| Type |
Details |
Score |
| Protein Domain |
| Name: |
Enolase |
| Type: |
Family |
| Description: |
Enolase (2-phospho-D-glycerate hydrolase) is an essential, homodimeric enzyme that catalyses the reversible dehydration of 2-phospho-D-glycerate to phosphoenolpyruvate as part of the glycolytic and gluconeogenesis pathways [
,
]. The reaction is facilitated by the presence of metal ions []. In vertebrates, there are 3 different, tissue-specific isoenzymes, designated alpha, beta and gamma. Alpha is present in most tissues, beta is localised in muscle tissue, and gamma is found only in nervous tissue. The functional enzyme exists as a dimer of any 2 isoforms. In immature organs and in adult liver, it is usually an alpha homodimer, in adult skeletal muscle, a beta homodimer, and in adult neurons, a gamma homodimer. In developing muscle, it is usually an alpha/beta heterodimer, and in the developing nervous system, an alpha/gamma heterodimer []. The tissue specific forms display minor kinetic differences. Tau-crystallin, one of the major lens proteins in some fish, reptiles and birds, has been shown [] to be evolutionary related to enolase.Neuron-specific enolase is released in a variety of neurological diseases, such as multiple sclerosis and after seizures or acute stroke. Several tumour cells have also been found positive for neuron-specific enolase. Beta-enolase deficiency is associated with glycogenosis type XIII defect. |
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| Protein Domain |
| Name: |
Enolase, N-terminal |
| Type: |
Domain |
| Description: |
Enolase (2-phospho-D-glycerate hydrolase) is an essential, homodimeric enzyme that catalyses the reversible dehydration of 2-phospho-D-glycerate to phosphoenolpyruvate as part of the glycolytic and gluconeogenesis pathways [
,
]. The reaction is facilitated by the presence of metal ions []. In vertebrates, there are 3 different, tissue-specific isoenzymes, designated alpha, beta and gamma. Alpha is present in most tissues, beta is localised in muscle tissue, and gamma is found only in nervous tissue. The functional enzyme exists as a dimer of any 2 isoforms. In immature organs and in adult liver, it is usually an alpha homodimer, in adult skeletal muscle, a beta homodimer, and in adult neurons, a gamma homodimer. In developing muscle, it is usually an alpha/beta heterodimer, and in the developing nervous system, an alpha/gamma heterodimer []. The tissue specific forms display minor kinetic differences. Tau-crystallin, one of the major lens proteins in some fish, reptiles and birds, has been shown [] to be evolutionary related to enolase.Neuron-specific enolase is released in a variety of neurological diseases, such as multiple sclerosis and after seizures or acute stroke. Several tumour cells have also been found positive for neuron-specific enolase. Beta-enolase deficiency is associated with glycogenosis type XIII defect. |
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| Protein Domain |
| Name: |
Peptidase C26, gamma-glutamyl hydrolase |
| Type: |
Family |
| Description: |
Gamma-glutamyl hydrolase (GH) is a lysosomal and secreted glycoprotein that hydrolyses the gamma-glutamyl tail of antifolate and folate polyglutamates. Tumour cells that have high levels of GH are inherently resistant to classical antifolates, and further resistance can be acquired by elevations in GH following exposure to this class of anti-tumour agents. The highest level of expression in normal tissues occurs in the liver and kidney in humans. GH is a low-affinity (micromolar), high-turnover enzyme that has a cysteine at the active site. GH is being evaluated as an intracellular target for inhibition in order to enhance the therapeutic activity of antifolates and fluorouracil [
].The 3-dimensional structure of GH shows a central eight-stranded β-sheet, which is sandwiched by three and five α-helices on each side (see []. The fold resembles that of glutamine amidotransferases (GATase) of class I, which are characterised by a conserved Cys-His-Glu active site. The major differences consist of extensions in four loops and at the C terminus of GGH. The active site residues are well conserved and the catalytically essential cysteine, positioned at a nucleophile elbow, suggests that GGH is a cysteine peptidase. |
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| Protein Domain |
| Name: |
Imidazole glycerol phosphate synthase, subunit H |
| Type: |
Family |
| Description: |
Imidazole glycerol phosphate synthetase (IGPS) is a key metabolic enzyme, which links amino acid and nucleotide biosynthesis: it catalyses the closure of the imidazole ring within histidine biosynthesis (fifth step), and provides the substrate for de novo purine biosynthesis. IGPS consists of two different subunits: HisH, a glutamine amidotransferase (glutaminase), and HisF, a synthase (cyclase). HisH functions to provide a source of nitrogen, which is required for the synthesis of histidine and purines. In the HisH glutaminase reaction, the hydrolysis of glutamine yields ammonia, which is then used by HisF in the subsequent synthase reaction. The X-ray structure of the HisH/HisF heterodimer of IGPS reveals a putative tunnel for the transfer of ammonia from HisH to HisF via a (beta-alpha)8 barrel fold within HisF that abuts HisH [
]. Ammonia tunnels connect the glutaminase and synthase active sites.HisH belongs to a large group of enzymes found in diverse and fundamental anabolic pathways. These enzymes share a common domain, referred to as the type-I glutamine amidotransferase (GATase) domain, which can occur either as single polypeptides (as with HisH) or as domains of large multifunctional proteins. |
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| Protein Domain |
| Name: |
Condensin complex subunit 1, N-terminal |
| Type: |
Domain |
| Description: |
Condensin is a multi-subunit protein complex that acts as an essential regulator of chromosome condensation [
,
]. It contains both SMC (structural maintenance of chromosomes) and non-SMC subunits. Condensin plays an important role during mitosis in the compaction and resolution of chromosomes to remove and prevent catenations that would otherwise inhibit segregation. This is thought to be achieved by the introduction of positive supercoils into relaxed DNA in the presence of type I topoisomerases and converts nicked DNA into positive knotted forms in the presence of type II topoisomerases. During interphase condensin promotes clustering of dispersed loci into subnuclear domains and inhibits associations between homologues. In meiosis, condensin has been shown to influence the number of crossover events by regulating programmed double-strand breaks. Roles in gene regulation and lymphocyte development have also been defined.
Condensin subunit 1 (known as Cnd1 in Schizosaccharomyces pombe (Fission yeast), and XCAP-D2 in Xenopus laevis laevis) represents one of the non-SMC subunits in the complex. This subunit is phosphorylated at several sites by Cdc2. This phosphorylation process increases the supercoiling activity of condensin [
,
].This entry represents the conserved N-terminal domain of Cnd1. |
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| Protein Domain |
| Name: |
FMN-dependent dehydrogenase |
| Type: |
Domain |
| Description: |
A number of oxidoreductases that act on alpha-hydroxy acids and which are FMN-containing flavoproteins have been shown [
,
,
] to be structurally related. These enzymes are:Lactate dehydrogenase (
), which consists of a dehydrogenase domain and a haem-binding domain called cytochrome b2 and which catalyses the conversion of lactate into pyruvate.
Glycolate oxidase (
) ((S)-2-hydroxy-acid oxidase), a peroxisomal enzyme that catalyses the conversion of glycolate and oxygen to glyoxylate and hydrogen peroxide.
Long chain alpha-hydroxy acid oxidase from rat (
), a peroxisomal enzyme.
Lactate 2-monooxygenase (
) (lactate oxidase) from Mycobacterium smegmatis, which catalyses the conversion of lactate and oxygen to acetate, carbon dioxide and water.
(S)-mandelate dehydrogenase from Pseudomonas putida (gene mdlB), which catalyses the reduction of (S)-mandelate to benzoylformate.The first step in the reaction mechanism of these enzymes is the abstraction of the proton from the α-carbon of the substrate producing a carbanion which can subsequently attach to the N5 atom of FMN. A conserved histidine has been shown [
] to be involved in the removal of the proton. The region around this active site residue is highly conserved and contains an arginine residue which is involved in substrate binding. |
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| Protein Domain |
| Name: |
Superoxide dismutase, copper/zinc binding domain |
| Type: |
Domain |
| Description: |
Superoxide dismutases (SODs) are ubiquitous metalloproteins that prevent damage by oxygen-mediated free radicals by catalysing the dismutation of superoxide into molecular oxygen and hydrogen peroxide [
]. Superoxide is a normal by-product of aerobic respiration and is produced by a number of reactions, including oxidative phosphorylation and photosynthesis. The dismutase enzymes have a very high catalytic efficiency due to the attraction of superoxide to the ions bound at the active site [,
].There are three forms of superoxide dismutase, depending on the metal cofactor: Cu/Zn (which binds both copper and zinc), Fe and Mn types. The Fe and Mn forms are similar in their primary, secondary and tertiary structures, but are distinct from the Cu/Zn form [
]. Prokaryotes and protists contain Mn, Fe or both types, while most eukaryotic organisms utilise the Cu/Zn type.Defects in the human SOD1 gene causes familial amyotrophic lateral sclerosis (Lou Gehrig's disease). Cytoplasmic and periplasmic SODs exist as dimers, whereas chloroplastic and extracellular enzymes exist as tetramers. Structural analysis supports the notion of independent functional evolution in prokaryotes (P-class) and eukaryotes (E-class) [
,
,
,
,
,
,
,
]. |
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| Protein Domain |
| Name: |
DNA replication licensing factor Mcm2 |
| Type: |
Family |
| Description: |
The MCM2-7 complex consists of six closely related proteins that are highly conserved throughout the eukaryotic kingdom. In eukaryotes, Mcm2 is a component of the MCM2-7 complex (MCM complex), which consists of six sequence-related AAA + type ATPases/helicases that form a hetero-hexameric ring [
]. MCM2-7 complex is part of the pre-replication complex (pre-RC). In G1 phase, inactive MCM2-7 complex is loaded onto origins of DNA replication [,
,
]. During G1-S phase, MCM2-7 complex is activated to unwind the double stranded DNA and plays an important role in DNA replication forks elongation [].The components of the MCM2-7 complex are: DNA replication licensing factor MCM2, DNA replication licensing factor MCM3, DNA replication licensing factor MCM4, DNA replication licensing factor MCM5, DNA replication licensing factor MCM6, DNA replication licensing factor MCM7, In addition to its role in initiation of DNA replication, Mcm2 is able to
inhibit the Mcm4,6,7 helicase. Studies on murine Mcm2 indicate that itsC terminus is required for interaction with MCM4, as well as for inhibition
of the DNA helicase activity of the Mcm4,6,7 complex. The N-terminal region,which contains an H3-binding domain and a region required for nuclear
localisation, is required for the phosphorylation by CDC7 kinase. |
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| Protein Domain |
| Name: |
Glycoside hydrolase, family 79 |
| Type: |
Family |
| Description: |
O-Glycosyl hydrolases (
) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families [
,
]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.This is a family of endo-beta-N-glucuronidase, or heparanase belonging to glycoside hydrolase family 79 (
). Heparan sulphate proteoglycans (HSPGs) play a key role in the self- assembly, insolubility and barrier properties of basement membranes and extracellular matrices. Hence, cleavage of heparan sulphate (HS) affects the integrity and functional state of tissues and thereby fundamental normal and pathological phenomena involving cell migration and response to changes in the extracellular microenvironment. Heparanase degrades HS at specific intrachain sites. The enzyme is synthesized as a latent approximately 65kDa protein that is processed at the N terminus into a highly active approximately 50kDa form. Experimental evidence suggests that heparanase may facilitate both tumor cell invasion and neovascularization, both critical steps in cancer progression. The enzyme is also involved in cell migration associated with inflammation and autoimmunity [
