic sequence 4-8 bp in length. Most enzymes require magnesium ions as a cofactor for catalysis. Although they can vary in their mode of recognition, many restriction endonucleases share a similar structural core comprising four β-strands and one α-helix, as well as a similar mechanism of cleavage, suggesting a common ancestral origin [
]. However, there is still considerable diversity amongst restriction endonucleases [,
]. The target site recognition process triggers large conformational changes of the enzyme and the target DNA, leading to the activation of the catalytic centres. Like other DNA binding proteins, restriction enzymes are capable of non-specific DNA binding as well, which is the prerequisite for efficient target site location by facilitated diffusion. Non-specific binding usually does not involve interactions with the bases but only with the DNA backbone []. This entry includes the CfrBI restriction endonuclease which recognises and cleaves C^CWWGG [
]. |
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|
| Protein Domain |
| Name: |
Tumour necrosis factor receptor 1B |
| 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 1B (also known as TNF-R2 and CD120b antigen) is present on many cell types, especially those of myeloid origin, and is strongly expressed on stimulated T and B lymphocytes. It is the main TNF receptor found on circulating T cells and is the major mediator of autoregulatory apoptosis in CD8+ cells []. |
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| Protein Domain |
| Name: |
Na(+)-translocating NADH-quinone reductase subunit E |
| 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 the Na(+)-translocating E subunit from NADH:ubiquinone oxidoreductase. NADH can be oxidized by the respiratory chain of bacteria via NADH:quinone oxidoreductases that belong to three distinct enzyme families: NDH-1, NDH-2, and NQR. The NQR-type enzymes are sodium-motive NADH:quinone oxidoreductases consisting of six subunits (NqrA-F) and several cofactors: FAD, 2 FMN, a 2Fe-2S cluster and riboflavin. The NADH:quinone oxidoreductase activity of these enzymes is stimulated by sodium ions and is coupled with pumping of Na+ but not H+. Subunits NqrA, NqrC and NqrF represent the three major subunits of the NQR complex, which are alpha, gamma and beta, respectively. Subunits NqrB, NqrD and NqrE are very hydrophobic polypeptides that were found to co-localise with the alpha subunit []. |
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| Protein Domain |
| Name: |
Aldo-keto reductase family 5C1 |
| Type: |
Family |
| Description: |
This entry represents aldo-keto reductase family 5C1 (AKR5C1), including DkgA from Corynebacterium sp. DkgA catalyses the reduction of 2,5-diketo-D-gluconic acid (25DKG) to 2-keto-L-gulonic acid (2KLG). 5-keto-D-fructose and dihydroxyacetone can also serve as substrates [
,
].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 5G |
| Type: |
Family |
| Description: |
This entry represents aldo-keto reductase family 5G (AKR5G), including glyoxal reductase (GR) and uncharacterised oxidoreductase YtbE from Bacillus subtilis [
]. GR reduces glyoxal and methylglyoxal (2-oxopropanal). It is not involved in vitamin B6 biosynthesis [].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: |
Transcription factor Otx1 |
| Type: |
Family |
| Description: |
Otx proteins constitute a class of vertebrate homeodomain-containing
transcription factors that have been shown to be essential for anteriorhead formation, including brain morphogenesis. They are orthologous to the
product of the Drosophila head gap gene, orthodenticle (Otd), and appear toplay similar roles in both, since the developmental abnormalities caused by
disruption of these transcription factors in one, can be recovered bysubstitution of the factor(s) from the other. Such studies have provided
strong evidence that there exists a conserved genetic programme for insectand mammalian brain development, which presumably arose in a more primitive
common ancestor [,
].Two vertebrate orthodenticle-related transcription factors have been
indentified, Otx1 and Otx2, which have sizes of 355 and 289 residuesrespectively. They contain a bicoid-like homeodomain, which features a
conserved lysine residue at position 9 of the DNA recognition helix, whichis thought to confer high-affinity binding to TAATCC/T elements on DNA [
].Otd-like transcription factors have also been found in zebrafish and
certain lamprey species. Studies of mice lacking Otx1 (due to targeted gene disruption) have shed light on its role in development, such mice showing impaired corticogenesis and sense organ development. Phenotypic abnormalities noted in the cerebral cortices include reduced cell proliferation and total cell number, together with disruption of the formation of the normally well-ordered cortical cell layers, which are characteristic of these structures. Abnormalities are also observed in the eye and inner ear. |
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| Protein Domain |
| Name: |
S-adenosylmethionine synthetase, domain 3 |
| Type: |
Homologous_superfamily |
| Description: |
S-adenosylmethionine synthetase (MAT,
) is the enzyme that catalyzes the formation of S-adenosylmethionine (AdoMet) from methionine and ATP [
]. AdoMet is an important methyl donor for transmethylation and is also the propylamino donor in polyamine biosynthesis.In bacteria there is a single isoform of AdoMet synthetase (gene metK), there are two in budding yeast (genes SAM1 and SAM2) and in mammals while in plants there is generally a multigene family.The sequence of AdoMet synthetase is highly conserved throughout isozymes and species. The active sites of both the Escherichia coli and rat liver MAT reside between two subunits, with contributions from side chains of residues from both subunits, resulting in a dimer as the minimal catalytic entity. The side chains that contribute to the ligand binding sites are conserved between the two proteins. In the structures of complexes with the E. coli enzyme, the phosphate groups have the same positions in the (PPi plus Pi) complex and the (ADP plus Pi) complex and are located at the bottom of a deep cavity with the adenosyl group nearer the entrance [
].This superfamily represents the C-terminal domain found in S-adenosylmethionine synthase. Structurally, this domain consists of 6 beta strands and 3 alpha helices. Within S-adenosylmethionine synthetase, the domain is not made up a contiguous polypeptide chain, and has some residues contributed from regions away from the C-terminal. |
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| Protein Domain |
| Name: |
Phospholamban |
| Type: |
Family |
| Description: |
Phospholamban (PLB) is a small protein (52 amino acids) that regulates the affinity of the cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) for calcium. PLB is present in cardiac myocytes, in slow-twitch and smooth muscle and is expressed also in aorta endothelial cells in which it could play a role in tissue relaxation. The phosphorylation/dephosphorylation of phospholamban removes and restores, respectively, its inhibitory activity on SERCA2a. It has in fact been shown that phospholamban, in its non-phosphorylated form, binds to SERCA2a and inhibits this pump by lowering its affinity for Ca
2+, whereas the phosphorylated form does not exert the inhibition. PLB is phosphorylated at two sites, namely at Ser-16 for a
cAMP-dependent phosphokinase and at Thr-17 for a Ca2+/calmodulin-dependent phosphokinase, phosphorylation at Ser-16 being a prerequisite for the phosphorylation at Thr-17.
The structure of a 36-amino-acid-long N-terminal fragment of human phospholamban phosphorylated at Ser-16 and Thr-17 and Cys36Ser mutated was determined from nuclear magnetic resonance data. The peptide assumes a conformation characterised by two α-helices connected by an irregular strand, which
comprises the amino acids from Arg-13 to Pro-21. The proline is in a trans conformation. The two phosphate groups on Ser-16 and Thr-17 are shown to interact preferably with the side chains of Arg-14 and Arg-13, respectively [].Mutations of the phospholamban gene cause cardiomyopathy, such as Cardiomyopathy, dilated 1P (CMD1P) [
,
] and Cardiomyopathy, familial hypertrophic 18 (CMH18) []. |
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| Protein Domain |
| Name: |
Alpha-amylase, domain C |
| Type: |
Domain |
| Description: |
Alpha-amylase is classified as family 13 of the glycosyl hydrolases and is present in archaea, bacteria, plants and animals. Alpha-amylase is an essential enzyme in alpha-glucan metabolism, acting to catalyse the hydrolysis of alpha-1,4-glucosidic bonds of glycogen, starch and related polysaccharides. Although all alpha-amylases possess the same catalytic function, they can vary with respect to sequence. In general, they are composed of three domains: a TIM barrel containing the active site residues and chloride ion-binding site (domain A), a long loop region inserted between the third beta strand and the α-helix of domain A that contains calcium-binding site(s) (domain B), and a C-terminal β-sheet domain that appears to show some variability in sequence and length between amylases (domain C) []. Amylases have at least one conserved calcium-binding site, as calcium is essential for the stability of the enzyme. The chloride-binding functions to activate the enzyme, which acts by a two-step mechanism involving a catalytic nucleophile base (usually an Asp) and a catalytic proton donor (usually a Glu) that are responsible for the formation of the beta-linked glycosyl-enzyme intermediate. This domain is found at the C-terminal of various fungal alpha-amylase proteins. It has been identified as a secondary binding site, which might be part of a starch interaction site [
,
]. It has a β-sandwich fold comprising an antiparallel β-sheet with eight strands. |
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| Protein Domain |
| Name: |
Glycosyltransferase, activator-dependent family |
| Type: |
Family |
| Description: |
Many biosynthesis clusters for secondary metabolites feature a glycosyltransferase gene next to a P450 homologue, often with the P450 lacking a critical heme-binding Cys. These P540-derived sequences seem to be allosteric activators of glycosyltransferases such as the member of this family. This entry represents a set of related glycosyltransferases, many of which can be recognised as activator-dependent from genomic context. Proteins in this entry include:3-alpha-mycarosylerythronolide B desosaminyl transferase eryCIII from Saccharopolyspora erythraea. It catalyzes the conversion of alpha-L-mycarosylerythronolide B into erythromycin D in the erythromycin biosynthesis pathway [
].Aclacinomycin-T 2-deoxy-L-fucose transferase AknK from Streptomyces galilaeus. It is involved in the biosynthesis of the trisaccharide moiety characteristic of the antitumor drug aclacinomycins [
]. Aklavinone 7-beta-L-rhodosaminyltransferase AknS from Streptomyces galilaeus. It is involved in the biosynthesis of the anthracycline antitumor agent aclacinomycin A [
]. Tylactone mycaminosyltransferase from Streptomyces fradiae. It is involved in the biosynthesis of the macrolide antibiotic tylosin derived from the polyketide lactone tylactone [
]. Erythronolide mycarosyltransferase EryBV from Saccharopolyspora erythraea. It is involved in the biosynthesis of the macrolide antibiotic erythromycin [
]. TDP-daunosamine transferase DnrS from Streptomyces peucetius. It is involved in the biosynthesis of the anthracyclines carminomycin and daunorubicin (daunomycin) which are aromatic polyketide antibiotics that exhibit high cytotoxicity and are widely applied in the chemotherapy of a variety of cancers [
]. |
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| Protein Domain |
| Name: |
DNA fragmentation factor 40, C-terminal |
| Type: |
Domain |
| Description: |
Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans [
]. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.DNA fragmentation factor (DFF) is a complex of the DNase DFF40 (CAD) and its chaperone/inhibitor DFF45 (ICAD-L). In its inactive form, DFF is a heterodimer composed of a 45kDa chaperone inhibitor subunit (DFF45 or ICAD), and a 40kDa latent endonuclease subunit (DFF40 or CAD). Upon caspase-3 cleavage of DFF45, DFF40 forms active endonuclease homo-oligomers. It is activated during apoptosis to induce DNA fragmentation. DNA binding by DFF is mediated by the nuclease subunit, which can also form stable DNA complexes after release from DFF [
,
]. The nuclease subunit is inhibited in DNA cleavage but not in DNA binding []. DFF45 can also be cleaved and inactivated by caspase-7 but not by caspase-6 and caspase-8. The cleaved DFF45 fragments dissociate from DFF40, allowing DFF40 to oligomerise, forming a large complex that cleaves DNA by introducing double strand breaks. Histone H1 confers DNA binding ability to DFF and stimulates the nuclease activity of DFF40 [
]. |
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| Protein Domain |
| Name: |
TraI, 2B/2B-like domain |
| Type: |
Domain |
| Description: |
This is the 2B and 2B-like sub-domain found in TraI, a relaxase of F-family plasmids. It contains four domains: a trans-esterase domain that executes the nicking and covalent attachment of the T-strand to the relaxase, a vestigial helicase domain (carrying the 2B/2B-like sub-domain) that operates as an ssDNA-binding domain, an active 5' to 3' helicase domain, and a C-terminal domain that functions as a recruitment platform for relaxosome components. The 2B sub-domains in TraI are formed by residues 625-773 in the vestigial helicase domain and residues 1255-1397 in the active helicase domain. The 2B/2B-like sub-domain interacts with ssDNA where it contributes to the surface area where ssDNA bind. In other words, the ssDNA-binding site is located in a groove between the 2B and 2B-like parts of the sub-domain. The sub-domain parts appear to act as clamps holding the ssDNA in place, resulting in the ssDNA being completely surrounded by protein. In previous studies, the 2B/2B-like sub-domain of the TraI vestigial helicase domain has been identified as translocation signal A (TSA) since it contains sequences essential for the recruitment of TraI to the T4S system. Thus, the 2B/2B-like sub-domain plays two major roles in relaxase function: (1) interacting with the DNA and possibly promoting high processivity and (2) mediating recruitment of the relaxosome to the T4S system [
]. |
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| Protein Domain |
| Name: |
Long hematopoietin receptor, soluble alpha chain, conserved site |
| Type: |
Conserved_site |
| Description: |
A number of receptors for lymphokines, hematopoietic growth factors and growth hormone-related molecules have been found to share a common binding domain. These receptors are designated as hematopoietin receptors [
] and the corresponding ligands as hematopoietins. Further, hematopoietins have been subdivided into two major structural groups: Large/long and small/short hematopoietins.One subset of individual receptor chains that are part of receptor complexes for large hematopoietins contain common structural elements in their extracellular parts: an immunoglobulin-like domain at the N-terminal end of the hematopoietin receptor domain (except for the EBCV-induced interleukin-12