]. |
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| Protein Domain |
| Name: |
Aromatic-ring-hydroxylating dioxygenase, 2Fe-2S-binding site |
| Type: |
Binding_site |
| Description: |
Aromatic ring hydroxylating dioxygenases are multicomponent 1,2-dioxygenase complexes that convert closed-ring structures to non-aromatic cis-diols [
]. The complex has both hydroxylase and electron transfer components. The hydroxylase component is itself composed of two subunits: an alpha-subunit of about 50kDa, and a beta-subunit of about 20kDa. The electron transfer component is either composed of two subunits: a ferredoxin and a ferredoxin reductase or by a single bifunctional ferredoxin/reductase subunit. Sequence analysis of hydroxylase subunits of ring hydroxylating systems (including toluene, benzene and napthalene 1,2-dioxygenases) suggests they are derived from a common ancestor []. The alpha-subunit binds both a Rieske-like 2Fe-2S cluster and an iron atom: conserved Cys and His residues in the N-terminal region may provide 2Fe-2S ligands, while conserved His and Tyr residues may coordinate the iron. The beta subunit may be responsible for the substrate specificity of the dioxygenase system [].The alpha-subunit of the hydroxylase components bind both a 2Fe-2S type iron-sulphur centre and an iron atom. There is, in the N-terminal section of these proteins, a conserved region of 24 residues which contains two cysteines and two histidines which have been shown to be involved in the binding of the iron-sulphur centre [
]. |
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| Protein Domain |
| Name: |
NADH-ubiquinone oxidoreductase, 20 Kd subunit |
| 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 [].Among the many polypeptide subunits that make up complex I, there is one with a molecular weight of 20kDa (in mammals) [
], which is a component of the iron-sulphur (IP) fragment of the enzyme. It seems to bind a 4Fe-4S iron-sulphur cluster. The 20kDa subunit has been found to be nuclear encoded, as a precursor form with a transit peptide in mammals, and in Neurospora crassa. It is mitochondrial encoded in Paramecium (gene psbG) and chloroplast encoded in various higher plants (gene ndhK or psbG). |
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| Protein Domain |
| Name: |
Uracil-DNA glycosylase, active site |
| Type: |
Active_site |
| Description: |
Uracil-DNA glycosylase
(UNG) [
] is a DNA repair enzyme that excises uracil residues from DNA by cleaving the N-glycosylic bond. Uracil in DNA can arise as a result of mis-incorporation of dUMP residues by DNA polymerase or deamination of cytosine.The sequence of uracil-DNA glycosylase is extremely well conserved [
] in bacteria and eukaryotes as well as in herpes viruses. More distantly related uracil-DNA glycosylases are also found in poxviruses []. In eukaryotic cells, UNG activity is found in both the nucleus and the mitochondria. Human UNG1 protein is transported to both the mitochondria and the nucleus []. The N-terminal 77 amino acids of UNG1 seem to be required for mitochondrial localisation [], but the presence of a mitochondrial transitpeptide has not been directly demonstrated. The most N-terminal conserved region contains an aspartic acid residue which has been proposed, based on X-ray structures [
,
] to act as a general base in the catalytic mechanism.This signature pattern covers the most N-terminal conserved region, which contains an aspartic acid residue that has been proposed, based on X-ray structures [
,
] to act as a general base in the catalytic mechanism. |
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| Protein Domain |
| Name: |
DNA primase large subunit, eukaryotic/archaeal |
| Type: |
Family |
| Description: |
DNA primase is the polymerase that synthesises small RNA primers for the Okazaki fragments made during discontinuous DNA replication. Primases are grouped into two classes, bacteria/bacteriophage and archaeal/eukaryotic. The proteins in the two classes differ in structure and the replication apparatus components. Archaeal/eukaryotic core primase is a heterodimeric enzyme consisting of a small catalytic subunit (PriS or Pri1) and a large subunit (PriL or Pri2). In the yeast Saccharomyces cerevisiae the small subunit is 48kDa and the large subunit 58kDa [
]. In eukaryotic organisms, a heterotetrameric enzyme formed by DNA polymerase alpha, the B subunit and two primase subunits has primase activity. Although the catalytic activity and the the ATP binding site reside within PriS [], the PriL subunit is essential for primase function as disruption of the PriL gene in yeast is lethal. PriL is composed of two structural domains. Several functions have been proposed for PriL such as stabilization of the PriS, involvement in synthesis initiation, improvement of primase processivity, determination of product size and transfer of the products to DNA polymerase alpha []. Primase function has also been demonstrated for human and mouse primase subunits []. |
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| Protein Domain |
| Name: |
DNA primase, large subunit, eukaryotic |
| Type: |
Family |
| Description: |
DNA primase is the polymerase that synthesises small RNA primers for the Okazaki fragments made during discontinuous DNA replication. Primases are grouped into two classes, bacteria/bacteriophage and archaeal/eukaryotic. The proteins in the two classes differ in structure and the replication apparatus components. Archaeal/eukaryotic core primase is a heterodimeric enzyme consisting of a small catalytic subunit (PriS or Pri1) and a large subunit (PriL or Pri2). In the yeast Saccharomyces cerevisiae the small subunit is 48kDa and the large subunit 58kDa [
]. In eukaryotic organisms, a heterotetrameric enzyme formed by DNA polymerase alpha, the B subunit and two primase subunits has primase activity. Although the catalytic activity and the the ATP binding site reside within PriS [
], the PriL subunit is essential for primase function as disruption of the PriL gene in yeast is lethal. PriL is composed of two structural domains. Several functions have been proposed for PriL such as stabilization of the PriS, involvement in synthesis initiation, improvement of primase processivity, determination of product size and transfer of the products to DNA polymerase alpha []. Primase function has also been demonstrated for human and mouse primase subunits [].This group represents the eukaryotic DNA primase, large subunit. |
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| Protein Domain |
| Name: |
Homocysteine-binding domain |
| Type: |
Domain |
| Description: |
The homocysteine (Hcy) binding domain is an ~300-residue module which is found in a set of enzymes involved in alkyl transfer to thiols:Prokaryotic and eukaryotic B12-dependent methionine synthase (MetH) (EC 2.1.1.13), a large, modular protein that catalyses the transfer of a methyl group from methyltetrahydrofolate (CH3-H4folate) to Hcy to form methionine, using cobalamin as an intermediate methyl carrier.Mammalian betaine-homocysteine S-methyltransferase (BHMT) (EC 2.1.1.5). It catalyzes the transfer of a methyl group from glycine betaine to Hcy, forming methionine and dimethylglycine.Plant selenocysteine methyltransferase (EC 2.1.1.-).Plant and fungal AdoMet homocysteine S-methyltransferases (EC 2.1.1.10).The Hcy-binding domain utilises a Zn(Cys)3 cluster to bind and activate Hcy. It has been shown to form a (beta/alpha)8 barrel. The Hcy binding domain barrel is distorted to form the metal- and substrate-binding sites. To accommodate the substrate, strands 1 and 2 of the barrel are loosely joined by nonclassic hydrogen bonds; to accommodate the metal, strands 6 and 8 are drawn together and strand 7 is extruded from the end of the barrel. The cysteines ligating the catalytic zinc atom are located at the C-terminal ends of strands 6 and 8 [
,
]. |
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| Protein Domain |
| Name: |
P-loop containing nucleoside triphosphate hydrolase |
| Type: |
Homologous_superfamily |
| Description: |
The P-loop NTPase fold is the most prevalent domain of the several distinct
nucleotide-binding protein folds.The most common reaction catalysed by enzymes of the P-loop NTPase fold is the hydrolysis of the beta-gamma phosphate bond of a bound nucleoside triphosphate (NTP). The energy from NTP hydrolysis is typically utilised to induce conformational changes in other molecules, which constitutes the basis of the biological functions of most P-loop NTPases. P-loop NTPases show substantial substrate preference for either ATP or GTP [
]. P-loop NTPases are characterised by two conserved sequence signatures, the
Walker A motif (the P-loop proper) and Walker B motifs which bind, respectively, the beta and gamma phosphate moieties of the bound NTP, and a Mg2+ cation [].P-loop ATPase domains belong to one of the two major divisions. The kinase-GTPase (KG) division includes the kinases and GTPases, and the ASCE division, characterised by an additional strand in the core sheet, which is located
between the P-loop strand and the Walker B strand. Most members of the ASCE division utilise ATP and members of this group include AAA+, ABC, PilT, HerA-FtsK, superfamily 1/2 (SF1/2) helicases, and the RecA/ATP-synthase superfamilies of ATPases, etc [,
]. |
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| Protein Domain |
| Name: |
Glycoside hydrolase, family 19 |
| Type: |
Family |
| Description: |
O-Glycosyl hydrolases (
) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families [
,
]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.Glycoside hydrolase family 19
comprises enzymes with only one known activity; chitinase (
).
Chitinases [
] are enzymes that catalyze the hydrolysis of the beta-1,4-N-acetyl-D-glucosamine linkages in chitin polymers. Chitinases belong to glycoside hydrolase families 18 or 19 []. Chitinases of family 19 (also known as classes IA or I and IB or II) are enzymes from plants that function in the defence against fungal and insect pathogens by destroying their chitin-containing cell wall. Class IA/I and IB/II enzymes differ in the presence (IA/I) or absence (IB/II) of a N-terminal chitin-binding domain. The catalytic domain of these enzymes consist of about 220 to 230 amino acid residues. The At2g43600 protein from Arabidopsis thaliana is presumably inactive as a chitinase because it lacks the Glu residue that is essential for catalytic activity. |
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| Protein Domain |
| Name: |
Ku70 |
| Type: |
Family |
| Description: |
Ku70 (also known as XRCC6 in animals), a single-stranded DNA-dependent ATP-dependent helicase, is a subunit of the Ku protein, which plays a key role in multiple nuclear processes such as DNA repair, chromosome maintenance, transcription regulation, DNA non-homologous end joining (NHEJ) and V(D)J recombination [
,
,
,
,
,
,
].Some findings have implicated yeast Ku in telomeric structure maintenance in addition to non-homologous end-joining. Some of the phenotypes of Ku-knockout mice may indicate a similar role for Ku at mammalian telomeres [
]. Ku70 also plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway [].Both subunits of the eukaryotic Ku heterodimer (Ku70 and Ku80) share a topology comprised of three domains: an α/β N-terminal, a central β-barrel domain and a helical C-terminal arm [
]. Structural analysis of the Ku70/80 heterodimer bound to DNA indicates that subunit contacts lead to the formation of a highly charged channel through which the DNA passes without making any contacts with the DNA bases []. |
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| Protein Domain |
| Name: |
Lipoxygenase, C-terminal |
| Type: |
Domain |
| Description: |
Lipoxygenases ([intenz:1.13.11.-]) are a class of iron-containing dioxygenases which catalyses the hydroperoxidation of lipids, containing a cis,cis-1,4-pentadiene structure. They are common in plants where they may be involved in a number of diverse aspects of plant physiology including growth and development, pest resistance, and senescence or responses to wounding. In mammals a number of lipoxygenases isozymes are involved in the metabolism of prostaglandins and leukotrienes []. Sequence data is available for the following lipoxygenases: Plant lipoxygenases (
). Plants express a variety of cytosolic isozymes as well as what seems to be a chloroplast isozyme [
].Mammalian arachidonate 5-lipoxygenase ().
Mammalian arachidonate 12-lipoxygenase (
).
Mammalian arachidonate 15-lipoxygenase B (also known as erythroid cell-specific 15-lipoxygenase;
).
The iron atom in lipoxygenases is bound by four ligands, three of which are
histidine residues []. Six histidines are conserved in all lipoxygenase sequences, five of them are found clustered in a stretch of 40 amino acids. This region contains two of the three iron-ligands; the other histidines have been shown [] to be important for the activity of lipoxygenases.This entry represents the C-terminal region of these proteins. |
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| Protein Domain |
| Name: |
NADH:ubiquinone oxidoreductase, ESSS subunit |
| 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 [].Mitochondrial complex I, which is located in the inner mitochondrial membrane, is the largest multimeric respiratory enzyme in the mitochondria, consisting of more than 45 subunits, one FMN co-factor and eight FeS clusters [
]. The assembly of mitochondrial complex I is an intricate process that requires the cooperation of the nuclear and mitochondrial genomes [,
].This entry represents the ESSS subunit from mitochondrial NADH:ubiquinone oxidoreductase (complex I). It carries mitochondrial import sequences [
]. |
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| Protein Domain |
| Name: |
Phosphatidylinositol-specific phospholipase C, X domain |
| Type: |
Domain |
| Description: |
Phosphatidylinositol-specific phospholipase C, a eukaryotic intracellular enzyme, plays
an important role in signal transduction processes []. It catalyzes the hydrolysis of 1-phosphatidyl-D-myo-inositol-3,4,5-triphosphate into the second messenger molecules diacylglycerol
and inositol-1,4,5-triphosphate. This catalytic process is tightly regulated by reversible phosphorylation and binding of regulatory proteins [
,
,
]. In mammals, there are at least 6 different isoforms of PI-PLC, they differ in their domain structure, their regulation, and their
tissue distribution. Lower eukaryotes also possess multiple isoforms of PI-PLC. All eukaryotic PI-PLCs contain two regions of homology, sometimes referred to as the 'X-box' and 'Y-box'. The order of these two
regions is always the same (NH2-X-Y-COOH), but the spacing is variable. In most isoforms, the distancebetween these two regions is only 50-100 residues but in the gamma isoforms one PH domain, two SH2 domains,
and one SH3 domain are inserted between the two PLC-specific domains. The two conserved regions have been shown to be important for the catalytic activity. By profile analysis, we could show that sequences with
significant similarity to the X-box domain occur also in prokaryotic and trypanosome PI-specific phospholipases C. Apart from this region, the prokaryotic enzymes show no similarity to their eukaryotic
counterparts. |
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| Protein Domain |
| Name: |
Legume lectin, beta chain, Mn/Ca-binding site |
| Type: |
Binding_site |
| Description: |
Lectins are carbohydrate-binding proteins. Leguminous lectins form one of the largest lectin families and resemble each other in their physicochemical properties, though they differ in their carbohydrate specificities. They bind either glucose/mannose or galactose [
]. Carbohydrate-binding activity depends on the simultaneous presence of both acalcium and a transition metal ion [
]. The exact function of legume lectins is not known, but they may be involved in the attachment of nitrogen-fixing bacteria to legumes and in the protection against pathogens [,
].Some legume lectins are proteolytically processed to produce two chains, beta (which corresponds to the N-terminal) and alpha (C-terminal) [
]. The lectin concanavalin A (conA) from jack bean is exceptional in that the two chains are transposed and ligated (by formation of a new peptide bond). The N terminus of mature conA thus corresponds to that of the alpha chain and the C terminus to the beta chain []. Though the legume lectins monomer is structurally well conserved, their quaternary structures vary widely [].The signature pattern for this entry is located in the C-terminal section of the beta chain and contains a conserved aspartic acid residue important for the binding of calcium and manganese. |
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| Protein Domain |
| Name: |
Peptidase M20 |
| Type: |
Family |
| Description: |
This group of proteins contains the metallopeptidases and non-peptidase homologues (amidohydrolases) that belong to the MEROPS peptidase family M20 (clan MH) [
]. The peptidases of this clan 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 amino acid, usually neutral or hydrophobic, from a polypeptide []. The peptidase M20 family has four subfamilies:M20A - type example, glutamate carboxypeptidase from Pseudomonas sp. RS16 (
)
M20B - type example, peptidase T from Escherichia coli (
)
M20C - type example, X-His dipeptidase from E. coli (
)
M20D - type example, carboxypeptidase Ss1 from Sulfolobus solfataricus (
)
Homologues from the family that are not peptidases include:Acetylornithine deacetylase, which releases an acetyl group and L-ornithine from N(2)-acetyl-L-ornithine [
]
N-acetyldiaminopimelate deacetylase, which catalyses the conversion of N-acetyl-diaminopimelate to diaminopimelate and acetate [
]
N-carbamoyl-L-amino-acid hydrolase, which converts D,L-5-monosubstituted hydantoins into D- or L-amino acids [
]
Aminoacylase-1, which hydrolyses N-acylated or N-acetylated amino acids [
]
Succinyl-diaminopimelate desuccinylase (
), which catalyses the hydrolysis of N-succinyl-L,L-diaminopimelic acid, forming succinate and LL-2,6-diaminoheptanedioate (DAP, a component of bacterial cell walls) [
]
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| Protein Domain |
| Name: |
Aldo-keto reductase |
| Type: |
Family |
| Description: |
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: |
Aspartate/glutamate/uridylate kinase |
| Type: |
Domain |
| Description: |
This entry contains proteins with various specificities and includes the aspartate, glutamate and uridylate kinase families. In prokaryotes and plants the synthesis of the essential amino acids lysine and threonine is predominantly regulated by feed-back inhibition of aspartate kinase (AK) and dihydrodipicolinate synthase (DHPS). In Escherichia coli, thrA, metLM, and lysC encode aspartokinase isozymes that show feedback inhibition by threonine, methionine, and lysine, respectively [
]. The lysine-sensitive isoenzyme of aspartate kinase from spinach leaves has a subunit composition of 4 large and 4 small subunits []. In plants although the control of carbon fixation and nitrogen assimilation has been studied in detail, relatively little is known about the regulation of carbon and nitrogen flow into amino acids. The metabolic regulation of expression of an Arabidopsis thaliana aspartate kinase/homoserine dehydrogenase (AK/HSD) gene, which encodes two linked key enzymes in the biosynthetic pathway of aspartate family amino acids has been studied [
]. The conversion of aspartate into either the storage amino acid asparagine or aspartate family amino acids may be subject to a coordinated, reciprocal metabolic control, and this biochemical branch point is a part of a larger, coordinated regulatory mechanism of nitrogen and carbon storage and utilization. |
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| Protein Domain |
| Name: |
Sec1-like, domain 2 |
| Type: |
Homologous_superfamily |
| Description: |
Sec1-like molecules have been implicated in a variety of eukaryotic vesicle transport processes including neurotransmitter release by exocytosis [
].They regulate vesicle transport by binding to a t-SNARE from the syntaxin family. This process is thought to prevent SNARE complex formation, a protein complex required for membrane fusion. Whereas Sec1 molecules are essential for neurotransmitter release and other secretory events, their interaction with syntaxin molecules seems to represent a negative regulatory step in secretion []. The nSec1 polypeptide chain can be divided into three domains. The first domain, consists of a five-stranded parallel β-sheet flanked by five α-helices. The second domain, like the first one, has an α-β-alpha fold, however the β-sheet of domain 2 features five parallel strands with an additional antiparallel strand on one edge. The third domain is a large insertion between the third and fourth parallel strands of domain 2, and can be subdivided in two [
].This entry represents domain 2 from the Sec1 family which includes Sec1, Sly1, Slp1/Vps33, yeast Vps45/Stt10, Unc-18 from nematodes, Munc-18b/muSec1, Munc-18c from mouse, Rop from Drosophila, Munc-18/n-Sec1/rbSec1A and rbSec1B from rat [
,
,
,
]. |
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| Protein Domain |
| Name: |
Ribonuclease T2-like |
| Type: |
Family |
| Description: |
Ribonuclease T2 (RNase T2) is a widespread family of secreted RNases found in every organism examined thus far. This family includes RNase Rh, RNase MC1, RNase LE, and self-incompatibility RNases (S-RNases) [
,
,
,
,
]. Plant T2 RNases are expressed during leaf senescence in order to scavenge phosphate from ribonucleotides. They are also expressed in response to wounding or pathogen invasion. S-RNases are thought to prevent self-fertilization by acting as selective cytotoxins of "self"pollen. Generally, RNases have two distinct binding sites: the primary site (B1 site) and the subsite (B2 site), for nucleotides located at the 5'- and 3'- terminal ends of the sissile bond, respectively.
The fungal ribonucleases T2 from Aspergillus oryzae, M from Aspergillus saitoi and Rh from Rhizopus niveus are structurally and functionally related 30 Kd glycoproteins [
] that cleave the 3'-5' internucleotide linkage of RNA via a nucleotide 2',3'-cyclic phosphate intermediate (). Two histidines residues have been shown [
,
] to be involved in the catalytic mechanism of RNase T2 and Rh. These residues and the region around them are highly conserved in a number of other RNAses that have been found to be evolutionary related to these fungal enzymes. |
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| Protein Domain |
| Name: |
Alpha/beta hydrolase fold-1 |
| Type: |
Domain |
| Description: |
The α/β hydrolase fold [
] is common to a number of hydrolytic enzymes of widely differing phylogenetic origin and catalytic function. The core of each enzyme is an α/β-sheet (rather than a barrel), containing 8 strands connected by helices []. The enzymes are believed to have diverged from a common ancestor, preserving the arrangement of the catalytic residues. All have a catalytic triad, the elements of which are borne on loops, which are the best conserved structural features of the fold. Esterase (EST) from Pseudomonas putida is a member of the α/β hydrolase fold superfamily of enzymes [].In most of the family members the β-strands are parallel, but some have an inversion of the first strands, which gives it an antiparallel orientation. The catalytic triad residues are presented on loops. One of these is the nucleophile elbow and is the most conserved feature of the fold. Some other members lack one or all of the catalytic residues. Some members are therefore inactive but others are involved in surface recognition. The ESTHER database [
] gathers and annotates all the published information related to gene and protein sequences of this superfamily [].This entry represents fold-1 of alpha/beta hydrolase. |
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| Protein Domain |
| Name: |
Phosphotransferase system EIIB, cysteine phosphorylation site |
| Type: |
Conserved_site |
| Description: |
The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) [
,
] is a major carbohydrate transport system in bacteria. The PTS catalyzes the phosphorylation of incoming sugar substrates concomitant with their translocation across the cell membrane. The general mechanism of the PTS is the following: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred to enzyme-I (EI) of PTS which in turn transfers it to a phosphoryl carrier protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar-specific permease which consists of at least three structurally distinct domains (IIA, IIB, and IIC) [] which can either be fused together in a single polypeptide chain or exist as two or three interactive chains, formerly called enzymes II (EII) and III (EIII).The first domain (IIA) carries the first permease-specific phoshorylation site, a histidine, which is phosphorylated by phospho-HPr. The second domain (IIB) is phosphorylated by phospho-IIA on a cysteinyl or histidyl residue, depending on the permease. Finally, the phosphoryl group is transferred from the IIB domain to the sugar substrate in a process catalyzed by the IIC domain; this process is coupled to the transmembrane transport of the sugar.This entry covers the phosphorylation site of EIIB domains. |
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| Protein Domain |
| Name: |
Bacterial lipid A biosynthesis 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 molecules are 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.The bacterial lipid A biosynthesis protein, or lipid A biosynthesis (KDO)2-(lauroyl)-lipid IVA acyltransferase
, transfers myristate or laurate, activated on ACP, to the lipid IVA moiety of (KDO)2-(lauroyl)-lipid IVA during lipopolysaccharide core biosynthesis []. |
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| Protein Domain |
| Name: |
Phytochelatin synthase, N-terminal domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Phytochelatins are well known as the heavy metal-detoxifying peptides in higher plants, eukaryotic algae, fungi, nematode and cyanobacteria. Phytochelatin synthase (PCS, also known as glutathione gamma-glutamylcysteinyltransferase;