beta chain) and a short (or no) cytoplasmic domain. They define a structural subgroup containing the following chains: Interleukin-6 receptor alpha chain (IL6RA). Interleukin-11 receptor alpha chain (IL11RA), Ciliary neurotrophic factor receptor alpha chain (CNTFRA), Interleukin-12 beta chain p40 (IL12BC), Interleukin-12 beta chain induced by Epstein-Barr virus (strain GD1) (HHV-4) (Human herpesvirus 4).Members of this subgroup bind to their cognate cytokines with low affinity and possess transmembrane and short cytoplasmic domains (IL6RA and IL11RA), or are GPi-linked membrane proteins (CNTFRA). Truncated soluble forms of IL-6 and CNTF receptors alpha chains are physiologically active [
]. IL-12 is an heterodimeric cytokine made of an alpha chain (p35) and a beta chain (p40). p40 (IL12BC) can be regarded as an alpha chain receptor devoid of cytoplasmic domain []. Members of this family have the ability to bind corresponding cytokines with no signalling function. |
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| Protein Domain |
| Name: |
Photosynthetic reaction centre, H subunit, N-terminal |
| Type: |
Domain |
| 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 represents the N-terminal domain of the photosynthetic reaction centre H subunit, which includes the transmembrane domain and part of the cytoplasmic domain [
]. |
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| Protein Domain |
| Name: |
Photosynthetic reaction centre, H subunit, N-terminal domain superfamily |
| Type: |
Homologous_superfamily |
| 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 represents the N-terminal domain superfamily of the photosynthetic reaction centre H subunit, which includes the transmembrane domain and part of the cytoplasmic domain [
]. |
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| Protein Domain |
| Name: |
NADH:ubiquinone oxidoreductase, chain 2 |
| 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 2 (ND2 or chain 2) from NADH:ubiquinone oxidoreductase (complex I). Defects in the ND2 gene are one of the causes of Leber's hereditary optic neuropathy, a maternally inherited disease resulting in acute bilateral blindness due to retinal degeneration, predominantly in young men [,
]. Cardiac conduction defects and neurological defects have also been described, resulting in optic nerve degeneration and cardiac dysrhythmia []. The clinical manifestations of this disease are thought to be the product of an overall decrease in mitochondrial energy production, rather than the result of a defect in a specific mitochondrial enzyme []. Further research has shown that a point mutation in ND2 is a potential risk factor for Alzheimer's disease []. |
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| Protein Domain |
| Name: |
Voltage gated sodium channel, alpha-5 subunit |
| Type: |
Family |
| 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 [
,
,
].The SCN5A gene encodes the NaH1 channel and is expressed in cardiac muscle,
foetal skeletal muscle and denervated adult skeletal muscle. Mutationsin the SCN5A gene affect the function of NaH1 channels in the heart and areone of the three causes of Long QT syndrome, an inherited cardiac arrhythmia
that can cause abrupt loss of consciousness, seizures and sudden death []; it is also associated with Brugada syndrome [
] and conduction systemdisease [
]. |
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| Protein Domain |
| Name: |
Eukaryotic molybdopterin oxidoreductase |
| Type: |
Family |
| Description: |
A number of different eukaryotic oxidoreductases that require and bind a molybdopterin cofactor have been shown [
] to share a few regions of sequence similarity. These enzymes include xanthine dehydrogenase (), aldehyde oxidase (
), nitrate reductase (
), and sulphite oxidase (
). The multidomain redox
enzyme NAD(P)H:nitrate reductase (NR) catalyses the reduction of nitrate to nitrite in a single polypeptide electron transport chain with electron flow from NAD(P)H-FAD-cytochrome b5-molybdopterin-NO(3). Three forms of NR are known, an NADH-specific enzyme found in higher plants and algae (
); an NAD(P)H-bispecific enzyme found in higher plants,
algae and fungi (); and an NADPH-specific enzyme found only in fungi (
) [
]. The mitochondrial enzyme sulphite oxidase (sulphite:ferricytochrome c oxidoreductase; ) catalyses oxidation of
sulphite to sulphate, using cytochrome c as the physiological electron acceptor. Sulphite oxidase consists of two structure/function domains, an N-terminal haem domain, similar to cytochrome b5; and a C-terminal molybdopterin domain [
].Despite functional parallels, members of the family show no sequence similarity to the C-terminal molybdopterin domain of xanthine dehydrogenase, although xanthine dehydrogenase, nitrate reductases and sulphite oxidase all
contain the eukaryotic molybdopterin oxidoreductases signature. Sequence comparison suggests that only a single Cys residue (Cys186 in chicken sulphite oxidase), is invariant in all these enzymes, indicating that it may play a role in binding molybdopterin to the protein [
,
]. |
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| Protein Domain |
| Name: |
Endonuclease III, iron-sulphur binding site |
| Type: |
Binding_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 MutY recognises 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. The structures 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 the Fe4S4 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 is referred to as a Fe4S4 cluster loop (FCL) []. Two DNA-binding motifs have been proposed, one at either end of the interdomain groove: the helix-hairpin-helix (HhH) region (see ) and FCL motif, described in this entry. 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 of the FCL motif [
,
]. This signature pattern covers the four Cys residues that act as 4Fe-4S ligands. |
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| Protein Domain |
| Name: |
Peptidase S33 |
| 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 a group of serine peptidase belonging to peptidase family S33 (clan SC). They include prolinases (Pro-Xaa dipeptidase,
), prolyl aminopeptidases (
), and L-amino acid amidases.
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| Protein Domain |
| Name: |
3'5'-cyclic nucleotide phosphodiesterase PDE8 |
| Type: |
Domain |
| Description: |
The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They are divided into 11 families. They regulate the localisation, duration and amplitude of cyclic nucleotide signalling within subcellular domains. PDEs are therefore important for signal transduction.PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors include: Roflumilast for chronic obstructive pulmonary disease and asthma [
], Sildenafil for erectile dysfunction [] and Cilostazol for peripheral arterial occlusive disease [], amongst others.Retinal 3',5'-cGMP phosphodiesterase is located in photoreceptor outer segments: it is light activated, playing a pivotal role in signal transduction. In rod cells, PDE is oligomeric, comprising an alpha-, a beta- and 2 gamma-subunits, while in cones, PDE is a homodimer of alpha chains, which are associated with several smaller subunits. Both rod and cone PDEs catalyse the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5' monophosphates, both enzymes also binding cGMP with high affinity. The cGMP-binding sites are located in the N-terminal half of the protein sequence, while the catalytic core resides in the C-terminal portion.This region is found at the N terminus of members of PDE8 phosphodiesterase family [
]. Phosphodiesterase 8 (PDE8) regulates chemotaxis of activated lymphocytes []. |
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| Protein Domain |
| Name: |
Galanin |
| Type: |
Domain |
| Description: |
Galanin is a peptide hormone that controls various biological activities [
]. Galanin-like immuno-reactivity has been found in the central and peripheral nervous systems of mammals, with high concentrations demonstrated in discrete regions of the central nervous system, including the median eminence, hypothalamus, arcuate nucleus, septum, neuro-intermediate lobe of the pituitary, and the spinal cord. Its localisation within neurosecretory granules suggests that galanin may function as a neurotransmitter, and it has been shown to coexist with a variety of other peptide and amine neurotransmitters within individual neurons [].Although the precise physiological role of galanin is uncertain, it has a number of pharmacological properties: it stimulates food intake, when injected into the third ventricle of rats; it increases levels of plasma growth hormone and prolactin, and decreases dopamine levels in the median eminence [
]; and infusion into humans results in hyperglycemia and glucose intolerance, and inhibits pancreatic release of insulin, somatostatin and pancreatic peptide. Galanin also modulates smooth muscle contractility within the gastro-intestinal and genito-urinary tracts, all such activities suggesting that the hormone may play an important role in the nervous modulation of endocrine and smooth muscle function [].Galanin is a 29 amino acid peptide processed from a larger precursor protein. Except in human, galanin is C-terminally amidated. Its sequence is highly conserved and the first 14 residues are identical in all currently known sequences. |
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| Protein Domain |
| Name: |
Caspase-8, death effector domain 1 |
| Type: |
Domain |
| Description: |
Caspase-8 (MEROPS identifier C14.009) is a cytoplasmic cysteine endopeptidase with a preference for aspartyl bonds, acing at neutral pH [
]. It is active as a homodimer or as a heterodimer in association with the long isoform of FLICE, and proteolytic processing of the caspase-8 precursor is required for stabilisation of the dimer [,
,
]. It is one of the activator caspases. Caspase-8 has a strict requirement for Asp in P1, a preference for Glu in P3 and small residues in P1' []. The caspase-8 proenzyme has two N-terminal death effector domains which are removed upon activation along with a linker region between the large and small subunits of the C-terminal catalytic domain. The death inducing signalling complex, composed of a transmembrane death receptor and the adapter protein FADD assembles at the cell membrane following binding of a death ligand. Procaspase-8 is recruited to this complex, and becomes active by dimerisation. Active caspase-8 can then activate the executioner caspases -3 and -7 [].Caspase-8 cleaves RIPK1, which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response. In humans, non-cleavable RIPK1 leads to autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response [
,
].This entry represents the first repeat of the Death effector domain (DED1) found at the N-terminal end of CASP8. This domain plays a unique structural role. |
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| Protein Domain |
| Name: |
Cobalamin-dependent methionine synthase |
| Type: |
Family |
| Description: |
Cobalamin (vitamin B12) dependent methionine synthase
(MetH; 5-methyltetrahydrofolate--homocysteine S-methyltransferase) catalyses the conversion of 5-methyltetrahydrofolate and L-homocysteine to tetrahydrofolate and L-methionine as the final step in
de novomethionine biosynthesis. The enzyme requires methylcobalamin as a cofactor. In humans, defects in this enzyme are the cause of autosomal recessive inherited methylcobalamin deficiency (CBLG), which causes mental retardation, macrocytic anemia and homocystinuria. Mild deficiencies in activity may result in mild hyperhomocysteinemia, and mutations in the enzyme may be involved in tumorigenesis. Vitamin B12 dependent methionine synthase is found in prokaryotes and eukaryotes, but in prokaryotes the cofactor is cobalamin.This enzyme is a large protein composed of four structurally and functionally distinct modules: the first two modules bind homocysteine and tetrahydrofolate [
], the third module binds the B12 cofactor [], and the C-terminal module (activation domain) binds S-adenosylmethionine. The activation domain is essential for the reductive activation of the enzyme. During the catalytic cycle, the highly reactive cob(I)alamin intermediate can be oxidised to produce an inactive cob(II)alamin enzyme; the enzyme is then reactivated via reductive methylation by the activation domain []. The activation domain adopts an unusual alpha/beta fold.Recent studies suggest that this enzyme exists as an ensemble of conformations with equilibria dependent on the oxidation and methylation state of the cobalamin and on the concentrations of substrates or products []. |
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| Protein Domain |
| Name: |
Trypanosome sialidase |
| Type: |
Family |
| Description: |
Trypanosoma cruzi is a kinetoplastid protozoan parasite of humans and other animals, the causative agent of Chagas disease. It is transmitted via an insect vector, and exists as an intracellular form, the amastigote, or as a trypomastigote form in the blood after infection. In the human host, chronic infection by T. cruzi affects the nervous system and heart,
leading to various neurological disorders, damage to the heart muscle andeventually death.The parasite expresses a variety of virulence factors in order to successfully invade the mammalian or insect host. One of these is unique to the genus Trypanosoma, a sialic acid-metabolising enzyme, dubbed "trans-sialidase"[
], classified as a member of glycosyl hydrolase family 33. The protein catalyses the transfer of host cell sialic acids to acceptor receptors on the protozoan cell membrane, allowing the parasite to evade the immune response and enter the cell undetected. It also acts as the major 85kDa surface antigen of T. cruzi, and exhibits neuraminidase activity similar to that of some pathogenic viruses [].Research into the gene has revealed a massive diversity in the expression of this surface antigen/sialidase [
]. The variation in its amino acid sequences begs the question why such a successful parasite should need so many different versions of the same virulence factor.In addition to Trypanosoma spp., this entry also matches a number of bacterial sialidases. |
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| Protein Domain |
| Name: |
Cobaltochelatase subunit CobS |
| Type: |
Family |
| Description: |
These sequences are related to the Pseudomonas denitrificans CobS gene product, which is a cobalt chelatase subunit of MW ~37kDa [
] that functions in cobalamin biosynthesis. Cobalamin (vitamin B12) can be synthesized via several pathways, including an aerobic pathway (found in P. denitrificans) and an anaerobic pathway (found in Salmonella typhimurium). These pathways differ in the point of cobalt insertion during corrin ring formation []. There are apparently a number of variations on these two pathways, where the major differences seem to be concerned with the process of ring contraction []. Confusion regarding the functions of enzymes found in the aerobic vs. anaerobic pathways has arisen because nonhomologous genes in these different pathways were given the same gene symbols. Thus, cobS in the aerobic pathway (P. denitrificans) is not a homologue of cobS in the anaerobic pathway (S. typhimurium). It should be noted that Escherichia coli synthesizes cobalamin only when it is supplied with the precursor cobinamide, which is a complex intermediate. Additionally, all E. coli cobalamin synthesis genes (cobU, cobS and cobT) were named after their S. typhimurium homologues which function in the anaerobic cobalamin synthesis pathway []. The aerobic pathway cobalt chelatase is a heterotrimeric, ATP-dependent enzyme that catalyzes cobalt insertion during cobalamin biosynthesis. The other two subunits are the P. denitrificans CobT () and CobN (
CobN/magnesium chelatase) proteins.