) is involved in the synthesis of phytochelatins (PC) and homophytochelatins (hPC). This enzyme is required for detoxification of heavy metals such as cadmium and arsenate. The N-terminal region of phytochelatin synthase contains the active site, as well as four highly conserved cysteine residues that appear to play an important role in heavy-metal-induced phytochelatin catalysis. The C-terminal region is rich in cysteines, and may act as a metal sensor, whereby the Cys residues bind cadmium ions to bring them into closer proximity and transferring them to the activation site in the N-terminal catalytic domain [
]. The C-terminal region displays homology to the functional domains of metallothionein and metallochaperone.This entry represents the N-terminal catalytic PCS domain superfamily. Proteins in this entry belong to the peptidase family C83 of the papain superfamily of cysteine proteases, with a structurally conserved "catalytic triad"and oxyanion hole in the active site. It has an overall "crescent"shape with alpha/beta fold containing eight α-helices and six β-strands [
]. |
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| Protein Domain |
| Name: |
Synaptotagmin-13, C2B domain |
| Type: |
Domain |
| Description: |
Synaptotagmin-13 (Syt13), a member of class 6 synaptotagmins, belongs to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains (also known as C2A and C2B domains). Most of the synaptotagmins have a unique N-terminal domain (transmembrane region) that is involved in membrane anchoring or specific ligand binding. Unlike most of the synaptotagmins, SYT13 does not have an N-terminal transmembrane region. Its C2 domains are lacking almost all the residues involved in Ca2+ binding [
]. It is highly expressed in brain and also detectable at lower levels in non-neuronal tissues []. SYT13 can suppress liver tumour cells and this function may be mediated through pathways implicated in mesenchymal to epithelial transition []. It also affects insulin secretion []. This entry represents the second and C-terminal C2 domain (C2B), responsible for the binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence. It also regulates also the recycling step of synaptic vesicles. This domain folds into an eight-standed β-sandwich with a Type I arrangement that shows a circular permutation involving their N- and C-terminal β-strands [,
,
]. |
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| Protein Domain |
| Name: |
NSP1 globular domain superfamily, betacoronavirus |
| Type: |
Homologous_superfamily |
| Description: |
Nonstructural protein 1 (NSP1) is a critical virulence factor of coronaviruses (CoV) and plays key roles in suppressing host gene expression, which facilitates viral replication and immune evasion. NSP1 is a characteristic feature of alpha and betacoronavirus, which exhibits both functional conservation and mechanistic diversity in inhibiting host gene expression and antiviral responses [
,
,
,
]. NSP1 binds to the 40S ribosomal subunit and inhibits host translation, and it also induces a template-dependent endonucleolytic cleavage of host mRNAs [,
,
,
,
], while viral mRNAs are less susceptible to NSP1-mediated inhibition of translation, because of their 5'-end leader sequence [,
]. NSP1 also suppresses the host innate immune functions by inhibiting type I interferon expression and host antiviral signalling pathways. The C-terminal domain binds to the mRNA entry tunnel interfering with mRNA binding () [
,
,
]. NSP1 consists of a globular domain arranged in a mixed parallel/antiparallel 6-stranded β-barrel with an α-helix covering one end of the barrel and another helix alongside the barrel []. In addition to the globular domain, bCoV NSP1s havea C-terminal domain [
,
,
]. |
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| Protein Domain |
| Name: |
Novel toxin 21 superfamily |
| Type: |
Homologous_superfamily |
| Description: |
This entry represents an RNase toxin found in bacterial polymorphic toxin systems that is proposed to adopt the BECR (Barnase-EndoU-ColicinE5/D-RelE) fold, with two conserved lysine residues and [DS]xDxxxH, RxG[ST]and RxxD motifs. In bacterial polymorphic toxin systems, the toxin is usually exported by the type 2, type 4, type 5 or type 7 secretion system [
]. This is also referred to as the E. cloacae CdiAC and has been shown to target tRNAs [].The CdiAC proteins carry a variety of sequence-diverse C-terminal domains, which represent a collection of distinct toxins [
]. Many CdiA-CT toxins have nuclease activities. In accord with the structural homology, CdiA-CT cleaves 16S rRNA at the same site as colicin E3 and this nuclease activity is responsible for growth inhibition []. These toxins are composed of three domains, each responsible for a distinct step in the cell-killing pathway. The central domain binds specific receptors on the surface of susceptible bacteria, the N-terminal domain mediates translocation across the cell envelope, and the C-terminal domain carries the bacteriocidal activity. This modular structure allows for delivery of diverse C-terminal toxins using conserved translocation and receptor-binding domains []. |
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| Protein Domain |
| Name: |
G-box binding factor 1-like, bZIP domain, plant |
| Type: |
Domain |
| Description: |
This domain can be found in plant bZIP transcription factors, including Arabidopsis thaliana G-box binding factor 1 (GBF1) [
], Zea mays Opaque-2 [] and Ocs element-binding factor 1 (OCSBF-1) [], Triticum aestivum Histone-specific transcription factor HBP1 (or HBP-1a) [], Petroselinum crispum Light-inducible protein CPRF3 and CPRF6, and Nicotiana tabacum BZI-3 [], among many others []. Opaque-2 plays a role in affecting lysine content and carbohydrate metabolism, acting indirectly on starch/amino acid ratio []. bZIP G-box binding factors (GBFs) contain an N-terminal proline-rich domain in addition to the bZIP domain. GBFs are involved in developmental and physiological processes in response to stimuli such as light or hormones [,
]. bZIP factors act in networks of homo and heterodimers in the regulation of a diverse set of cellular processes. The bZIP structural motif contains a basic region and a leucine zipper, composed of alpha helices with leucine residues 7 amino acids apart, which stabilize dimerization with a parallel leucine zipper domain. Dimerization of leucine zippers creates a pair of the adjacent basic regions that bind DNA and undergo conformational change. Dimerization occurs in a specific and predictable manner resulting in hundreds of dimers having unique effects on transcription []. |
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| Protein Domain |
| Name: |
Adrenoceptor family |
| Type: |
Family |
| Description: |
The adrenoceptors (or adrenergic receptors) are rhodopsin-like G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline). Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system, effect blood pressure, myocardial contractile rate and force, airway reactivity, and a variety of metabolic and central nervous system functions. The clinical uses of adrenergic compounds are vast. Agonists and antagonists interacting with adrenoceptors have proved useful in the treatment of a variety of diseases, including hypertension, angina pectoris, congestive heart failure, asthma, depression, benign prostatic hypertrophy, and glaucoma. These drugs are also useful in several other therapeutic situations including shock, premature labour and opioid withdrawal, and as adjuncts to general anaesthetics.There are three classes of adrenoceptors, based on their sequence similarity, receptor pharmacology and signalling mechanisms [
]. These three classes are alpha 1 (a Gq coupled receptor), alpha 2 (a Gi coupled receptor) and beta (a Gs coupled receptor), and each can be further divided into subtypes []. The different subtypes can coexist in some tissues, but one subtype normally predominates.This entry represents the adrenoceptor family. |
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| Protein Domain |
| Name: |
Flavin monooxygenase (FMO) 1 |
| Type: |
Family |
| Description: |
Flavin-containing monooxygenases (FMOs) constitute a family of xenobiotic-
metabolising enzymes []. Using an NADPH cofactor and FAD prosthetic group, these microsomal proteins catalyse the oxygenation of nucleophilic nitrogen, sulphur, phosphorous and selenium atoms in a range of structurally diverse compounds. FMOs have been implicated in the metabolism of a number of pharmaceuticals, pesticides and toxicants. In man, lack of hepatic FMO-catalysed trimethylamine metabolism results in trimethylaminuria (fish odour syndrome). Five mammalian forms of FMO are now known and have been designated FMO1-FMO5 [
,
,
,
,
].Human FMO1 mRNA is more abundant in foetal than in adult liver, indicating
that the enzyme is subject to developmental regulation in man []. The deduced amino sequence contains putative FAD- (GxGxxG) and NADP+-binding (GxGxxA) sites, a 'FATGY' motif that has also been observed in a range of siderphore biosynthetic enzymes [
], and a C-terminal hydrophobic segment that is believed to anchor the monooxygenase to the microsomal membrane []. The human sequence shares 88 and 86% identity, respectively, with pig and rabbit 'hepatic' forms of FMO, but is only 58% similar to the abbit 'pulmonary' FMO []. |
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| Protein Domain |
| Name: |
Glucose transporter, type 1 (GLUT1) |
| Type: |
Family |
| Description: |
Facilitative sugar transport is mediated by members of the GLUT transporter family, which form an aqueous pore across the membrane through which sugars can move in a passive (i.e., energy-independent) manner. The GLUT family of glycosylated transmembrane proteins are predicted to span the membrane 12 times with both amino- and carboxyl-termini located in the cytosol. On the basis of sequence homology and structural similarity, three subclasses of sugar transporters have been defined: Class I (GLUTs 1-4) are glucose transporters; Class II (GLUTs 5, 7, 9 and 11) are fructose transporters; and Class III (GLUTs 6, 8, 10, 12 and HMIT1) are structurally atypical members of the GLUT family, which are poorly defined at present, indeed GLUT6 may only be a pseudo-gene [
,
,
,
,
].This entry represents GLUT1 (also called HepG2), which is the most ubiquitously distributed of the glucose transporter isoform. It is highly expressed in foetal tissues and adult brain microvessels. It is thought to provide
glucose transport in various cells that form barriers between body tissuesand the blood supply. It is found in epithelial and endothelial barrier
cells, such as those that constitute the blood-brain barrier, and also inthe placenta. |
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| Protein Domain |
| Name: |
FAD synthetase with the MoaB/Mog domain |
| Type: |
Family |
| Description: |
This group represents a predicted FAD synthetase with the MoaB/Mog domain. It requires magnesium as a cofactor and is highly specific for ATP as a phosphate donor [
]. The cofactors FMN and FAD participate in numerous processes in all organisms, including mitochondrial electron transport, photosynthesis, fatty-acid oxidation, and metabolism of vitamin B6, vitamin B12 and folates []. This entry includes the eukaryotic enzymes.Riboflavin is converted into catalytically active cofactors (FAD and FMN) by the actions of riboflavin kinase (
), which converts it into FMN, and FAD synthetase (
), which adenylates FMN to FAD. Eukaryotes usually have two separate enzymes, while most prokaryotes have a single bifunctional protein that can carry out both catalyses, although exceptions occur in both cases. While eukaryotic monofunctional riboflavin kinase is orthologous to the bifunctional prokaryotic enzyme [
], the monofunctional FAD synthetase differs from its prokaryotic counterpart, and is instead related to the PAPS-reductase family []. The bacterial FAD synthetase that is part of the bifunctional enzyme has remote similarity to nucleotidyl transferases and, hence, it may be involved in the adenylylation reaction of FAD synthetases []. |
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| Protein Domain |
| Name: |
Profilin superfamily |
| Type: |
Homologous_superfamily |
| Description: |
This entry represents the Profilin superfamily, which are small eukaryotic proteins that have different functions. In plants, they are major allergens present in pollens [
].The majority of the Profilin family members binds to monomeric actin (G-actin) in a 1:1 ratio thus preventing the polymerisation of actin into filaments (F-actin). They can also in certain circumstance promote actin polymerisation [
]. However, some Profilin family members, such as Profilin4 from mammals, does not binds to actin and may have functions distinct from regulating actin dynamics []. It plays a role in the assembly of branched actin filament networks, by activating WASP via binding to WASP's proline rich domain []. Profilin may link the cytoskeleton with major signalling pathways by interacting with components of the phosphatidylinositol cycle and Ras pathway [,
].Some Profilins can also bind to polyphosphoinositides such as PIP2 [
]. Overall sequence similarity among profilinfrom organisms which belong to different phyla (ranging from fungi to mammals) is low, but the N-terminal region is relatively well conserved. The N-terminal region is thought to be involved in actin binding.