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 3, N-terminal |
| Type: |
Domain |
| Description: |
Tumor necrosis factor receptor superfamily member 3 (TNFRSF3, also known as lymphotoxin beta receptor, LTbetaR, CD18, TNFCR, TNFR3, D12S370, TNFR-RP, TNFR2-RP, LT-BETA-R, TNF-R-III) plays a role in lipid metabolism, immune response, programmed cell death, and in signaling during development of lymphoid and other organs [
,
]. Its ligands include lymphotoxin (LT) alpha/beta membrane form (heterotrimer) and tumor necrosis factor ligand superfamily member 14 (also known as LIGHT) []. TNFRSF3 agonism by these ligands initiates canonical, as well as non-canonical nuclear factor-kappaB (NF-kappaB) signaling, and preferentially results in the translocation of p52-RELB complexes into the nucleus []. While these ligands are often expressed by T and B cells, TNFRSF3 is conspicuously absent on T and B lymphocytes and NK cells, suggesting that signaling may be unidirectional for TNFRSF3 []. Activity of this receptor has also been linked to carcinogenesis; it helps trigger apoptosis and can also lead to release of the interleukin 8 (IL8) [,
]. Alternatively spliced transcript variants encoding multiple isoforms have been observed.This entry represents the N-terminal domain of TNFRSF3. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [
,
,
]. |
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| Protein Domain |
| Name: |
Coenzyme A transferase family I |
| Type: |
Family |
| Description: |
Coenzyme A (CoA) transferases belong to an evolutionary conserved [
,
] family of enzymes catalyzing the reversible transfer of CoA from one carboxylic acid to another. They have been identified in many prokaryotes and in mammalian tissues. The bacterial enzymes are heterodimer of two subunits (A and B) of about 25 Kd each while eukaryotic SCOT consist of a single chain which is colinear with the two bacterial subunits.CoA-transferases are found in organisms from all kingdoms of life. They catalyse reversible transfer reactions of coenzyme A groups from CoA-thioesters to free acids. There are at least three families of CoA-transferases, which differ in sequence and reaction mechanism:Family I consists of CoA-transferases for 3-oxoacids (
,
), short-chain fatty acids (
,
) and glutaconate (
). Most use succinyl-CoA or acetyl-CoA as CoA donors.
Family II consists of the homodimeric alpha-subunits of citrate lyase and citramalate lyase (
,
). These enzymes catalyse the transfer of acyl carrier protein (ACP) with a covalently bound CoA derivative, but can accept free CoA thioesters as well.
Family III consists of formyl-CoA:oxalate CoA-transferase [
], succinyl-CoA:(R)-benzylsuccinate CoA-transferase [], (E)-cinnamoyl-CoA:(R)-phenyllactate CoA-transferase [], succinyl-CoA:mesaconate CoA-transferase [] and butyrobetainyl-CoA:(R)-carnitine CoA-transferase []. These CoA-transferases occur in prokaryotes and eukaryotes, and catalyse CoA-transfer reactions in a highly substrate- and stereo-specific manner [].This family consists of 3-oxoacid CoA-transferases and related CoA-transferases from family I. |
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| Protein Domain |
| Name: |
Hotdog acyl-CoA thioesterase (ACOT)-type domain |
| Type: |
Domain |
| Description: |
The HotDog domain is widespread in eukaryotes, bacteria, and archaea and is
involved in a range of cellular processes, from thioester hydrolysis, tophenylacetic acid degradation and transcriptional regulation of fatty acid
biosynthesis. The HotDog domain has a mixed alpha+beta fold structure, whichadopts a five- to seven-stranded antiparallel β-sheet as the 'bun' wrapping
around a central α-helix sausage [].The largest HotDog domain subfamily represents over a hundred acyl-CoA
thioesterases (ACOTs) that are widespread throughout the prokaryotic kingdom,with members also found in eukaryotes. This group of enzymes catalyze the
hydrolysis of acyl-CoA thioesters to free fatty acids and coenzyme A (CoA-SH). The subfamily includes thioesterases with activity towards medium and
long chain acyl-CoAs (medium chain acyl-CoA hydrolase and cytosolic long-chainacyl-CoA hydrolase/brain acyl-CoA hydrolase (BACH) respectively) and also
cytoplasmic acetyl-CoA hydrolase (CACH), which hydrolyzes acetyl-CoA toacetate and CoA-SH. Brown-fat-inducible thioesterase (BFIT), a cold-induced
protein found in brown adipose tissue (BAT) is also included in this group.Both BFIT and CACH possess a StAR-related lipid-transfer (START) domain that is involved in lipid binding, consistent with the role of
BFIT and CACH in lipid metabolism. Duplication of the HotDog domain andrecruitment of the START domain seems to be a mammalian innovation [
].The HotDog ACOT-type domain consists of a five-stranded β-sheet with
topology beta1/beta3/beta4/beta5/beta2 that wraps around a central five-turnalpha helix, alpha1, positioned between beta1 and beta2
[,
,
]. |
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| Protein Domain |
| Name: |
MAP3K, PH domain |
| Type: |
Domain |
| Description: |
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [
].This PH-like domain is found in the regulatory region of ASK1/2/3 (also known as MAP3K5/6/15). The central regulatory region of ASK1 mediates a compact arrangement of the kinase and thioredoxin-binding domains which allows the binding of substrates for phosphorylation. This PH-like domain adopts the typical form of two antiparallel β-sheets followed by a C-terminal amphipathic helix [
]. |
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| Protein Domain |
| Name: |
Nuclear cap-binding complex subunit CBP30 |
| Type: |
Family |
| Description: |
In protozoa of the family Trypanosomatidae RNA polymerase II (Pol II) generates polycistronic pre-mRNAs which are then processed by trans-splicing and polyadenylation to produce monocistronic mature mRNAs. Trans-splicing transfers the 39-nucleotide (nt)-long capped spliced leader (SL) from the SL RNA to the 5' end of mRNAs. The mRNA cap in these organisms has the unusual feature of containing, in addition to 7-methylguanosine, four modified nucleotides making it by definition a cap 4 structure (m7equation M2AmpAmpCmpm3Um) which appears to be conserved across this family. This highly modified cap is essential for utilisation of the SL RNA during the trans-splicing process, a key event in RNA metabolism [
,
]. In yeast and human cells, nuclear cap binding complexes (CBCs) consists of two subunits, cap binding proteins 20 and 80 (CBP20 and CBP80), the first being highly conserved from yeast to humans and contains an RNA binding motif. In Trypanosomatidae family, this complex consists of five subunits, the highly conserved CBP20 subunit, an alpha-importin which imports the complex from the cytoplasm similar to the yeast and human counterparts and three subunits that appear to be unique for this family of organisms, namely CBP30, CBP66 and CBP110 []. The CBC complex in trypanosomatids are essential for cell viability.This entry represents the CBP30 subunit of the trypanasome nuclear cap-binding complex. CBP30 is part of the complex that recognises this cap. |
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| Protein Domain |
| Name: |
Nuclear cap-binding complex subunit CBP110 |
| Type: |
Family |
| Description: |
In protozoa of the family Trypanosomatidae RNA polymerase II (Pol II) generates polycistronic pre-mRNAs which are then processed by trans-splicing and polyadenylation to produce monocistronic mature mRNAs. Trans-splicing transfers the 39-nucleotide (nt)-long capped spliced leader (SL) from the SL RNA to the 5' end of mRNAs. The mRNA cap in these organisms has the unusual feature of containing, in addition to 7-methylguanosine, four modified nucleotides making it by definition a cap 4 structure (m7equation M2AmpAmpCmpm3Um) which appears to be conserved across this family. This highly modified cap is essential for utilisation of the SL RNA during the trans-splicing process, a key event in RNA metabolism [
,
]. In yeast and human cells, nuclear cap binding complexes (CBCs) consists of two subunits, cap binding proteins 20 and 80 (CBP20 and CBP80), the first being highly conserved from yeast to humans and contains an RNA binding motif. In Trypanosomatidae family, this complex consists of five subunits, the highly conserved CBP20 subunit, an alpha-importin which imports the complex from the cytoplasm similar to the yeast and human counterparts and three subunits that appear to be unique for this family of organisms, namely CBP30, CBP66 and CBP110 [
]. The CBC complex in trypanosomatids are essential for cell viability.This entry represents the CBP110 subunit of the trypanasome nuclear cap-binding complex. CBP110 is part of the complex that recognises this cap. |
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| Protein Domain |
| Name: |
Nuclear hormone receptor |
| Type: |
Family |
| Description: |
Steroid or nuclear hormone receptors (NRs) constitute an important superfamily of transcription regulators that are involved in widely diverse physiological functions, including control of embryonic development, cell differentiation and homeostasis. Members of the superfamily include the steroid hormone receptors and receptors for thyroid hormone, retinoids, 1,25-dihydroxy-vitamin D3 and a variety of other ligands [
]. The proteins function as dimeric molecules in nuclei to regulate the transcription of target genes in a ligand-responsive manner [,
]. In addition to C-terminal ligand-binding domains, these nuclear receptors contain a highly-conserved, N-terminal zinc-finger that mediates specific binding to target DNA sequences, termed ligand-responsive elements. In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity.NRs are extremely important in medical research, a large number of them being implicated in diseases such as cancer, diabetes, hormone resistance syndromes, etc. While several NRs act as ligand-inducible transcription factors, many do not yet have a defined ligand and are accordingly termed 'orphan' receptors. During the last decade, more than 300 NRs have been described, many of which are orphans, which cannot easily be named due to current nomenclature confusions in the literature. However, a new system has recently been introduced in an attempt to rationalise the increasingly complex set of names used to describe superfamily members. |
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| Protein Domain |
| Name: |
Photosystem I PsaJ, reaction centre subunit IX |
| Type: |
Family |
| Description: |
Oxygenic photosynthesis uses two multi-subunit photosystems (I and II) located in the cell membranes of cyanobacteria and in the thylakoid membranes of chloroplasts in plants and algae. Photosystem II (PSII) has a P680 reaction centre containing chlorophyll 'a' that uses light energy to carry out the oxidation (splitting) of water molecules, and to produce ATP via a proton pump. Photosystem I (PSI) has a P700 reaction centre containing chlorophyll that takes the electron and associated hydrogen donated from PSII to reduce NADP+ to NADPH. Both ATP and NADPH are subsequently used in the light-independent reactions to convert carbon dioxide to glucose using the hydrogen atom extracted from water by PSII, releasing oxygen as a by-product.This family consists of the photosystem I reaction centre subunit IX or PsaJ from various organisms including Synechocystis sp. (strain PCC 6803), Pinus thunbergii (Japanese black pine) and Zea mays (Maize). PsaJ (
) is a small 4.4kDa, chloroplast encoded, hydrophobic subunit of the photosystem I reaction complex whose function is not yet fully understood [
]. PsaJ can be cross-linked to PsaF () and has a single predicted transmembrane domain. It may help in the organization of the PsaE and PsaF subunits. It has a proposed role in maintaining PsaF in the correct orientation to allow for fast electron transfer from soluble donor proteins to P700+ [
]. |
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| Protein Domain |
| Name: |
Aldo-keto reductase family 2D |
| Type: |
Family |
| Description: |
This entry represents aldo-keto reductase family 2D (AKR2D), including NAD(P)H-dependent D-xylose reductase xyl1 from Aspergillus niger. Xyl1 catalyses the initial reaction in the xylose utilization pathway by reducing D-xylose into xylitol in a NAD(P)H dependent manner [
].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 3C1 |
| Type: |
Family |
| Description: |
This entry represents aldo-keto reductase family 3C1 (AKR3C1), including Ara1 from Saccharomyces cerevisiae. Ara1 catalyses the oxidation of D-arabinose, L-xylose, L-fucose and L-galactose in the presence of NADP [
,
].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 3G |
| Type: |
Family |
| Description: |
This entry represents aldo-keto reductase family 3G, including slr094 from Synechocystis sp. Slr094 is an aldo/keto reductase that catalyses the NADPH-dependent reduction of aldehyde- and ketone-groups of different classes of carbonyl compounds to the corresponding alcohols [
].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: |
CHASE domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
The CHASE domain is an extracellular domain of 200-230 amino acids, which is found in transmembrane receptors from bacteria, lower eukaryotes and plants. It has been named CHASE (Cyclases/Histidine kinases Associated Sensory Extracellular) because of its presence in diverse receptor-like proteins with histidine kinase and nucleotide cyclase domains. The CHASE domain always occurs N-terminally in extracellular or periplasmic locations, followed by an intracellular tail housing diverse enzymatic signalling domains such as histidine kinase (
), adenyl cyclase, GGDEF-type nucleotide cyclase and EAL-type phosphodiesterase domains, as well as non-enzymatic domains such PAS (