The Profilin structure has two α-helices and five-stranded antiparallel sheet, it has three alpha/beta/alpha layers. |
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| Protein Domain |
| Name: |
Metallothionein |
| Type: |
Family |
| Description: |
Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium, nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds [
,
]. An empirical classification into three classes has been proposed by Fowler and coworkers [] and Kojima []. Members of class I are defined to include polypeptides related in the positions of their cysteines to equine MT-1B, and include mammalian MTs as well as from crustaceans and molluscs. Class II groups MTs from a variety of species, including sea urchins,fungi, insects and cyanobacteria. Class III MTs are atypical polypeptides composed of gamma-glutamylcysteinyl units [
].This original classification system has been found to be limited, in the sense that it does not allow clear differentiation of patterns of structural similarities, either between or within classes. Subsequently, a new classification was proposed on the basis of sequence similarity derived from phylogenetic relationships, which basically proposes an MT family for each main taxonomic group of organisms [
]. This entry includes metallothioneins from vertebrates [
] and MT-10 type metallothioneins from aquatic molluscs []. |
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| Protein Domain |
| Name: |
Class II myosin, Myh3, motor domain |
| Type: |
Domain |
| Description: |
Developing skeletal muscles express unique myosin isoforms, including embryonic myosin heavy chain 3 (MYH3) [
]. This entry represents the myosin motor domain of MYH3 (MYHC-EMB, MYHSE1, HEMHC, SMHCE) in tetrapods including mammals, lizards, and frogs. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome [].Class II myosins, also called conventional myosins, are the myosin type responsible for producing actomyosin contraction in metazoan muscle and non-muscle cells. Myosin II contains two heavy chains made up of the head (N-terminal) and tail (C-terminal) domains with a coiled-coil morphology that holds the two heavy chains together. The intermediate neck domain is the region creating the angle between the head and tail. It also contains 4 light chains which bind the heavy chains in the 'neck' region between the head and tail. The head domain is a molecular motor, which utilizes ATP hydrolysis to generate directed movement toward the plus end along actin filaments [
,
,
]. |
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| Protein Domain |
| Name: |
Formyltetrahydrofolate deformylase, ACT domain |
| Type: |
Domain |
| Description: |
An Escherichia coli gene designated purU has been identified and characterised. The gene codes for a 280-amino-acid protein, PurU (
,
). PurU is an enzyme that catalyses the hydrolysis of 10-formyltetrahydrofolate (formyl-FH4) to FH4 and formate
[,
].10-formyltetrahydrofolate + H(2)O = formate +tetrahydrofolate Formyl-FH4 hydrolase generates the formate that is used by purT-encoded 5'-phosphoribosylglycinamide transformylase for step three of de novo purine nucleotide synthesis. Formyl-FH4 hydrolase, a hexamer of 32kDa subunits, is activated by methionine and inhibited by glycine. Heterotropic cooperativity is observed for activation by methionine in the presence of glycine and for inhibition by glycine in the presence of methionine. These results suggest that formyl-FH4 hydrolase is a regulatory enzyme whose main function is to balance the pools of FH4 and C1-FH4 in response to changing growth conditions. The enzyme uses methionine and glycine to sense the pools of C1-FH4 and FH4, respectively.This entry also includes PurU from Arabidopsis, which is involved in photorespiration. It prevents the excessive accumulation of 5-formyl tetrahydrofolate (THF), a potent inhibitor of the Gly decarboxylase/Ser hydroxymethyltransferase complex [
].This entry represents the N-terminal ACT domain of formyltetrahydrofolate deformylase. |
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| Protein Domain |
| Name: |
Lig-like, OB-fold domain |
| Type: |
Domain |
| Description: |
Bacterial DNA ligases are divided into two broad classes: NAD-dependent and ATP-dependent. All bacterial species have a NAD-dependent DNA ligase (LigA). Some bacterial genomes contain multiple genes for DNA ligases that are predicted to use ATP as their cofactor, including Mycobacterium tuberculosis LigB, LigC, and LigD. ATP dependent DNA ligases have a highly modular architecture consisting of a unique arrangement of two or more discrete domains including a DNA-binding domain, an adenylation (nucleotidyltransferase (NTase)) domain, and an oligonucleotide/oligosaccharide binding (OB)-fold domain []. The adenylation and C-terminal OB-fold domains comprise a catalytic core unit that is common to most members of the ATP-dependent DNA ligase family. The adenylation domain binds ATP and contains many of the active-site residues. The catalytic core unit contains six conserved sequence motifs (I, III, IIIa, IV, V and VI) that define this family of related nucleotidyltransferases. The OB-fold domain contacts the nicked DNA substrate and is required for the ATP-dependent DNA ligase nucleotidylation step. The RxDK motif (motif VI), which is essential for ATP hydrolysis, is located in the OB-fold domain [].This entry represents the OB-fold domain found in Mycobacterium tuberculosis LigC and related proteins. |
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| Protein Domain |
| Name: |
LigC-like, adenylation domain |
| Type: |
Domain |
| Description: |
Bacterial DNA ligases are divided into two broad classes: NAD-dependent and ATP-dependent. All bacterial species have a NAD-dependent DNA ligase (LigA). Some bacterial genomes contain multiple genes for DNA ligases that are predicted to use ATP as their cofactor, including Mycobacterium tuberculosis LigB, LigC, and LigD. ATP dependent DNA ligases have a highly modular architecture consisting of a unique arrangement of two or more discrete domains including a DNA-binding domain, an adenylation (nucleotidyltransferase (NTase)) domain, and an oligonucleotide/oligosaccharide binding (OB)-fold domain []. The adenylation and C-terminal OB-fold domains comprise a catalytic core unit that is common to most members of the ATP-dependent DNA ligase family. The adenylation domain binds ATP and contains many of the active-site residues. The catalytic core unit contains six conserved sequence motifs (I, III, IIIa, IV, V and VI) that define this family of related nucleotidyltransferases. The OB-fold domain contacts the nicked DNA substrate and is required for the ATP-dependent DNA ligase nucleotidylation step. The RxDK motif (motif VI), which is essential for ATP hydrolysis, is located in the OB-fold domain [].This entry represents the adenylation domain found in Mycobacterium tuberculosis LigC and related proteins. |
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| Protein Domain |
| Name: |
Acetylglutamate kinase-like superfamily |
| Type: |
Homologous_superfamily |
| Description: |
This entry contains proteins with various specificities and includes the acetylglutamate, aspartate, glutamate and uridylate kinase families. In prokaryotes and plants the synthesis of the essential amino acids lysine and threonine is predominantly regulated by feedback inhibition of aspartate kinase (AK) and dihydrodipicolinate synthase (DHPS). In Escherichia coli, thrA, metLM, and lysC encode aspartokinase isozymes that show feedback inhibition by threonine, methionine, and lysine, respectively [
]. The lysine-sensitive isoenzyme of aspartate kinase from spinach leaves has a subunit composition of 4 large and 4 small subunits [].In plants although the control of carbon fixation and nitrogen assimilation has been studied in detail, relatively little is known about the regulation of carbon and nitrogen flow into amino acids. The metabolic regulation of expression of an Arabidopsis thaliana aspartate kinase/homoserine dehydrogenase (AK/HSD) gene, which encodes two linked key enzymes in the biosynthetic pathway of aspartate family amino acids has been studied [
]. The conversion of aspartate into either the storage amino acid asparagine or aspartate family amino acids may be subject to a coordinated, reciprocal metabolic control, and this biochemical branch point is a part of a larger, coordinated regulatory mechanism of nitrogen and carbon storage and utilization. |
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| Protein Domain |
| Name: |
Poxvirus poly(A) polymerase, catalytic subunit, C-terminal |
| Type: |
Domain |
| Description: |
Poly(A) polymerase (
) catalyses template-independent extension of the 3'-end of a DNA or RNA strand by one nucleotide at a time. The Poxvirus enzyme creates the 3'(poly)A tail of mRNAs, and is a heterodimer of a catalytic and a regulatory subunit. The Poxvirus enzyme creates the 3'(poly)A tail of mRNAs, and is a heterodimer composed of a catalytic (VP55, also known as PAP-L) and a regulatory subunit (VP39). VP55 comprises three domains: the N-terminal or N domain, the central or catalytic domain, and the C-terminal or C domain, all three domains having distinct topologies. The core comprises a mixed nine-stranded twisted beta sheet, with the first seven strands being folded from one long (118 residue) polypeptide segment that follows the N domain and the last two strands originating from the extreme C-terminal-most 15 residues of the entire polypeptide chain. Of the four α-helices in the catalytic domain, the two longest (J and L) near the surface pack against one side of the β-sheet in a nearly parallel orientation to the β-strands []. This domain is found at the C terminus of the pox virus PolyA polymerase protein VP55 [
]. |
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| Protein Domain |
| Name: |
Poxvirus poly(A) polymerase, catalytic subunit, N-terminal |
| Type: |
Domain |
| Description: |
Poly(A) polymerase (
) catalyses template-independent extension of the 3'-end of a DNA or RNA strand by one nucleotide at a time. The Poxvirus enzyme creates the 3'(poly)A tail of mRNAs, and is a heterodimer of a catalytic and a regulatory subunit. The Poxvirus enzyme creates the 3'(poly)A tail of mRNAs, and is a heterodimer composed of a catalytic (VP55, also known as PAP-L) and a regulatory subunit (VP39). VP55 comprises three domains: the N-terminal or N domain, the central or catalytic domain, and the C-terminal or C domain, all three domains having distinct topologies. The core comprises a mixed nine-stranded twisted beta sheet, with the first seven strands being folded from one long (118 residue) polypeptide segment that follows the N domain and the last two strands originating from the extreme C-terminal-most 15 residues of the entire polypeptide chain. Of the four α-helices in the catalytic domain, the two longest (J and L) near the surface pack against one side of the β-sheet in a nearly parallel orientation to the β-strands [
]. This domain is found at the N terminus of the pox virus Poly(A) polymerase protein VP55 [
]. |
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| Protein Domain |
| Name: |
FMN hydroxy acid dehydrogenase domain |
| Type: |
Domain |
| Description: |
A number of oxidoreductases that act on alpha-hydroxy acids and which are
FMN-containing flavoproteins have been shown to be structurallyrelated [
,
,
,
]; these enzymes are:Lactate dehydrogenase (
), which consists of a dehydrogenase
domain and a heme-binding domain called cytochrome b2 and which catalyzesthe conversion of lactate into pyruvate.
Glycolate oxidase (
) ((S)-2-hydroxy-acid oxidase), a peroxisomal
enzyme that catalyzes the conversion of glycolate and oxygen to glyoxylateand hydrogen peroxide.
Long chain alpha-hydroxy acid oxidase from rat (
), a peroxisomal
enzyme.Lactate 2-monooxygenase (
) (lactate oxidase) from Mycobacterium
smegmatis, which catalyzes the conversion of lactate and oxygen to acetate,carbon dioxide and water.
(S)-mandelate dehydrogenase from Pseudomonas putida (gene mdlB), which
catalyzes the reduction of (S)-mandelate to benzoylformate.The first step in the reaction mechanism of these enzymes is the abstraction
of the proton from the α-carbon of the substrate producing a carbanionwhich can subsequently attach to the N5 atom of FMN. A conserved histidine has
been shown [] to be involved in the removal of the proton. Three-dimensional structures of FMN-dependent alpha-hydroxy aciddehydrogenases show a common fold with a TIM barrel structure.