), GAF (
), phosphohistidine and response regulatory domains. The CHASE domain is predicted to bind diverse low molecular weight ligands, such as the cytokinin-like adenine derivatives or peptides, and mediate signal transduction through the respective receptors [
,
].The CHASE domain has a predicted alpha+beta fold, with two extended alpha helices on both boundaries and two central alpha helices separated by beta sheets. The termini are less conserved compared with the central part of the domain, which shows strongly conserved motifs.The N terminus of the AHK4 sensor module folds into a long stalk helix followed by two PAS-like domains which are connected by a helical linker. The last β-strand of the membrane-proximal PAS domain is covalently linked to the N terminus of the stalk helix by a disulphide bridge, bringing the flanking membrane helices into close proximity []. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 3 |
| 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 []. This entry represents tumour necrosis factor receptor superfamily member 3 (TNF receptor 3; also known as lymphotoxin-beta receptor). TNF receptor 3 acts as a receptor for the heterotrimer of lymphotoxin-alpha and beta, and also for the TNF ligand LIGHT. Activation of the receptor promotes apoptosis via recruitment of TNFR-associated factor 3 (TRAF3) [
]. |
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| Protein Domain |
| Name: |
Photosynthetic reaction centre, H 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 H subunit, which has a single transmembrane helix and a large cytoplasmic domain [
]. The core of the cytoplasmic domain has a PRC-barrel structure. |
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| Protein Domain |
| Name: |
HMW kininogen |
| Type: |
Family |
| Description: |
The kininogens are multidomain proteins, belonging to the Type 3 cystatin family [
]. It contains three tandemly repeated type 2-like cystatin domains of which only the second and third (D2 and D3) exhibit cysteine peptidase inhibitory activity, and which belong to MEROPS inhibitor family I25B. High molecular weight kininogen (HK) [
] is synthesised as a single polypeptide chain in the liver and secreted into the plasma, where it complexes with prekallikrein and factor XI. On cleavage by human plasma kallikrein, or factor XIIa, HK liberates bradykinin, which mimics inflammatory phenomena such as pain induction, vasodilation and increased vascular
permeability. Kallikrein- cleavage yields the nonapeptide bradykinin, together with a cleaved product containing an N-terminal heavy chain, bound to a C-terminal light chain by a single inter-chain disulphide bridge. Human kininogen maps to 3q26-qter [,
]. It is intravascular, found in blood plasma, and as a result of diffusion, in synovial and amniotic fluids. As cysteine peptidase inhibitors, the kininogens are the major source of inhibitory activity in the circulation, for systemic protection against leaking lysosomal cysteine peptidases or enzymes derived from invading micro-organisms []. This activity depends on a number of factors, including the binding of cleaved HK to anionic surfaces [], which is thought to be mediated through a His-Gly-rich region. Evidence has suggested that critical amino acid sequences within the His-Gly-rich region of HK serve as a primary structural feature for binding to a negatively charged surface []. |
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| Protein Domain |
| Name: |
Peptide methionine sulphoxide reductase MrsB domain |
| Type: |
Domain |
| Description: |
Peptide methionine sulphoxide reductase (Msr) reverses the inactivation of many proteins due to the oxidation of critical methionine residues by reducing methionine sulphoxide, Met(O), to methionine [
]. It is present in most living organisms, and the cognate structural gene belongs to the so-called minimum gene set [,
].The domains: MsrA and MsrB, reduce different epimeric forms of methionine sulphoxide. This group represents MsrB, the crystal structure of which has been determined to 1.8A [
]. The overall structure shows no resemblance to the structures of MsrA () from other organisms; though the active sites show approximate mirror symmetry. In each case, conserved amino acid motifs mediate the stereo-specific recognition and reduction of the substrate. Unlike the MsrA domain, the MsrB domain activates the cysteine or selenocysteine nucleophile through a unique Cys-Arg-Asp/Glu catalytic triad. The collapse of the reaction intermediate most likely results in the formation of a sulphenic or selenenic acid moiety. Regeneration of the active site occurs through a series of thiol-disulphide exchange steps involving another active site Cys residue and thioredoxin.
In a number of pathogenic bacteria, including Neisseria gonorrhoeae, the MsrA and MsrB domains are fused; the MsrA being N-terminal to MsrB. This arrangement is reversed in Treponema pallidum. In N. gonorrhoeae and Neisseria meningitidis, a thioredoxin domain is fused to the N terminus. This may function to reduce the active sites of the downstream MsrA and MsrB domains. |
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| Protein Domain |
| Name: |
Polymerase, nucleotidyl transferase domain |
| Type: |
Domain |
| Description: |
A small region that overlaps with a nuclear localization signal and binds to the RNA primer contains three aspartates that are essential for catalysis. Sequence and secondary structure comparisons of regions surrounding these aspartates with sequences of other polymerases revealed a significant homology to the palm structure of DNA polymerase beta, terminal deoxynucleotidyltransferase and DNA polymerase IV of Saccharomyces cerevisiae, all members of the family X of polymerases. This homology extends as far as cca: tRNA nucleotidyltransferase and streptomycin adenylyltransferase, an antibiotic resistance factor [
,
].Proteins containing this domain include kanamycin nucleotidyltransferase (KNTase) which is a plasmid-coded enzyme responsible for some types of bacterial resistance to aminoglycosides. KNTase inactivates antibiotics by catalysing the addition of a nucleotidyl group onto the drug. In experiments, Mn2+ strongly stimulated this reaction due to a 50-fold lower Ki for 8-azido-ATP in the presence of Mn2+. Mutations of the highly conserved
Asp residues 113, 115, and 167, critical for metal binding in the catalytic domain of bovine poly(A) polymerase, led to a strongreduction of cross-linking efficiency, and Mn2+ no longer stimulated the reaction. Mutations in the region of the "helical turn motif"(a domain binding the triphosphate moiety of the nucleotide) and in the suspected nucleotide-binding helix of bovine poly(A) polymerase
impaired ATP binding and catalysis. The results indicate that ATP is bound in part by the helical turn motif and in part by a region thatmay be a structural analogue of the fingers domain found in many polymerases. |
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| Protein Domain |
| Name: |
DNA topoisomerase, type IIA, alpha-helical domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Type IIA topoisomerases include the enzymes DNA gyrase, eukaryotic topoisomerase II (topo II), and bacterial topoisomerase IV (topo IV). Type IIA topoisomerases together manage chromosome integrity and topology in cells. 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 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.This superfamily represents a mainly alpha helical subdomain of eukaryotic topoisomerase II domain 3, also found in subunit A (gyrA and parC) of bacterial gyrase and topoisomerase IV. |
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| Protein Domain |
| Name: |
Nicotianamine synthase |
| Type: |
Family |
| Description: |
Nicotianamine synthase
catalyzes the trimerization of S-adenosylmethionine to yield one molecule of
nicotianamine. Nicotianamine has an important role in plant iron uptake mechanisms. Plants adopt two strategies (termed I and II) of iron acquisition. Strategy I is adopted by all higher plants except graminaceous plants, which adopt strategy II[
,
]. In strategy I plants, the role of nicotianamine is not fully determined: possible roles include the formation of morestable complexes with ferrous than with ferric ion, which might serve as a sensor of the physiological status of iron within
a plant, or which might be involved in the transport of iron []. In strategy II (graminaceous) plants, nicotianamine is thekey intermediate (and nicotianamine synthase the key enzyme) in the synthesis of the mugineic family (the only known
family in plants) of phytosiderophores. Phytosiderophores are iron chelators whose secretion by the roots is greatlyincreased in instances of iron deficiency [
].The 3D structures of five example NAS from Methanothermobacter thermautotrophicus reveal the monomer to consist of a five-helical bundle N-terminal domain on top of a classic Rossmann fold C-terminal domain. The N-terminal domain is unique to the NAS family, whereas the C-terminal domain is homologous to the class I family of SAM-dependent methyltransferases. An active site is created at the interface of the two domains, at the rim of a large cavity that corresponds to the nucleotide binding site such as is found in other proteins adopting a Rossmann fold [
]. |
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| Protein Domain |
| Name: |
DNA polymerase A |
| 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 most important events in the cell life cycle. This function is mediated by DNA-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. DNA-dependent DNA polymerases have been grouped into families, denoted A, B and X, on the basis of sequence similarities [
,
]. Members of family A, which includes bacterial and bacteriophage polymerases, share significant similarity to Escherichia coli polymerase I; hence family A is also known as the pol I family. The bacterial polymerases also contain an exonuclease activity, which is coded for in the N-terminal portion. 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 (E. 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 [].This entry represents the DNA-polymerase A family. |
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| Protein Domain |
| Name: |
Methionyl/Leucyl tRNA synthetase |
| 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 entry represents the methionyl and leucyl tRNA synthetases, which are class I aminoacyl-tRNA synthetases. |
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| Protein Domain |
| Name: |
Chorismate synthase |
| Type: |
Family |
| Description: |
Chorismate synthase (CS; 5-enolpyruvylshikimate-3-phosphate phospholyase; 1-carboxyvinyl-3-phosphoshikimate phosphate-lyase; E.C. 4.2.3.5) catalyzes the seventh and final step in the shikimate pathway which is used in prokaryotes, fungi and plants for the biosynthesis of aromatic amino acids. It catalyzes the 1,4-trans elimination of the phosphate group from 5-enolpyruvylshikimate-3-phosphate (EPSP) to form chorismate which can then be used in phenylalanine, tyrosine or tryptophan biosynthesis. Chorismate synthase requires the presence of a reduced flavin mononucleotide (FMNH2 or FADH2) for its activity. Chorismate synthase from various sources shows a high degree of sequence conservation [
,
]. It is a protein of about 360 to 400 amino-acid residues.Depending on the capacity of these enzymes to regenerate the reduced form of FMN, chorismate synthases are divided into two groups: enzymes, mostly from plants and eubacteria, that sequester CS from the cellular environment, are monofunctional, while those that can generate reduced FMN at the expense of NADPH, such as found in fungi and the ciliated protozoan Euglena gracilis, are bifunctional, having an additional NADPH:FMN oxidoreductase activity. Recently, bifunctionality of the Mycobacterium tuberculosis enzyme (MtCS) was determined by measurements of both chorismate synthase and NADH:FMN oxidoreductase activities. Since shikimate pathway enzymes are present in bacteria, fungi and apicomplexan parasites (such as Toxoplasma gondii, Plasmodium falciparum, and Cryptosporidium parvum) but absent in mammals, they are potentially attractive targets for the development of new therapy against infectious diseases such as tuberculosis (TB) [
,
,
,
,
,
,
,
,
,
]. |
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| Protein Domain |
| Name: |
Methionyl/Valyl/Leucyl/Isoleucyl-tRNA synthetase, anticodon-binding |
| 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 methionyl, valyl, leucyl and isoleucyl tRNA synthetases. It binds to the anticodon of the tRNA. |
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| Protein Domain |
| Name: |
Aminoacyl-tRNA synthetase, class I, conserved site |
| Type: |
Conserved_site |
| 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 entry represents a conserved sequence in their N-terminal section of class I aminoacyl-tRNA synthetases. |
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| Protein Domain |
| Name: |
Aminoacyl-tRNA synthetase, class II (G/ P/ S/T) |
| 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 the core catalytic domain of tRNA synthetases and includes glycyl, prolyl, seryl and threonyl tRNA synthetases. |
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| Protein Domain |
| Name: |
Aminoacyl-tRNA synthetase, class II |
| 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 entry recognises all class-II enzymes except for heterodimeric glycyl-tRNA synthetases
and alanyl-
tRNA synthetases. |
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| Protein Domain |
| Name: |
Alanine-tRNA ligase, class IIc |
| Type: |
Family |
| Description: |
Alanine-tRNA ligase (also known as alanyl-tRNA synthetase) (
) is an alpha4 tetramer that belongs to class IIc.
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: |
Alanyl-tRNA synthetase, class IIc, core 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 [
].Alanine-tRNA ligase (also known as alanyl-tRNA synthetase) (
) is an alpha4 tetramer that belongs to class IIc.
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| Protein Domain |
| Name: |
Alanyl-tRNA synthetase, class IIc, 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 [].Alanine-tRNA ligase (also known as alanyl-tRNA synthetase) (
) is an alpha4 tetramer that belongs to class IIc.
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| Protein Domain |
| Name: |
Aminotransferase class IV |
| Type: |
Family |
| Description: |
Aminotransferases share certain mechanistic features with other pyridoxal-phosphate dependent enzymes, such as the covalent binding of the pyridoxal-phosphate group to a lysine residue. On the basis of sequence similarity, these various enzymes can be grouped [
] into subfamilies.This entry represents a subfamily of aminotransferases, called class-IV, with currently consists of proteins of about 270 to 415 amino-acid residues that share a few regions of sequence similarity. Surprisingly, the best conserved region does not include the lysine residue to which the pyridoxal-phosphate group is known to be attached, in ilvE, but is located some 40 residues at the C terminus side of the pyridoxal-phosphate-lysine. The D-amino acid transferases (D-AAT), which are among the members of this entry, are required by bacteria to catalyse the synthesis of D-glutamic acid and D-alanine, which are essential constituents of bacterial cell wall and are the building block for other D-amino acids. Despite the difference in the structure of the substrates, D-AATs and L-ATTs have strong similarity [
,
].This group also includes transaminase htyB from
Aspergillus rugulosus, which is one of the enzymes required for the biosynthesis of the antifungal agent echinocandin B. HtyB catalyses the production of L-homotyrosine from the intermediate 2-oxo-4-(4-hydroxybenzyl)butanoic acid [
]. Also included in this group is branched-chain amino acid aminotransferase gloG from the yeast Glarea lozoyensis, which is required for biosynthesis of the mycotoxin pneumocandin, also a lipohexapeptide of the echinocandin family [
]. |
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| Protein Domain |
| Name: |
DNA-directed DNA polymerase, family B, exonuclease 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 DNAchain 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 aremediated 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 regionsof 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 suggestedthat 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 [
]. This domain is the exonuclease domain of family B DNA polymerases. It adopts a ribonuclease H type fold [
]. |
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| Protein Domain |
| Name: |
Branched-chain amino acid aminotransferase II |
| Type: |
Family |
| Description: |
Aminotransferases share certain mechanistic features with other pyridoxal-phosphate dependent enzymes, such as the covalent binding of the pyridoxal-phosphate group to a lysine residue. On the basis of sequence similarity, these various enzymes can be grouped [
] into subfamilies.One of these, called class-IV, currently consists of proteins of about 270 to 415 amino-acid residues that share a few regions of sequence similarity. Surprisingly, the best conserved region does not include the lysine residue to which the pyridoxal-phosphate group is known to be attached, in ilvE, but is located some 40 residues at the C terminus side of the PlP-lysine.Among the class IV aminotransferases are two phylogenetically separable groups of branched-chain amino acid aminotransferase (IlvE) (
). The last common ancestor of the two lineages appears also to have given rise to a family of D-amino acid aminotransferases (DAAT). This model represents the IlvE family less similar to the DAAT family.
Also included in this group is branched-chain amino acid aminotransferase gloG from the yeast
Glarea lozoyensis, which is required for biosynthesis of the mycotoxin pneumocandin, a lipohexapeptide of the echinocandin family [
]. Transaminase AMT5 from the Alternaria rot fungus is one of many enzymes required for the non-ribosomal biosynthesis of the cyclic depsipeptides known as AM-toxins []. The aminotransferase FGSG_00049 from Fusarium graminearum is part of the gene cluster that mediates the biosynthesis of gramillins A and B, bicyclic lipopeptides that induce cell death in maize leaves but not in wheat, suggesting host-specific adaptation []. |
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| Protein Domain |
| Name: |
Aminoacyl-tRNA synthetase, class II (D/K/N) |
| 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 entry includes the asparagine, aspartic acid and lysine tRNA synthetases. |
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| Protein Domain |
| Name: |
MarR-type HTH domain |
| Type: |
Domain |
| Description: |
The MarR-type HTH domain is a DNA-binding, winged helix-turn-helix (wHTH) domain of about 135 amino acids present in transcription regulators of the MarR/SlyA family, involved in the development of antibiotic resistance. The MarR family of transcription regulators is named after Escherichia coli MarR, a repressor of genes which activate the multiple antibiotic resistance and oxidative stress regulons, and after slyA from Salmonella typhimurium and E. coli, a transcription regulator that is required for virulence and survival in
the macrophage environment. Regulators with the MarR-type HTH domain arepresent in bacteria and archaea and control a variety of biological functions,
including resistance to multiple antibiotics, household disinfectants, organicsolvents, oxidative stress agents and regulation of the virulence factor
synthesis in pathogens of humans and plants. Many of the MarR-like regulatorsrespond to aromatic compounds [
,
,
].The crystal structures of MarR, MexR and SlyA have been determined and show a winged HTH DNA-binding core flanked by helices involved in dimerisation. The DNA-binding domains are ascribed to the superfamily of winged
helix proteins, containing a three (four)-helix (H) bundle and a three-stranded antiparallel β-sheet (B) in the topology: H1-(H1')-H2-B1-H3-H4-B2-B3-H5-H6. Helices 3 and 4 comprise the helix-turn-helix motif and the β-sheet is called the wing. Helix 4 is termed the recognition helix, like in other HTHs where it binds the DNA major groove. The helices 1, 5 and 6 are involved in dimerisation, as most MarR-like transcription regulators form dimers [
,
]. |
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| Protein Domain |
| Name: |
Cysteinyl-tRNA synthetase, class Ia, DALR |
| 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 DALR domain is found in cysteinyl-tRNA-synthetases [
]. |
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| Protein Domain |
| Name: |
Lipid A biosynthesis lauroyl/palmitoleoyl acyltransferase |
| Type: |
Family |
| Description: |
Bacterial lipopolysachharides (LPS) are glycolipids that make up the outer monolayer of the outer membranes of most Gram-negative bacteria. Though LPS moleculesare variable, they all show the same general features: an outer polysaccharide which is attached to the lipid component, termed lipid A [
]. The polysaccharide component consists of a variable repeat-structure polysaccharide known as the O-antigen, and a highly conserved short core oligosaccharide which connects the O-antigen to lipid A. Lipid A is a glucosamine-based phospholipid that makes up the membrane anchor region of LPS []. The structure of lipid A is relatively invariant between species, presumably reflecting its fundamental role in membrane integrity. Recognition of lipid A by the innate immune system can lead to a response even at picomolar levels. In some genera, such as Neisseria and Haemophilus, lipooligosaccharides (LOS) are the predominant glycolipids []. These are analogous to LPS except that they lack O-antigens, with the LOS oligosaccharide structures limited to 10 saccharide units.This entry represents a narrow clade of acyltransferases, nearly all of which transfer a lauroyl group to KDO2-lipid IV-A, a lipid A precursor; these proteins are termed lipid A biosynthesis lauroyl acyltransferase, lpxL. An exception is a closely related paralog of E. coli lpxL, LpxP, which acts in cold shock conditions by transferring a palmitoleoyl rather than lauroyl group to the lipid A precursor. Members of this family are homologous to the family of acyltransferases responsible for the next step in lipid A biosynthesis [
]. |
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| Protein Domain |
| Name: |
Transcription factor, Brachyury |
| Type: |
Family |
| Description: |
The T-box gene family is an ancient group of putative transcription factors that appear to play a critical role in the development of all animal species.These genes were uncovered on the basis of similarity to the DNA binding domain [
] of murine Brachyury (T) gene product, which similarity is the defining feature of the family. The Brachyury gene is named for its phenotype, which was identified 70 years ago as a mutant mouse strain with a short blunted tail. The gene, and its paralogues, have become a well-studied model for the family, and hence much of what is known about the T-box family is derived from the murine Brachyury gene.Consistent with its nuclear location, Brachyury protein has a sequence-specific DNA-binding activity and can act as a transcriptional regulator [
]. Homozygous mutants for the gene undergo extensive developmental anomalies, thus rendering the mutation lethal []. The postulated role of Brachyury is as a transcription factor, regulating the specification and differentiation of posterior mesoderm during gastrulation in a dose-dependent manner [].Common features shared by T-box family members are, DNA-binding and transcriptional regulatory activity, a role in development and conserved expression patterns, most of the known genes in all species being expressed in mesoderm of mesoderm precursors [
]. Members of the T-box family contain a domain of about 170 to 190 amino acids known as the T-box domain [,
,
] and which probably binds DNA. |
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| Protein Domain |
| Name: |
HetR, flap domain |
| Type: |
Homologous_superfamily |
| Description: |
HetR is a DNA-binding serine-type protease required for heterocyst differentiation in the nitrogen-fixing cyanobacteria under conditions of nitrogen deprivation. The protein binds to a DNA palindrome upstream of hetP and other genes. The HetR monomer is composed of three distinct domains: the N-terminal domain which is involved in DNA binding, the middle domain designated the "flap", and a slightly smaller C-terminal domain designated the "hood"[
]. HetR forms a dimer upon DNA binding. That structure contains four distinct domains: an extended DNA-binding unit containing helix-turn-helix (HTH) motifs comprised of two canonical α-helices in the DNA-binding domain and an auxiliary α-helix from the flap domain of the neighboring subunit; two histidine-rich flaps protruding on either side of the extended structure; and finally a hood comprised of the two C-terminal sequences [,
]. The whole HetR dimer becomes more symmetric in the presence of DNA. Overall, the flap orientations are adjusted to provide a more extended interaction with the twofold symmetric DNA duplex.This entry represents the flap domain, or the middle domain, which interacts with the phosphate backbone of the DNA. It is composed of four α-helices, one helix, and a β-hairpin [
]. The beta hairpin in the flap domain runs along the minor groove of DNA. In the dimer, the two flap domains protrude away from the central N-terminal-C-terminal core structure. These domains are also in position to contact DNA, perhaps at the exterior phosphates, which could enhance the interaction with DNA throughout the length of HetR. |
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| Protein Domain |
| Name: |
Bacterial photosynthetic reaction centre, H-chain, C-terminal |
| Type: |
Homologous_superfamily |
| 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 superfamily represents the barrel domain of the H subunit from the photosynthetic reaction centre (PRC). The H subunit has a single transmembrane helix and a large cytoplasmic domain [
,
]. The core of the cytoplasmic domain contains the PRC-barrel. |
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| Protein Domain |
| Name: |
Corticotropin-releasing factor |
| Type: |
Domain |
| Description: |
This entry represents a domain found in the corticotropin-releasing factor family members. Corticotropin-releasing factor (CRF), urotensin-I, urocortin and sauvagine form a family of related neuropeptides in vertebrates. The family can be grouped into 2 separate paralogous lineages, with urotensin-I, urocortin and sauvagine in one group and CRF forming the other group. Urocortin and sauvagine appear to represent orthologues of fish urotensin-I in mammals and amphibians, respectively. The peptides have a variety of physiological effects on stress and anxiety, vasoregulation, thermoregulation, growth and metabolism, metamorphosis and reproduction in various species, and are all released as preprohormones [
].CRF [
] is a hormone found mainly in the paraventricular nucleus of the mammalian hypothalamus that regulates the release of corticotropin (ACTH) from the pituitary gland. From here, CRF is transported to the anterior pituitary, stimulating adrenocorticotropic hormone (ACTH) release via CRF type 1 receptors, thereby activating the hypothalamo-pituitary-adrenocortical axis (HPA) and thus glucocorticoid release.CRF is evolutionary related to a number of other active peptides. Urocortin acts in vitro to stimulate the secretion of adrenocorticotropic hormone. Urotensin is found in the teleost caudal neurosecretory system and may play a role in osmoregulation and as a corticotropin-releasing factor. Urotensin-I is released from the urophysis of fish, and produces ACTH and subsequent cortisol release in vivo. The nonhormonal portion of the prohormone is thought to be the urotensin binding protein (urophysin). Sauvagine (
), isolated from frog skin, has a potent hypotensive and diuretic effect.