This entry represents the FMN hydroxy acid dehydrogenase domain. |
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| Protein Domain |
| Name: |
Apyrase superfamily |
| Type: |
Homologous_superfamily |
| Description: |
This superfamily contains several eukaryotic apyrase (or adenosine diphosphatase) proteins (
), and related nucleoside diphosphatases (
). The salivary apyrases of blood-feeding arthropods are nucleotide hydrolysing enzymes implicated in the inhibition of host platelet aggregation through the hydrolysis of extracellular adenosine diphosphate [
,
]. Soluble calcium-activated nucleotidase 1 (CANT1) is the human homologue []. The structure of apyrase consists of five 4-stranded β-sheet motifs [
]. The apo structure reveals an unusual five-bladed beta propeller. The five twisted β-sheets (1-5), each formed from four antiparallel beta strands (a, b, c, and d), are radially arranged around a central tunnel. The interface between neighbouring blades is predominantly hydrophobic, with residues on the adjacent faces of the beta sheets in van der Waals contact. The central tunnel is slightly conical in shape and is lined with amide and carbonyl oxygen groups from the edges of the five inner strands, with only a few side chains projecting into the cavity. Structural and biochemical analysis suggests that the striking difference in substrate preference between human and insect apyrases (GDP versus ADP) results from divergence at one or more of the nonconserved active-site residues []. |
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| Protein Domain |
| Name: |
Homocysteine-binding domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
The homocysteine (Hcy) binding domain is an ~300-residue module which is found in a set of enzymes involved in alkyl transfer to thiols:Prokaryotic and eukaryotic B12-dependent methionine synthase (MetH) (EC 2.1.1.13), a large, modular protein that catalyses the transfer of a methyl group from methyltetrahydrofolate (CH3-H4folate) to Hcy to form methionine, using cobalamin as an intermediate methyl carrier.Mammalian betaine-homocysteine S-methyltransferase (BHMT) (EC 2.1.1.5). It catalyzes the transfer of a methyl group from glycine betaine to Hcy, forming methionine and dimethylglycine.Plant selenocysteine methyltransferase (EC 2.1.1.-).Plant and fungal AdoMet homocysteine S-methyltransferases (EC 2.1.1.10).The Hcy-binding domain utilises a Zn(Cys)3 cluster to bind and activate Hcy. It has been shown to form a (beta/alpha)8 barrel. The Hcy binding domain barrel is distorted to form the metal- and substrate-binding sites. To accommodate the substrate, strands 1 and 2 of the barrel are loosely joined by nonclassic hydrogen bonds; to accommodate the metal, strands 6 and 8 are drawn together and strand 7 is extruded from the end of the barrel. The cysteines ligating the catalytic zinc atom are located at the C-terminal ends of strands 6 and 8 [
,
]. |
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| Protein Domain |
| Name: |
Superoxide dismutase-like, copper/zinc binding domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Superoxide dismutases (SODs) are ubiquitous metalloproteins that prevent damage by oxygen-mediated free radicals by catalysing the dismutation of superoxide into molecular oxygen and hydrogen peroxide [
]. Superoxide is a normal by-product of aerobic respiration and is produced by a number of reactions, including oxidative phosphorylation and photosynthesis. The dismutase enzymes have a very high catalytic efficiency due to the attraction of superoxide to the ions bound at the active site [,
].There are three forms of superoxide dismutase, depending on the metal cofactor: Cu/Zn (which binds both copper and zinc), Fe and Mn types. The Fe and Mn forms are similar in their primary, secondary and tertiary structures, but are distinct from the Cu/Zn form [
]. Prokaryotes and protists contain Mn, Fe or both types, while most eukaryotic organisms utilise the Cu/Zn type. The Cu/Zn form has an immunoglobulin-like β-sandwich fold.Defects in the human SOD1 gene causes familial amyotrophic lateral sclerosis (Lou Gehrig's disease). Cytoplasmic and periplasmic SODs exist as dimers, whereas chloroplastic and extracellular enzymes exist as tetramers. Structural analysis supports the notion of independent functional evolution in prokaryotes (P-class) and eukaryotes (E-class) [
,
,
,
,
,
,
,
]. |
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| Protein Domain |
| Name: |
Cobalamin adenosyltransferase-like superfamily |
| Type: |
Homologous_superfamily |
| Description: |
ATP:cob(I)alamin (or ATP:corrinoid) adenosyltransferases (
), catalyse the conversion of cobalamin (vitamin B12) into its coenzyme form, adenosylcobalamin (AdoCbl)or coenzyme B12 [
]. AdoCbl contains an adenosyl moiety liganded to the cobalt ion of cobalamin via a covalent Co-C bond. AdoCbl is required as a cofactor for the activity of certain enzymes. ATP:cob(I)alamin adenosyltransferases are classed into three groups: CobA-type [
], EutT-type [] and PduO-type []. Each of the three enzyme types appears to be specialised for particular AdoCbl-dependent enzymes or for the de novo synthesis AdoCbl. PduO and EutT are distantly related, sharing short conserved motifs, while CobA is evolutionarily unrelated and is an example of convergent evolution. This entry represents a structural domain consisting of 4-helical bundle with a left-handed twist and one cross-over loop that goes across to a different side of the 4-helical bundle; there is no internal metal-binding site. This domain is found in EutT- and PduO-type ATP:cob(I)alamin adenosyltransferases. PduO functions to convert cobalamin to AdoCbl for 1,2-propanediol degradation [
], while EutT produces AdoCbl for ethanolamine utilisation []. This domain is also found in the hypothetical protein Ta1238 from the archaeon Thermoplasma acidophilum []. |
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| Protein Domain |
| Name: |
Proenkephalin B |
| Type: |
Family |
| Description: |
Vertebrate endogenous opioid neuropeptides are released by post-translational proteolytic cleavage of precursor proteins. The precursors consist of the following components: a signal sequence that precedes a conserved region of about 50 residues; a variable-length region; and the sequence of the neuropeptide itself. Three types of precursor are known: preproenkephalin A (gene PENK), which is processed to produce 6 copies of Met-enkephalin, plus Leu-enkephalin; preproenkephalin B (gene PDYN), which is processed to produce neoendorphin, dynorphin, leumorphin, rimorphin and Leu-enkephalin; and prepronocipeptin (gene PNOC), whose processing produces nociceptin (orphanin FQ) and two other potential neuropeptides.Sequence analysis reveals that the conserved N-terminal region of the precursors contains 6 cysteines, which are probably involved in disulphide bond formation. It is speculated that this region might be important for neuropeptide processing [
].The primary structure of Sus scrofa (Pig) preproenkephalin B has been elucidated and shown to contain neoendorphin, dynorphin and leumorphin (containing rimorphin as its N terminus). These opioid peptides, each having a Leu-enkephalin structure, act on the kappa-receptor. The sequence similarity observed between preproenkephalin B and preproenkephalin A, coupled with the similarity between their gene organisations, suggests that the two genes have been generated from a common
ancestor by gene duplication []. |
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| Protein Domain |
| Name: |
Neural cell adhesion |
| Type: |
Family |
| Description: |
Neural cell adhesion molecules (NCAM) are cell surface glycoproteins that
share structural motifs related to immunoglobulin (Ig) and fibronectin typeIII (FNIII) domains. Expressed in neurons, glial cells and skeletal muscle,
NCAM binds both homophilically and heterophilically, mediating processessuch as neural cell growth and migration [
,
,
]. Polysialic acid binds toN-glycosylation sites in the Ig domains, affecting the binding of NCAM.
Decreasing levels of sialynation on NCAM promotes aggregation, and isthought to be important in regulation of tissue stability [
].The full length transcript contains (from N terminus to C terminus) five Ig
domains, two FNIII domains, a transmembrane (TM) region and a cytosolicdomain. Alternative splicing is known to generate at least four products
with (apparent desialylated) molecular weights of 180, 140, 120 and 105kDa.The longer TM products are expressed in neurons (180 and 140kDa) and glial
cells (140kDa), whereas the 120kDa product is GPI-anchored on the surfaceof myotubes and the 105kDa product is secreted (for review see [
]).Further splice variation arises from a variable alternatively spliced exon
(VASE) in the fourth Ig domain and a muscle-specific domain (MSD) betweenthe two FNIII domains containing an O-glycosylation site.
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| Protein Domain |
| Name: |
Vascular endothelial growth factor receptor 1 (VEGFR1) |
| Type: |
Family |
| Description: |
Vascular endothelial growth factor (VEGF) is a potent and specific endothelial cell mitogen that regulates blood and lymphatic vessel development and homeostasis [,
]. EGFs are predominantly produced by endothelial, hematopoietic, and stromal cells in response to hypoxia and upon stimulation by growth factors such as transforming growth factor beta (TGFbeta), interleukins, or platelet-derived growth factors []. VEGFs specifically interact with one or several receptor tyrosine kinases, VEGF receptors, and with distinct co-receptors such as neuropilins or heparan sulphate glycosaminoglycans. The VEGF receptor family consists of three members, VEGFR1 (FLT1), VEGFR2 (KDR/FLK1) and VEGFR3 (FLT4) []. Among these receptors, VEGFR1 binds strongest to VEGF, VEGF2 binds more weakly, and VEGFR3 shows essentially no binding, although it does bind to other members of the VEGF family. VEGF receptors have a characteristic structure, with 7 Ig-like domains in the extracellular domain and a cytoplasmic tyrosine kinase domain with a long kinase insert region. VEGF receptors are activated upon ligand-mediated dimerisation.This entry represents the VEGFR1 proteins. A null mutation of VEGFR1 in mice results in lethality in early embryogenesis, owing to a disorganisation of blood vessels and an overgrowth of endothelial-like cells. |
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| Protein Domain |
| Name: |
Ras-like guanine nucleotide exchange factor, N-terminal |
| Type: |
Domain |
| Description: |
The N-terminal domain of guanine nucleotide exchange factor (GEF) for Ras-like GTPases is also called REM domain (Ras exchanger motif). REM contacts the GTPase and is assumed to participate in the catalytic activity of the exchange factor. Proteins with the REM domain include Sos1 and Sos2, which relay signals from tyrosine-kinase mediated signalling to Ras, RasGRP1-4, RasGRF1,2, CNrasGEF, and RAP-specific nucleotide exchange factors, to name a few [
,
,
,
,
,
,
,
].The crystal structure of the GEF region of human Sos1 complexes with Ras hasbeen solved [
]. The structure consists of two distinct alpha helical structural domains: the N-terminal domain which seems to have a purely structural role and the C-terminal domain which is sufficient for catalyticactivity and contains all residues that interact with Ras. A main feature of
the catalytic domain is the protrusion of a helical hairpin important for thenucleotide-exchange mechanism. The N-terminal domain is likely to be important
for the stability and correct placement of the hairpin structure.This entry represents a domain found in several GEF for Ras-like small GTPases which lies N-terminal to the RasGef (Cdc25-like) domain.