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| Protein Domain |
| Name: |
Bifunctional nitroreductase/nicotinate-nucleotide-dimethylbenzimidazole, phosphoribosyltransferase |
| Type: |
Family |
| Description: |
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 [].This entry represents predicted bifunctional nitroreductase/nicotinate-nucleotide-dimethylbenzimidazole phosphoribosyltransferases. |
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| Protein Domain |
| Name: |
Adenylate kinase, active site lid domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Adenylate kinases (ADK;
) are phosphotransferases that catalyse the Mg-dependent reversible conversion of ATP and AMP to two molecules of ADP, an essential reaction for many processes in living cells. In large variants of adenylate kinase, the AMP and ATP substrates are buried in a domain that undergoes conformational changes from an open to a closed state when bound to substrate; the ligand is then contained within a highly specific environment required for catalysis. Adenylate kinase is a 3-domain protein consisting of a large central CORE domain flanked by a LID domain on one side and the AMP-binding NMPbind domain on the other [
]. The LID domain binds ATP and covers the phosphates at the active site. The substrates first bind the CORE domain, followed by closure of the active site by the LID and NMPbind domains.Comparisons of adenylate kinases have revealed a particular divergence in the active site lid. In some organisms, particularly the Gram-positive bacteria, residues in the lid domain have been mutated to cysteines and these cysteine residues (two CX(n)C motifs) are responsible for the binding of a zinc ion. The bound zinc ion in the lid domain is clearly structurally homologous to Zinc-finger domains. However, it is unclear whether the adenylate kinase lid is a novel zinc-finger DNA/RNA binding domain, or that the lid bound zinc serves a purely structural function [
].The ADK LID domain structure has a Rubredoxin-like fold, which consists of a metal (zinc or iron)-bound fold. |
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| Protein Domain |
| Name: |
Aspartate-semialdehyde dehydrogenase, peptidoglycan lacking |
| Type: |
Family |
| Description: |
Aspartate-semialdehyde dehydrogenase (
), the second enzyme in the aspartate pathway, converts aspartyl phosphate to aspartate-semialdehyde, the branch point intermediate between the lysine and threonine/methionine pathways. Based on sequence alignments, the aspartate-semialdehyde dehydrogenase family appears to have at least three distinct subfamilies. Most studies have been performed on enzymes isolated from Gram-negative bacteria [
,
,
,
]. The N-terminal domain forms the active site and NADP-binding pocket, while C-terminal domain is primarily involved in hydrophobic intersubunit contacts. The catalytic mechanism involves the formation of a covalent thioester acyl-enzyme intermediate mediated through nucleophilic attack by an active site cysteine residue on the substrate aspartyl phosphate. Release of inorganic phosphate is followed by hydride transfer from NADPH to yield the product. The recently described archaeal structure suggests that the two subgroups of aspartate semi-aldehyde dehydrogenase share similar structures and have an identical catalytic mechanism, despite their relatively low sequence identity []. Unlike the bacterial enzymes, the archaeal enzyme utilised both NAD and NADP as cofactor.This entry represents the subgroup of aspartate dehydrogenases found primarily in organisms lacking peptidoglycan. In addition to its role in aspartate metabolism, the enzyme from Sulfolobus solfataricus has been shown recently to exhibit RNase activity, suggesting that these enzymes may perform additional cellular functions [
].This entry also matches malonyl-CoA reductases from archaeal Metallosphaera and Sulfolobus spp, which have sequence identity to aspartate-semialdehyde dehydrogenase, suggesting a common ancestor for both proteins [
]. |
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| Protein Domain |
| Name: |
Propanediol/glycerol dehydratase, small subunit superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Diol dehydratase (
) and glycerol dehydratase (
) are two iso-functional enzymes that can each catalyse the conversion of 1,2-propanediol, 1,2-ethanediol and glycerol to the corresponding deoxy aldehydes (propionaldehyde, acetaldehyde and 3-hydroxypropionaldehyde, respectively). This reaction proceeds by a radical mechanism involving coenzyme B12 (adenosylcobalamin, AdoCbl) as an essential cofactor. Even though they catalyse the same reaction, these two enzymes (1) differ in their substrate preferences (diol dehydratase has a higher affinity for 1,2-propanediol and glycerol dehydratase for glycerol [
]); (2) they participate in different pathways (dihydroxyacetone [DHA]pathway for glycerol dehydratase and 1,2-propanediol degradation pathway for diol dehydratase); and (3) in those organisms where both enzymes are produced (such as Klebsiella and Citrobacter), the genes for them are independently regulated: glycerol dehydratase is induced when Klebsiella pneumoniae grows in glycerol-containing medium, whereas diol dehydratase is fully induced when it grows in propane-1,2-diol-containing medium, but only slightly in the glycerol medium [
,
]. Crystal structures, mechanism of action and structure-function relationship with the coenzyme B12 have been extensively studied for these enzymes [
]. Diol/glycerol dehydratases undergo inactivation during catalysis and require a reactivating factor. Propanediol dehydratase was found to be associated with and is believed to be encased in the proteinaceous shell of polyhedral organelles [].Both diol dehydratase and glycerol dehydratase comprise three subunits: PduC/PduD/PduE or PddA/PddB/PddC for propanediol dehydratase, and GldA/Gld/B/GldC or DhaB/DhaC/DhaE for glycerol dehydratase. This entry represents the small subunit PduE/PddC/GldC/DhaE. The structure of dehydratase consists of three helices. |
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| Protein Domain |
| Name: |
Nicotinate-nucleotide-dimethylbenzimidazole phosphoribosyltransferase, archaeal type |
| Type: |
Family |
| Description: |
This entry represents the archaeal-type nicotinate-nucleotide-dimethylbenzimidazole phosphoribosyltransferases.
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: |
CspA-like domain |
| Type: |
Domain |
| Description: |
This entry includes the peptidase domain of the subtilisin homologues CspA (MEROPS identifier S08.159), CspB (MEROPS identifier S08.108) and CspC (MEROPS identifier S08.158) from Clostridium species. These peptidases are important for the initiation of spore germination by activation of the hydrolase hydrolase SleC, which degrades the protective cortex layer of the spore, allowing it to germinate. In Clostridium perfringens, all three subtilisin homologues are active peptidases, but in C. difficile, CspA and CspC are described as "pseudopeptidases"[
], because active site residues have been mutated. In C. difficile, dormant spores are activated by the binding of bile salts, especially taurocholate, to CspC. SleC is activated by a CspA/CspB fusion protein [].This domain is part of a family of domains found in serine peptidases belonging to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin)) and S53 (sedolisin), both of which are members of clan SB [
,
,
,
].Peptidases S8 (or subtilases serine endo- and exo-peptidase clan) have an Asp/His/Ser catalytic triad similar to that found in trypsin-like proteases, but do not share their three-dimensional structure and are not homologous to trypsin. The stability of subtilases may be enhanced by calcium, some members have been shown to bind up to 4 ions via binding sites with different affinity. Some members of this clan contain disulfide bonds. These enzymes can be intra- and extracellular, some function at extreme temperatures and pH values [
,
,
,
]. |
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| Protein Domain |
| Name: |
Galanin receptor family |
| 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 the galanin receptor family, it also includes an insect allatostatin receptor, which is similar to mammalian galanin receptors [
]. |
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| Protein Domain |
| Name: |
eIF3B, RNA recognition motif |
| Type: |
Domain |
| Description: |
This entry represents the RNA recognition motif (RRM) found in eukaryotic translation initiation factor 3 (eIF-3), a large multisubunit complex that plays a central role in the initiation of translation by binding to the 40 S ribosomal subunit and promoting the binding of methionyl-tRNAi and mRNA. eIF-3B is the major scaffolding subunit of eIF-3. It interacts with eIF-3 subunits A, G, I, and J [
]. eIF-3B contains an N-terminal RNA recognition motif (RRM), which is involved in the interaction with eIF-3J. The interaction between eIF-3B and eIF-3J is crucial for the eIF-3 recruitment to the 40 S ribosomal subunit []. eIF-3B also binds directly to domain III of the internal ribosome-entry site (IRES) element of hepatitis-C virus (HCV) RNA through its N-terminal RRM, which may play a critical role in both cap-dependent and cap-independent translation []. Additional research has shown that eIF-3B may function as an oncogene in glioma cells and can be served as a potential therapeutic target for anti-glioma therapy []. Proteins containing this domain also include eIF-3 yeast homologue subunit B (also termed Prt1) that interacts with the yeast homologues of eIF-3 subunits A(TIF32), G(TIF35), I(TIF34), J(HCR1), and E(Pci8). In yeast, eIF-3B (Prt1) contains an N-terminal RRM that is directly involved in the interaction with eIF-3A (TIF32) and eIF-3J (HCR1) [
]. In contrast to its human homologue, yeast eIF-3B (Prt1) may have potential to bind its total RNA through its RRM []. |
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| Protein Domain |
| Name: |
Tumor necrosis factor receptor 5, N-terminal, teleost |
| Type: |
Domain |
| Description: |
Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), commonly known as CD40 and also as CDW40, p50 or Bp50, is widely expressed in diverse cell types including B lymphocytes, dendritic cells, platelets, monocytes, endothelial cells, and fibroblasts [
]. It is essential in mediating a wide variety of immune and inflammatory responses, including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal centre formation [,
,
,
]. Its natural immunomodulating ligand is CD40L, and a primary defect in the CD40/CD40L system is associated with X-linked hyper-IgM (XHIM) syndrome []. It is also involved in tumorigenesis. The CD40/CD40L system serves as a link between tumorigenesis, atherosclerosis, and the immune system, and offers a potential target for drug therapy for related diseases, such as cancer, atherosclerosis, diabetes mellitus, and immunological rejection [].TNFRSF5/CD40 homologues have been identified in teleosts. The zebrafish CD40 is a type I membrane-bound protein with a sequence pattern of four cysteine-rich domains in its extracellular N-terminal region. The consensus TNFR-associated factor (TRAF)2- and TRAF6-binding motifs in mammalian CD40 are found in the cytoplasmic tail of zebrafish CD40, which indicates similar signal transduction mechanisms to higher vertebrates [
]. Salmon CD40 and CD40L are widely expressed, particularly in immune tissues, and their importance for the immune response is indicated by their relatively high expression in salmon lymphoid organs and gills [].This entry represents the N-terminal domain of TNFRSF5 from teleosts. |
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| Protein Domain |
| Name: |
Tumor necrosis factor receptor 19, N-terminal |
| Type: |
Domain |
| Description: |
TNFRSF19 (also known as TAJ; TROY; TRADE; TAJ-alpha) is expressed in progenitor cells of the hippocampus, thalamus, and cerebral cortex and highly expressed during embryonic development. It has been shown to interact with TRAF family members, and to activate JNK signaling pathway when overexpressed in cells [
,
]. It is frequently overexpressed in colorectal cancer cell lines and primary colorectal carcinomas. TNFRSF19 is a beta-catenin target gene, in mesenchymal stem cells, and also activates NF-kappaB signaling, showing that beta-catenin regulates NF-kappaB activity via TNFRSF19. Since Wnt/beta-catenin signaling plays a crucial role in the regulation of colon tissue regeneration and the development of colon tumors, TNFRSF19 may contribute to the development of colorectal tumors []. These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development []. TNFRSF19 has been shown to promote glioblastoma (GBM) survival signaling and therefore targeting it may increase tumor vulnerability and improve therapeutic response in glioblastoma []. It may play an important role in myelin-associated inhibitory factors (MAIFs)-induced inhibition of neurite outgrowth in the postnatal central nervous system (CNS) or on axon regeneration following CNS injury [].This entry represents the N-terminal domain of TNFRSF19. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [
,
,
]. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 5, N-terminal |
| Type: |
Domain |
| Description: |
Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), commonly known as CD40 and also as CDW40, p50 or Bp50, is widely expressed in diverse cell types including B lymphocytes, dendritic cells, platelets, monocytes, endothelial cells, and fibroblasts [