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| Protein Domain |
| Name: |
HAD-superfamily phosphatase, subfamily IIIB, AphA |
| Type: |
Family |
| Description: |
This family of proteins is a member of the IIIB subfamily (
) of the haloacid dehalogenase (HAD) superfamily of hydrolases. All characterised members of subfamily III and most characterised members of the HAD superfamily are phosphatases. HAD superfamily phosphatases contain active site residues in several conserved catalytic motifs [
], all of which are found conserved in this family.AphA is a periplasmic acid phosphatase of Escherichia coli [
] belonging to class B bacterial phosphatases [], which is part of the DDDD superfamily of phosphohydrolases. The crystal structure of AphA has been determined at 2.2A and its resolution extended to 1.7A. Despite the lack of sequence homology, the AphA structure reveals a haloacid dehalogenase-like fold. This finding suggests that this fold could be conserved among members of the DDDD superfamily of phosphohydrolases. The active enzyme is a homotetramer built by using an extended N-terminal arm intertwining the four monomers. The active site of the native enzyme hosts a magnesium ion, which can be replaced by other metal ions. The structure explains the non-specific behaviour of AphA towards substrates, while a structure-based alignment with other phosphatases provides clues about the catalytic mechanism [
]. |
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| Protein Domain |
| Name: |
Thrombospondin-5, coiled coil domain |
| Type: |
Domain |
| Description: |
This entry represents the N-terminal coiled coil region of TSP-5, also known as cartilage oligomeric matrix protein (COMP). It forms a pentameric left-handed coiled coil (COMPcc) with a channel that is a unique carrier for lipophilic compounds [
]. It is known to bind hydrophilic signaling molecules such as vitamin D3 and vitamin A, making it a possible targeted drug delivery system []. TSP-5/COMP is expressed in all types of cartilage as well as in the vitreous of the eye, tendons, vascular smooth muscle cells, and heart. The pentamer is stabilized by inter-subunit disulfide bonds formed between cysteine residues adjacent to the C-terminal end of the coiled coil region []. TSP-5 is essential for modulating the phenotypic transition of vascular smooth muscle cells and vascular remodeling. Mutations in TSP-5 result in two different inherited chondrodysplasias and osteoarthritic phenotypes: pseudoachondroplasia and multiple epithelial dysplasia [
]. Deficiency of TSP-5 causes dilated cardiomyopathy (DCM), a common cause of congestive heart failure []. Early increase in serum TSP-5 is associated with joint damage progression in patients with rheumatoid arthritis, thus representing a novel indicator of an activated destructive process in the joint []. |
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| Protein Domain |
| Name: |
Cell wall/vacuolar inhibitor of fructosidase |
| Type: |
Family |
| Description: |
This entry represents a group of invertase inhibitors, known as cell wall/vacuolar inhibitor of fructosidase (C/VIF1) from plants. Cell-wall invertases (CWIs) are secreted apoplastic enzymes belonging to the glycoside hydrolase family 32 (
) that catalyze the hydrolytic cleavage of the disaccharide sucrose into glucose and fructose. Their activity is tightly regulated by compartment-specific inhibitor proteins at transcriptional and post-transcriptional levels [
]. Invertase inhibitors are structurally similar to those of pectin methylesterase (PMEIs), an enzyme that is involved in the control of pectin metabolism and is structurally unrelated to invertases. All inhibitors share a size of about 18kDa, two strictly conserved disulfide bridges and only moderate sequence homology (about 20% sequence identity). Interaction of invertase inhibitor Nt-CIF (Nicotiana tabacum cell-wall inhibitor of beta-fructosidase) with CWI is strictly pH-dependent, modulated between pH 4 and 6, with rapid dissociation at neutral pH mediated by structure rearrangement or surface charge pattern in the binding interface [
]. Comparison of the CIF/INV1 structure with the complex between the structurally CIF-related pectin methylesterase inhibitor (PMEI) and pectin methylesterase indicates a common targeting mechanism in PMEI and CIF []. |
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| Protein Domain |
| Name: |
Tumor necrosis factor receptor 27, N-terminal |
| Type: |
Domain |
| Description: |
TNFRSF27 (also known as ectodysplasin-A2 receptor (EDA2R), X-linked ectodermal dysplasia receptor (XEDAR), EDAA2R, EDA-A2R) is a member of the TNFR superfamily that is recognised by ectodysplasin-A2 (EDA-A2), which is generated by alternative splicing of the EDA receptor (EDAR) ligand EDA-A1 [
]. It is highly expressed during embryonic development and binds to ectodysplasin-A2 (EDA-A2), playing a crucial role in the p53-signaling pathway. EDA2R is a direct p53 target that is frequently down-regulated in colorectal cancer tissues due to its epigenetic alterations or through the p53 gene mutations [,
]. Mutations in the EDA-A2/XEDAR signaling give rise to ectodermal dysplasia, characterized by loss of hair, sweat glands, and teeth []. A non-synonymous SNP on EDA2R, along with genetic variants in human androgen receptor is associated with androgenetic alopecia (AGA) [].This entry represents the N-terminal domain of TNFRSF27/XEDAR. 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: |
Ras and Rab interactor 3, SH2 domain |
| Type: |
Domain |
| Description: |
RIN3, a member of the RIN (AKA Ras interaction/interference) family, have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs. RIN3 stimulates the formation of GTP-bound Rab31, a Rab5-subfamily GTPase, and forms enlarged vesicles and tubular structures, where it colocalizes with Rab31. Transferrin appears to be transported partly through the RIN3-positive vesicles to early endosomes. RIN3 interacts via its Pro-rich domain with amphiphysin II, which contains an SH3 domain and participates in receptor-mediated endocytosis. RIN3, a Rab5 and Rab31 GEF, plays an important role in the transport pathway from plasma membrane to early endosomes. Mutations in the region between the SH2 and RH domain of RIN3 specifically abolished its GEF action on Rab31, but not Rab5. RIN3 was also found to partially translocate the cation-dependent mannose 6-phosphate receptor from the trans-Golgi network to peripheral vesicles and that this is dependent on its Rab31-GEF activity. These data indicate that RIN3 specifically acts as a GEF for Rab31 [
]. This entry represents the SH2 domain of RIN3. |
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| Protein Domain |
| Name: |
Insulin-like growth factor I |
| Type: |
Family |
| Description: |
The insulin family of proteins groups together several evolutionarily related active peptides [
]: these include insulin [,
], relaxin [,
], insect prothoracicotropic hormone (bombyxin) [], insulin-like growth factors (IGF1 and IGF2) [,
], mammalian Leydig cell-specific insulin-like peptide (gene INSL3), early placenta insulin-like peptide (ELIP) (gene INSL4), locust insulin-related peptide (LIRP), molluscan insulin-related peptides (MIP) and Caenorhabditis elegans insulin-like peptides. The 3D structures of a number of family members have been determined [,
,
]. The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of 4 cysteines in their A chain, the first of which is linked by a disulphide bond to the third, while the second and fourth are linked by interchain disulphide bonds to cysteines in the B chain. The IGFs, or somatomedins, play a key role in pre-adolescent mammalian growth. IGFI expression is regulated by growth hormone and mediates post-natal growth [
]. Defects in IGF1 are the cause of insulin-like growth factor I deficiency (IGF1 deficiency), an autosomal recessive disorder characterised by growth retardation, sensorineural deafness and mental retardation []. |
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| Protein Domain |
| Name: |
AMP nucleosidase, phosphorylase domain |
| Type: |
Domain |
| Description: |
AMP nucleosidase (AMN) catalyses the hydrolysis of AMP to form adenine and ribose 5-phosphate. It is only found in prokaryotes, where it plays a role in purine nucleoside salvage and intracellular AMP level regulation [
]. The gene for AMP nucleosidase from Escherichia coli (amn) encodes a protein of 483 amino acids. A comparison of the amino acid sequence for AMP nucleosidase with that for yeast AMP deaminase shows that there is a region where only six out of eight amino acids are identical but there is no other overall homology. AMN also showed little similarity to consensus sequences for adenylate binding sites even though the enzyme is known to have a catalytic site for AMP and regulatory sites for MgATP and phosphate []. The enzyme is a homohexamer, and each monomer has two domains: a catalytic domain and a putative regulatory domain. The overall topology of the catalytic domain and some features of the substrate binding site resemble those of the nucleoside phosphorylases. The structure of the regulatory domain consists of a long helix and a four-stranded sheet, but has a novel topology [
]. This entry represents the phosphorylase domain from AMP nucleosidase. |
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| Protein Domain |
| Name: |
Isopropylmalate/citramalate/homocitrate synthase |
| Type: |
Domain |
| Description: |
Methanogenic archaea contain three closely related homologues of the 2-isopropylmalate synthases (LeuA) represented by
. Two of these in Methanococcus janaschii (MJ1392 - CimA [
]; MJ0503 - AksA []) have been characterised as catalyzing alternative reactions leaving the third (MJ1195) as the presumptive LeuA enzyme. CimA is citramalate (2-methylmalate) synthase, which condenses acetyl-CoA with pyruvate. This enzyme is believed to be involved in the biosynthesis of isoleucine in methanogens and possibly other species lacking threonine dehydratase. AksA is a homocitrate synthase which also produces (homo)2-citrate and (homo)3-citrate in the biosynthesis of Coenzyme B which is restricted solely to methanogenic archaea. Methanogens, then should and apparently do contain all three of these enzymes. Unfortunately, phylogenetic trees do not resolve into three unambiguous clades, making assignment of function to particular genes problematic. Other archaea, which lack a threonine dehydratase (mainly Euryarchaeota), should contain both CimA and LeuA genes. This is true for archaeoglobus fulgidis, but not for the Pyrococci which have none in this clade, but one in and one in
which may fulfil these roles. Proteins from other species, which have only one hit to this entry and lack threonine dehydratase, are very likely to be LeuA enzymes.
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| Protein Domain |
| Name: |
Single-minded, C-terminal |
| Type: |
Domain |
| Description: |
In Drosophila, single-minded (sim) is a transcription factor that acts as the master regulator of neurogenesis. Two mammalian homologues of Sim which have been identified, Sim1 and Sim2, are novel heterodimerisation partners for ARNT in vitro, and may function both as positive and negative transcriptional regulators in vivo, during embryogenesis and in the adult organism [
]. SIM2 is thought to contribute to some specific Down syndrome phenotypes []. There is a high level of homology among mammalian and Drosophila sim proteins in their amino-terminal half where the conserved bHLH, PAS () and PAC motifs are present (
). The PAC region occurs C-terminal to the PAS domains and are proposed to contribute to the PAS domain fold [
,
,
]. In contrast, the carboxy-terminal parts are only conserved in vertebrates []. The Sim1 C terminus contains a Ser-rich region, whereas the Sim2 C terminus both contain Ser/Thr-rich regions, Pro/Ser-rich regions, Pro/Ala-rich regions, and positively charged regions. Sim2s, a splice variant of Sim2, still contains the Ser/Thr- and Pro/Ser-rich regions shown to harbor repressive activities, but is missing the Pro/Ala-rich repressor region [,
,
]. |
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| Protein Domain |
| Name: |
ATPase, RavA, C-terminal |
| Type: |
Domain |
| Description: |
This domain is found at the C-terminal of bacterial regulatory ATPase RavA (Regulatory ATPase variant A)
[
,
]. RavA consists of three domains: the N-terminal domain is the AAA+ module, which is composed of two subdomains, the α-β-alpha subdomain with a Rossmann-type fold commonly found in nucleotide binding proteins and the all-alpha subdomain consisting of four antiparallel α-helices; the second domain is a discontinuous triple-helical domain which has a rigid structure stabilised by hydrophobic interactions localised at the interface between the three helices; and the third domain, named the LARA domain which forms a compact antiparallel β-barrel-like structure consisting of six β-strands and one α-helix [,
]. RavA forms an hexamer in which the triple helical domain mediates the lateral interactions between neighbouring RavA monomers []. This is the second subdomain that forms the discontinuous triple helical domain [
] and contains single completely conserved phenylalanine residue that makes hydrophobic contacts with the AAA+ module resulting in anchoring the triple-helical domain to the AAA+ module. This conserved Phe might serve to transmit the nucleotide-dependent conformational changes in the AAA+ domain to the C-terminal triple-helical and LARA domains of RavA []. |
|
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•
•
•
|
| Protein Domain |
| Name: |
Legumain prodomain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Asparaginyl endopeptidase, also known as legumain, is a family of cysteine proteases found in many organisms. This group of cysteine peptidases belong to the MEROPS peptidase family C13 (legumain family, clan CD). A type example is legumain from Canavalia ensiformis (Jack bean, Horse bean) [
]. Although legumains were first described from beans (also known as Vacuolar Processing Enzymes), homologues have been identified in plants, protozoa, vertebrates, and helminths [,
]. In blood-feeding helminths, asparaginyl endopeptidases (sometimes described as hemoglobinases) have been located in the gut and are considered to be involved in host hemoglobin digestion [,
,
,
].This domain is found in the proenzyme form legumain (also known of Vacuolar-processing enzyme). The mature active form of these proteins is generated by autoproteolytic maturation at acidic pH. In the 3D structure of the proenzyme, this prodomain is located on top of the protease domain, blocking access to the active site, conferring enzymatic latency and conformational stability. It shows an entirely α-helical fold, with an activation peptide and a region that assemblies into a death domain-like fold at the C-terminal (also referred to as as legumain stabilization and activity modulation (LSAM) domain) []. |
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•
•
|
| Protein Domain |
| Name: |
NSP1, globular domain, alpha/betacoronavirus |
| Type: |
Domain |
| Description: |
This is the globular domain of NSP1 from alpha and betacoronavirus.