]. It is essential in mediating a wide variety of immune and inflammatory responses, including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal centre formation [,
,
,
]. Its natural immunomodulating ligand is CD40L, and a primary defect in the CD40/CD40L system is associated with X-linked hyper-IgM (XHIM) syndrome []. It is also involved in tumorigenesis; CD40 expression is significantly higher in gastric carcinomas and it is associated with the lymphatic metastasis of cancer cells and their tumor node metastasis (TNM) classification []. Upregulated levels of CD40/CD40L on B cells and T cells may play an important role in the immune pathogenesis of breast cancer []. Consequently, the CD40/CD40L system serves as a link between tumorigenesis, atherosclerosis, and the immune system, and offers a potential target for drug therapy for related diseases, such as cancer, atherosclerosis, diabetes mellitus, and immunological rejection [].This entry represents the N-terminal domain of TNFRSF5. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [
,
,
]. |
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| Protein Domain |
| Name: |
Anaerobic cobalt chelatase |
| Type: |
Family |
| Description: |
This group, typified by Salmonella typhimurium CbiK, contains anaerobic cobalt chelatases that act in the anaerobic cobalamin biosynthesis pathway [
,
].Cobalamin (vitamin B12) can be complexed with metal via ATP-dependent reactions (aerobic pathway) (e.g., in Pseudomonas denitrificans) or via ATP-independent reactions (anaerobic pathway) (e.g., in S. typhimurium) [
,
]. The corresponding cobalt chelatases are not homologous. This group belongs to the class of ATP-independent, single-subunit chelatases that also includes distantly related protoporphyrin IX (PPIX) ferrochelatase (HemH) (Class II chelatases) []. The structure of S. typhimurium CbiK shows that it has a remarkably similar topology to Bacillus subtilis ferrochelatase despite only weak sequence conservation []. Both enzymes contain a histidine residue identified as the metal ion ligand, but CbiK contains a second histidine in place of the glutamic acid residue identified as a general base in PPIX ferrochelatase []. Site-directed mutagenesis has confirmed a role for this histidine and a nearby glutamic acid in cobalt binding, modulating metal ion specificity as well as catalytic efficiency [].It should be noted that CysG and Met8p, which are multifunctional proteins associated with siroheme biosynthesis, include chelatase activity and can therefore be considered as the third class of chelatases [
]. As with the class II chelatases, they do not require ATP for activity. However, they are not structurally similar to HemH or CbiK, and it is likely that they have arisen by the acquisition of a chelatase function within a dehydrogenase catalytic framework [,
]. |
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| Protein Domain |
| Name: |
Nidovirus 2-O-methyltransferase |
| Type: |
Domain |
| Description: |
Positive-stranded RNA (RNA) viruses that belong to the order Nidovirales infect a wide range of vertebrates (families Arteriviridae and Coronaviridae) or invertebrates (Mesoniviridae and Roniviridae). Examples of nidoviruses with high economic and societal impact are the arterivirus porcine reproductive and respiratory syndrome virus (PRRSV) and the zoonotic coronaviruses (CoVs) causing severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and Covid-19 (SARS-CoV-2) in humans.The 3'-terminal region of the most conserved ORF1b in three of the four families of the order Nidovirales (except for the family Arteriviridae) encodes a 2'-O-methyltransferase (2'-O-MTase), known as non structural protein (NSP) 16 in CoV and implicated in methylation of the 5' cap structure of nidoviral mRNAs. Assembly of a cap1 structure at the 5' end of viral mRNA assists in translation and evading host defense. The cap structure consists of a 7-methylguanosine (m7G) linked to the first nucleotide of the RNA transcript through a 5'-5' triphosphate bridge. The CoV NSP16 methyltransferase forms an obligatory complex with NSP10 to efficiently convert client mRNA species from the cap-0 ((me7)G(0)pppA(1)) to the cap-1 form ((me7)G(0)pppA(1m)) by methylating the ribose 2'-O of the first nucleotide of the nascent mRNA using S-adenosyl methionine (SAM) as the methyl donor [
,
,
,
].The nidovirus 2'-O-MTase domain exhibits the characteristic fold of the class I MTase family, comprising a β-sheet flanked by α-helices and loops. The nidovirus 2'-O-MTase domain harbors a catalytic K-D-K-E tetrad that is conserved among 2'-O-MTases [
,
,
]. |
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| Protein Domain |
| Name: |
M18 family aminopeptidase 2, putative |
| Type: |
Family |
| Description: |
Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation which is usually zinc, but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophillic role.
Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site []. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [].This group of metallopeptidases belong to the MEROPS peptidase family M18, (clan MH). The proteins have two catalytic zinc ions at the active site, bound by His/Asp, Asp, Glu, Asp/Glu and His. The catalysed reaction involves the release of an N-terminal aminoacid, usually neutral or hydrophobic, from a polypeptide [
].This entry represents aminopeptidase 2 from bacteria. |
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| Protein Domain |
| Name: |
5'-deoxynucleotidase YfbR |
| Type: |
Family |
| Description: |
This entry contains Escherichia coli (strain K12) YfbR. It is a 5'-deoxynucleotidase that functions as a dCMP phosphohydrolase in a salvage pathway for the synthesis of dUMP in a dcd/deoA mutant [
]. YfbR contains a conserved HD domain []. YfbR has phosphatase activity with deoxyribonucleoside 5'-monophosphates and does not hydrolyze ribonucleotides or deoxyribonucloside 3'-monophosphates []. Nucleotidase activity of YfbR was discovered in a high-throughput screen of purified proteins []. Crystal structures of YfbR have been solved; based on an analysis of crystal packing and size-exclusion chromatography, it was suggested that the biological unit is a dimer. Site-directed mutagenesis confirmed the importance of certain conserved active site residues, and mechanisms for substrate selectivity and catalysis were proposed [].This family also includes phage HD domain-containing hydrolase-like enzymes, such as A0A2H5BHG9 and A0A2L0V156 from Acinetobacter phage SH-Ab 15497 [
], which are associated with PurZ, an enzyme that catalyses the synthesis of diaminopurine (Z), a DNA modification that gives phages an advantage for evading host restriction enzymes activity. They have 2'-deoxyadenine 5'-triphosphate triphosphohydrolase (dATPase) activity, and catalyse the hydrolysis of 2'-deoxyadenine 5'-triphosphate (dATP) to 2'-deoxyadenine (dA) and triphosphate, with the highest activity using Co2+ as the divalent metal cofactor. These enzymes are highly specific for dATP and also catalyse the hydrolysis of dADP and dAMP into dA, releasing pyrophosphate and phosphate, respectively. Thus, these dATPases facilitate the synthesis of Z-genome synthesis removing dATP and dADP from the nucleotide pool of the host []. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 8 |
| 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 8 (also known as CD30 and Ki-1 antigen) was originally described as a marker of Hodgkin's and Reed-Sternberg cells in Hodgkin's lymphoma. Expression of the receptor is largely restricted to virus-infected lymphocytes, neoplasms of lymphoid origin and a subset of activated T cells that produce Th2-type cytokines [
]. The receptor has pleiotropic biological functions, including inducement apoptosis and enhancement of cell survival []. |
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| Protein Domain |
| Name: |
MAP3K, HisK-N-like globin domain |
| Type: |
Domain |
| Description: |
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [
].This domain represents a predicted non-heme-binding version of the globin domain identified in ASK1/2/3. It displays strongest affinities to the HisK-N family of sensor domains, which inhibit histidine kinase activation required for sporulation in bacteria of the firmicutes lineage. This globin domain is predicted to represent an independent sensory element recognizing a fatty acid or a related membrane-derived molecule which regulates activity of the ASK signalosome in apoptosis [
]. |
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| Protein Domain |
| Name: |
Aldo-keto reductase family 5C2 |
| Type: |
Family |
| Description: |
This entry represents aldo-keto reductase family 5C2 (AKR5C2), including DkgA/YqhE from Escherichia coli. It catalyses the reduction of 2,5-diketo-D-gluconic acid (25DKG) to 2-keto-L-gulonic acid (2KLG). It is also capable of stereoselective -keto ester reductions on ethyl acetoacetate and other 2-substituted derivatives [
,
,
].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: |
Propanediol/glycerol dehydratase, small subunit |
| Type: |
Family |
| Description: |
Diol dehydratase (
) and glycerol dehydratase (
) are two iso-functional enzymes that can each catalyse the conversion of 1,2-propanediol, 1,2-ethanediol and glycerol to the corresponding deoxy aldehydes (propionaldehyde, acetaldehyde and 3-hydroxypropionaldehyde, respectively). This reaction proceeds by a radical mechanism involving coenzyme B12 (adenosylcobalamin, AdoCbl) as an essential cofactor. Even though they catalyse the same reaction, these two enzymes (1) differ in their substrate preferences (diol dehydratase has a higher affinity for 1,2-propanediol and glycerol dehydratase for glycerol [
]); (2) they participate in different pathways (dihydroxyacetone [DHA]pathway for glycerol dehydratase and 1,2-propanediol degradation pathway for diol dehydratase); and (3) in those organisms where both enzymes are produced (such as Klebsiella and Citrobacter), the genes for them are independently regulated: glycerol dehydratase is induced when Klebsiella pneumoniae grows in glycerol-containing medium, whereas diol dehydratase is fully induced when it grows in propane-1,2-diol-containing medium, but only slightly in the glycerol medium [
,
]. Crystal structures, mechanism of action and structure-function relationship with the coenzyme B12 have been extensively studied for these enzymes [
]. Diol/glycerol dehydratases undergo inactivation during catalysis and require a reactivating factor. Propanediol dehydratase was found to be associated with and is believed to be encased in the proteinaceous shell of polyhedral organelles [].Both diol dehydratase and glycerol dehydratase comprise three subunits: PduC/PduD/PduE or PddA/PddB/PddC for propanediol dehydratase, and GldA/Gld/B/GldC or DhaB/DhaC/DhaE for glycerol dehydratase. This entry represents the small subunit PduE/PddC/GldC/DhaE. |
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| Protein Domain |
| Name: |
Propanediol/glycerol dehydratase, medium subunit |
| Type: |
Family |
| Description: |
Diol dehydratase (
) and glycerol dehydratase (
) are two iso-functional enzymes that can each catalyse the conversion of 1,2-propanediol, 1,2-ethanediol and glycerol to the corresponding deoxy aldehydes (propionaldehyde, acetaldehyde and 3-hydroxypropionaldehyde, respectively). This reaction proceeds by a radical mechanism involving coenzyme B12 (adenosylcobalamin, AdoCbl) as an essential cofactor. Even though they catalyse the same reaction, these two enzymes (1) differ in their substrate preferences (diol dehydratase has a higher affinity for 1,2-propanediol and glycerol dehydratase for glycerol [
]); (2) they participate in different pathways (dihydroxyacetone [DHA]pathway for glycerol dehydratase and 1,2-propanediol degradation pathway for diol dehydratase); and (3) in those organisms where both enzymes are produced (such as Klebsiella and Citrobacter), the genes for them are independently regulated: glycerol dehydratase is induced when Klebsiella pneumoniae grows in glycerol-containing medium, whereas diol dehydratase is fully induced when it grows in propane-1,2-diol-containing medium, but only slightly in the glycerol medium [
,
]. Crystal structures, mechanism of action and structure-function relationship with the coenzyme B12 have been extensively studied for these enzymes [
]. Diol/glycerol dehydratases undergo inactivation during catalysis and require a reactivating factor. Propanediol dehydratase was found to be associated with and is believed to be encased in the proteinaceous shell of polyhedral organelles [].Both diol dehydratase and glycerol dehydratase comprise three subunits: PduC/PduD/PduE [
] or PddA/PddB/PddC [] for propanediol dehydratase, and GldA/Gld/B/GldC or DhaB/DhaC/DhaE for glycerol dehydratase.This entry represents the medium subunit PduD/PddB/GldB/DhaC. |
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| Protein Domain |
| Name: |
Defensin, insect |
| Type: |
Family |
| Description: |
Insect defensins are a diverse family of anti-bacterial peptides, largely active against Gram-positive bacteria [
,
,
,
,
]. All these peptides range in length from 38 to 51 amino acids. There are six conserved cysteines all involved in intrachain disulphide bonds.A schematic representation of peptides from the arthropod defensin family is shown below.+----------------------------+
| | xxCxxxxxxxxxxxxxxCxxxCxxxxxxxxxCxxxxxCxCxx
| | | |+---|---------------+ |
+-----------------+'C': conserved cysteine involved in a disulphide bond.
Although low level sequence similarities have been reported [
] between the insect defensins and mammalian defensins, the topological arrangement of the disulphide bonds as well as the tertiary structure [] are completely different in the two families.A member of this family, coprisin, is a potent broad-spectrum antibacterial peptide against both Gram-positive and Gram-negative bacteria [
,
], also active against all antibiotic-resistant bacterial strains tested [], which acts through the permeabilization of the bacterial cell membrane []. It can induce apoptosis in C.albicans, without disrupting the fungal plasma membrane []. This defensin also shows potent anti-inflammatory activities, since it reduces both LPS-induced nitric oxide release and proinflammatory cytokine production []. The anti-inflammatory activities are initiated by suppressing the binding of LPS to toll-like receptor 4 (TLR4), and subsequently inhibiting the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear translocation of NF-kB (TNFRSF11A) []. This defensin is an interesting antibacterial compound that does not show hemolytic activity against human erythrocytes and does not affect human cell membranes []. |
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| Protein Domain |
| Name: |
Galanin message associated peptide (GMAP) |
| Type: |
Domain |
| Description: |
Galanin is a peptide hormone that controls various biological activities [
]. Galanin-like immuno-reactivity has been found in the central and peripheral nervous systems of mammals, with high concentrations demonstrated in discrete regions of the central nervous system, including the median eminence, hypothalamus, arcuate nucleus, septum, neuro-intermediate lobe of the pituitary, and the spinal cord. Its localisation within neurosecretory granules suggests that galanin may function as a neurotransmitter, and it has been shown to coexist with a variety of other peptide and amine neurotransmitters within individual neurons [].Although the precise physiological role of galanin is uncertain, it has a number of pharmacological properties: it stimulates food intake, when injected into the third ventricle of rats; it increases levels of plasma growth hormone and prolactin, and decreases dopamine levels in the median eminence [
]; and infusion into humans results in hyperglycemia and glucose intolerance, and inhibits pancreatic release of insulin, somatostatin and pancreatic peptide. Galanin also modulates smooth muscle contractility within the gastro-intestinal and genito-urinary tracts, all such activities suggesting that the hormone may play an important role in the nervous modulation of endocrine and smooth muscle function [].This domain represents the galanin message-associated peptide (GMAP) domain which is found C-terminal to the galanin domain in the preprogalanin precursor protein. GMAP sequences in different species show a high degree of homology, but the biological function of the GMAP peptide is not known [
]. |
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| Protein Domain |
| Name: |
Lantibiotic leader peptide-processing serine protease |
| Type: |
Family |
| Description: |
Lantibiotic genes reside on the bacterial chromosome, where they cluster with genes that adapt and secrete them to the extracellular space. Many of these so-called 'pathogenicity islands' have been characterised, including the epidermin (epi) cluster in Staphylococcus epidermis, and the nisin (nis) cluster in Lactococcus lactis [
]. The gene encoding the lantibiotic is flanked by 3 regulatory genes: 2 that are usually involved in a 2-component regulatory system, and another that cleaves the signal peptide from the precursor to produce the mature lantibiotic.This protein (usually designated with a "P"suffix - nisP, mutP, etc.) is highly conserved amongst pathogenic species, and is essential for virulence and survival of the bacterium against competitors in the host [
]. A novel pathogenicity island in resistant Enterococcus faecalis has been sequenced. In addition to the lantibiotic Cyl gene cluster, this revealed a novel set of virulence factors involved in vancomycin resistance and pathogenicity []. Lantiobiotic (lanthionine-containing antibiotics) specific proteases are serine proteases in the subtilisin family (family S8). The proteases that cleave the N-terminal leader peptides from lantiobiotics include: epiP, nsuP, mutP, and nisP. EpiP (MEROPS identifier S08.060), from Staphylococcus, is thought to cleave matured epidermin [
]. NsuP, a dehydratase from Streptococcus and NisP (MEROPS identifier S08.059), a membrane-anchored protease from Lactococcus, cleaves nisin []. MutP (MEROPS identifier S08.065) is highly similar to epiP and nisP and is thought to process the prepeptide mutacin III of S. mutans []. |
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| Protein Domain |
| Name: |
TRCF-like, C-terminal D7 domain |
| Type: |
Homologous_superfamily |
| Description: |
The transcription-repair coupling factor (TRCF, product of the mfd gene) couples transcription and DNA repair in bacteria. TRCF removes transcription elongation complexes stalled at DNA lesions and recruits the nucleotide excision repair (NER) machinery to the site. This protein, comprised of eight domains, including region of structurally similar to UvrB, shows to distinct activities: the relief of transcription-dependent inhibition of nucleotide excision repair (NER) by recognition and ATP-dependent removal of a stalled RNAP covering the damaged DNA; and the stimulation of DNA repair by recruitment of the Uvr(A)BC endonuclease. The C-terminal region of TRCF have been shown to be necessary for RNAP displacement [
,
].Structural domains comprising this superfamily share the structure of the C-terminal D7 (handle) domain of TRCF, whose precise role is yet to be clarified although some insights have been revealed. Most residues conserved between TRCF and UvrB in the putative UvrA binding surface are buried in the D2/D7 interface and are thus not available for binding UvrA. It is believed that once TRCF engages with the stalled RNAP and displaces it, an RNAP-triggered conformational change in TRCF moves D7 relative to D2, unmasking the putative UvrA binding surface. This enables the recruitment of Uvr(AB) via UvrA binding to D2. Overall, D7 appears to block the otherwise deleiterious interaction between TRCF and UrvA until a conformational change in the former, during its functional cycle, unmasks the UvrA binding determinant [
]. |
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| Protein Domain |
| Name: |
Voltage gated sodium channel, alpha-1 subunit |
| Type: |
Family |
| 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 [
,
,
].The SCN1A gene encodes the NaB1 channel and is particularly expressed in
the brain, but is also found in a variety of other tissues, ranging from theretina to the olfactory bulb. Epilepsy, a disorder of neuronal
hyperexcitability, has been associated with altered kinetics of SCN1A, aswell as delayed inactivation of SCN2A [
].This entry represents the alpha 1 subunits of the voltage-gated Na+ channel superfamily. For entries containing other members of this superfamily see
,
,
.
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| Protein Domain |
| Name: |
Hepatitis delta antigen (HDAg) domain |
| Type: |
Domain |
| Description: |
Transcription elongation by RNA polymerase II (RNAPII) is negatively regulated
by the human factors DRB-sensitivity inducing factor (DSIF) and negativeelongation factor (NELF). NELF is a transcription factor composed of four
subunits, NELF-A, -B, -C (or its variant -D), and -E, that are conserved fromDrosophila to humans. Certain subunits have been implicated in numerous
diseases ranging from neurological disorders to cancer. The N-terminal segmentof NELF-A shows sequence similarity to the hepatitis delta antigen (HDAg), the
viral protein required for replication of hepatitis delta virus (HDV) [E1].
Replication of HDV RNA appears to involve the host RNAPII and requires thepresence of HDAg. HDAg binds RNAPII directly and stimulates transcription by
displacing NELF and promoting RNAPII elongation. HDAg directly binds RNAPIIand inhibits NELF-RNAPII association, possibly because HDAg competes with
NELF-A for a common surface on RNAPII [,
].The C terminus of the HDAg domain forms the RNAPII-binding motif conserved in
humans and virus, while the NELF-C (or NELF-D)-binding region of NELF-A islocalized in the middle of the HDAg domain. The region of HDAg corresponding
to the NELF-C (or NELF-D)-binding region of NELF-A contains two arginine-richmotifs responsible for RNA-binding activity [
,
,
].The HDAg domain is composed of a long N-terminal helix, interrupted by a sharp
bend and continuing on into another short helix [
,
]. Themiddle part of the HDAg domain makes an 'extended region' that forms four
helices []. The structure of the C-terminal section is notyet known.
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| Protein Domain |
| Name: |
Dynein heavy chain, tail |
| Type: |
Domain |
| 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.Dynein heavy chains interact with other heavy chains to form dimers, and with intermediate chain-light chain complexes to form a basal cargo binding unit [
]. The region featured in this family includes the sequences implicated in mediating these interactions []. It is thought to be flexible and not to adopt a rigid conformation []. |
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| Protein Domain |
| Name: |
SAGA-associated factor 29 |
| Type: |
Family |
| Description: |
SAGA-associated factor 29 (SGF29) is a chromatin reader and a component of the transcription regulatory histone acetylation (HAT) complexes SAGA and SLIK [
,
]. In the SAGA complex, SGF29 binds histone H3 that has been methylated at Lys-4 (H3K4me), and preferably binds the trimethylated form (H3K4me3) []. SGF29 also acts as a boundary, preventing the spread of heterochromatin into neighbouring genes []. SGF29 contains two Tudor domains.The transcription regulatory histone acetylation complex Spt-Ada-Gcn5 acetyltransferase (SAGA) is involved in RNA polymerase II-dependent transcriptional regulation of approximately 10% of yeast genes. SAGA preferentially acetylates histones H3 and H2B and deubiquitinates histone H2B [
]. SAGA is known as PCAF in vertebrates and PCAF acetylates nucleosomal histone H3 []. The SAGA complex consists of at least TRA1, CHD1, SPT7, TAF5, ADA3, SGF73, SPT20/ADA5, SPT8, TAF12, TAF6, HFI1/ADA1, UBP8, GCN5, ADA2, SPT3, SGF29, TAF10, TAF9, SGF11 and SUS1, and some of these components are present as two copies. The complex is built up from distinct modules, each of which has a separate function and crosslinks with either other proteins or other modules in the complex [].SLIK (SAGA-like) is a multi-subunit histone acetyltransferase complex that preferentially acetylates histones H3 and H2B and deubiquitinates histone H2B. It is an embellishment of the SAGA complex. The yeast SLIK complex consists of at least TRA1, CHD1, SPT7, CC TAF5, ADA3, SPT20, RTG2, TAF12, TAF6, HFI1, UBP8 (a deubiquitinase), GCN5, ADA2, SPT3, SGF29, TAF10 and TAF9 [
,
]. |
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| Protein Domain |
| Name: |
Fructose-1,6-bisphosphatase, active site |
| Type: |
Active_site |
| Description: |
This entry represents fructose-1,6-bisphosphatase (FBPase), a critical regulatory enzyme in gluconeogenesis that catalyses the removal of 1-phosphate from fructose 1,6-bis-phosphate to form fructose 6-phosphate [
,
]. It is involved in many different metabolic pathways and found in most organisms. FBPase requires metal ions for catalysis (Mg2+and Mn
2+being preferred) and the enzyme is potently inhibited by Li
+. The fold of fructose-1,6-bisphosphatase was noted to be identical to that of inositol-1-phosphatase (IMPase) [
]. Inositol polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif (Asp-Pro-Ile/Leu-Asp-Gly/Ser-Thr/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial and yeast IMPase homologues. It has been suggested that these proteins define an ancient structurally conserved family involved in diverse metabolic pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone metabolism [].In mammalian FBPase, a lysine residue has been shown to be involved in the catalytic mechanism [
]. The region around this residue is highly conserved and can be used as a signature pattern for FBPase and sedoheptulose-1,7-bisphosphatase (SBPase) an enzyme found plant chloroplasts and in photosynthetic bacteria that is functionally and structurally related to FBPase []. SBPase catalyses the hydrolysis of sedoheptulose 1,7-bisphosphate to sedoheptulose 7-phosphate, a step in the Calvin's reductive pentose phosphate cycle. This signature contains the active site lysine, however, it must be noted that, in some bacterial FBPase sequences, the active site lysine is replaced by an arginine. |
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