Nonstructural protein 1 (NSP1) is a critical virulence factor of coronaviruses (CoV) and plays key roles in suppressing host gene expression, which facilitates viral replication and immune evasion. NSP1 is a characteristic feature of alpha and betacoronavirus, which exhibits both functional conservation and mechanistic diversity in inhibiting host gene expression and antiviral responses [
,
,
,
]. NSP1 binds to the 40S ribosomal subunit and inhibits host translation, and it also induces a template-dependent endonucleolytic cleavage of host mRNAs [
,
,
,
,
], while viral mRNAs are less susceptible to NSP1-mediated inhibition of translation, because of their 5'-end leader sequence [,
]. NSP1 also suppresses the host innate immune functions by inhibiting type I interferon expression and host antiviral signalling pathways. The C-terminal domain binds to the mRNA entry tunnel interfering with mRNA binding () [
,
,
]. NSP1 consists of a globular domain arranged in a mixed parallel/antiparallel 6-stranded β-barrel with an α-helix covering one end of the barrel and another helix alongside the barrel []. In addition to the globular domain, bCoV NSP1s have a C-terminal domain [,
,
]. |
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•
•
|
| Protein Domain |
| Name: |
NSP1, globular domain, betacoronavirus |
| Type: |
Domain |
| Description: |
This entry represents the globular domain of NSP1 from betacoronavirus lineage B and C.Nonstructural protein 1 (NSP1) is a critical virulence factor of coronaviruses (CoV) and plays key roles in suppressing host gene expression, which facilitates viral replication and immune evasion. NSP1 is a characteristic feature of alpha and betacoronavirus, which exhibits both functional conservation and mechanistic diversity in inhibiting host gene expression and antiviral responses [
,
,
,
]. NSP1 binds to the 40S ribosomal subunit and inhibits host translation, and it also induces a template-dependent endonucleolytic cleavage of host mRNAs [,
,
,
,
], while viral mRNAs are less susceptible to NSP1-mediated inhibition of translation, because of their 5'-end leader sequence [,
]. NSP1 also suppresses the host innate immune functions by inhibiting type I interferon expression and host antiviral signalling pathways. The C-terminal domain binds to the mRNA entry tunnel interfering with mRNA binding () [
,
,
]. NSP1 consists of a globular domain arranged in a mixed parallel/antiparallel 6-stranded β-barrel with an α-helix covering one end of the barrel and another helix alongside the barrel []. In addition to the globular domain, bCoV NSP1s have a C-terminal domain [,
,
]. |
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•
|
| Protein Domain |
| Name: |
NSP3, DPUP domain, murine hepatitis virus-like |
| Type: |
Domain |
| Description: |
MHV NSP3 contains a DPUP that is located N-terminal to the ubiquitin-like domain 2 (Ubl2) and papain-like protease 2 (PLP2) catalytic domain. It is structurally similar to the Severe Acute Respiratory Syndrome (SARS) CoV unique domain C (SUD-C), adopting a frataxin-like fold that has structural similarity to DNA-binding domains of DNA-modifying enzymes. SUD-C is also located N-terminal to Ubl2 and PLP2 in SARS NSP3, similar to the DPUP of MHV NSP3; however, unlike DPUP, it is preceded by SUD-N and SUD-M macrodomains that are absent in MHV NSP3. Though structurally similar, there is little sequence similarity between DPUP and SUD-C. SARS SUD-C has been shown to bind to single-stranded RNA and recognize purine bases more strongly than pyrimidine bases; it also regulates the RNA binding behavior of the SARS SUD-M macrodomain. It is not known whether DPUP functions in the same way [
].This entry represents the DPUP (domain preceding Ubl2 and PLP2) of murine hepatitis virus (MHV) non-structural protein 3 (NSP3) and other NSP3s from betacoronaviruses in the embecovirus subgenera (A lineage), including human CoV OC43, rabbit CoV HKU14 and porcine hemagglutinating encephalomyelitis virus (HEV), among others. |
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•
|
| Protein Domain |
| Name: |
Gid-type RING finger domain |
| Type: |
Domain |
| Description: |
The two major antagonistic pathways of carbon metabolism in cells, glycolysis and gluconeogenesis, are tightly regulated. In yeast, the switch from gluconeogenesis to glycolysis is brought about by proteasomal degradation of the gluconeogenic enzyme fructose-1,6-bisphosphate. The ubiquitin ligase responsible for polyubiquitylation of fructose-1,6-bisphosphate is the Gid (glucose induced degradation deficient) complex. This complex consists of seven subunits of which two, Gid2/Rmd5 and Gid9/Fyv10, contain a degenerated RING finger domain providing E3 ligase activity. The two subunits form the heterodimeric E3 ligase unit of the Gid complex [
,
]. The orthologous complex found in mammalian cells is called CTLH, which has been linked to several different functions like regulation of cell morphology, proteasome-dependent degradation of non-ubiquitinated alpha-catenin, or modulation of endosome/lysosome-dependent degradation of ubiquitinated proteins via interaction with HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) [,
].This entry represents the degenerated Gid-type RING finger which comprises an incomplete serie of Zn ion-coordinating residues compared with the canonical RING finger, which encompasses eight Cys/His residues coordinating two Zn cations. A complete cysteine and histidine pattern is not necessarily critical for the E3 function [
,
]. |
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•
•
•
•
|
| Protein Domain |
| Name: |
Serine/threonine-protein kinase Atg1-like, tMIT domain |
| Type: |
Domain |
| Description: |
This the Atg13-binding region of Atg1 which comprises two tandem MIT (microtubule interacting and transport) domains, named tMIT [
].Members of this entry are Serine/threonine-protein kinases, including Atg1 from yeasts, Unc-51 from C. elegans and Ulk1-2 from humans.Atg1 is required for vesicle formation in autophagy and the cytoplasm-to-vacuole targeting (Cvt) pathway [
,
].Ulk1-2 are involved in autophagy in response to starvation [
,
]. Ulk1 and Ulk2 regulate filopodia extension and branching of sensory axons. They are important for axon growth, playing an essential role in neurite extension of cerebellar granule cells [,
]. Unc-51 is important for axonal elongation and axonal guidance [
]. It is required for either the maintenance of axons (membrane turnover) or for an unknown neuronal function. C elegans worms lacking Unc-51 exhibit various abnormalities in axonal elongation and axonal structures. Unc-51 could also help control cell size along with Bec-1, as mutations in their corresponding genes results in a reduction in small body size without affecting cell number []. Unc-51 is also a component of the Unc-51/Atg-13 complex that is probably recruited by lgg-1 to preautophagosomes and is required for autophagosome formation []. |
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•
•
•
|
| Protein Domain |
| Name: |
Unconventional class IX myosin |
| Type: |
Family |
| Description: |
Myosin IX (Myo9) is a processive single-headed motor, which might play a role in signalling. Class IX myosins contain a GTPase-activating protein (GAP) domain in their tail region, which allows them to negatively regulate small Rho GTPases [
]. This entry includes unconventional myosin-IXb and unconventional myosin-IXa [,
].Myosin-IXb plays a role in the regulation of cell migration via its role as RHOA GTPase activator. This is regulated by its interaction with the SLIT2 receptor ROBO1; interaction with ROBO1 impairs interaction with RHOA and subsequent activation of RHOA GTPase activity, and thereby leads to increased levels of active, GTP-bound RHOA [
]. Myosin-IXa is highly expressed in the brain and binds the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) GluA2 subunit, and plays a key role in controlling the molecular structure and function of hippocampal synapses [
]. Moreover, Myosin-IXa functions in epithelial cell morphology and differentiation such that its knockout mice develop hydrocephalus and kidney dysfunction []. Myosin-IXa regulates collective epithelial cell migration by targeting RhoGAP activity to cell-cell junctions. Myosin-IXa negatively regulates Rho GTPase signalling, and functions as a regulator of kidney tubule function [,
,
,
]. |
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•
•
•
•
|
| Protein Domain |
| Name: |
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1, EF-hand domain |
| Type: |
Domain |
| Description: |
Phosphoinositide-specific phospholipase C (PI-PLC), also known as 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase, plays a role in the inositol phospholipid signaling by hydrolysing phosphatidylinositol-4,5-bisphosphate to produce the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These cause the increase of intracellular calcium concentration and the activation of protein kinase C (PKC), respectively.The PLC family in murine or human species is comprised of multiple subtypes. On the basis of their structure, they have been divided into five classes, beta (beta-1, 2, 3 and 4), gamma (gamma-1 and 2), delta (delta-1, 3 and 4), epsilon, zeta, and eta types [
,
].PLC-delta-1 is required for the maintenance of skin homeostasis. It functions as a calcium amplifier within the cell and is essential in trophoblasts for placental development. It is involved in Alzheimer's disease and hypertension. Furthermore, it regulates cell proliferation and cell-cycle progression [
,
,
,
]. Both PLC-delta-1 and PLC-delta-3 are essential in trophoblasts for placental development [].PLC-delta1 contains a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs domain (represented by this entry), a PLC catalytic core, and a single C2 domain. |
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|
| Protein Domain |
| Name: |
Neurotrophin-6 |
| Type: |
Family |
| Description: |
During the development of the vertebrate nervous system, many neurons become redundant (because they have died, failed to connect to target cells, etc.) and are eliminated. At the same time, developing neurons send out axon outgrowths that contact their target cells [
]. Such cells control their degree of innervation (the number of axon connections) by the secretion of various specific neurotrophic factors that are essential for neuron survival. One of these is nerve growth factor (NGF), which is involved in the survival of some classes of embryonic neuron (e.g., peripheral sympathetic neurons) []. NGF is mostly found outside the central nervous system (CNS), but slight traces have been detected in adult CNS tissues, although a physiological role for this is unknown []; it has also been found in several snake venoms [,
]. Proteins similar to NGF include brain-derived neurotrophic factor (BDNF) and neurotrophins 3 to 7, all of which demonstrate neuron survival and outgrowth activities. This entry represents Neurotrophin-6 (NT-6), which has been identified in two species of platty fish [
]. It has been shown to have trophic effects on embryonic sympathetic neurons, similar to those of NGF []. |
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•
|
| Protein Domain |
| Name: |
Dual-specificity phosphatase CDC14, C-terminal |
| Type: |
Domain |
| Description: |
This entry represents the C-terminal catalytic dual-specificity phosphatase domain of Cdc14. It has the PTP signature motif.
The cell division control protein 14 (CDC14) family is highly conserved in all eukaryotes, although the roles of its members seem to have diverged during evolution [
]. Yeast Cdc14, the best characterised member of this family, is a dual-specificity phosphatase that plays key roles in cell cycle control. It preferentially dephosphorylates cyclin-dependent kinase (CDK) targets, which makes it the main antagonist of CDK in the cell. Cdc14 functions at the end of mitosis and it triggers the events that completely eliminates the activity of CDK and other mitotic kinases [,
]. It is also involved in coordinating the nuclear division cycle with cytokinesis through the cytokinesis checkpoint, and in chromosome segregation. Cdc14 phosphatases also function in DNA replication, DNA damage checkpoint, and DNA repair []. Vertebrates may contain more than one Cdc14 homologues; humans have three (CDC14A, CDC14B, and CDC14C). CDC14 contains a highly conserved N-terminal pseudophosphatase domain that contributes to substrate specificity and a C-terminal catalytic dual-specificity phosphatase domain with the PTP signature motif []. |
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•
|
| Protein Domain |
| Name: |
Dehydrogenase, bacteria |
| Type: |
Family |
| Description: |
This entry represents a group of bacterial dehydrogenases (DHs).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: |
Formyl-CoA:oxalate CoA-transferase |
| Type: |
Family |
| Description: |
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 [].Family III CoA-transferase family member formyl-CoA transferase transfers coenzyme A from formyl-CoA to oxalate. It forms a pathway, together with oxalyl-CoA decarboxylase, for oxalate degradation; decarboxylation by the latter gene regenerates formyl-CoA. The two enzymes typically are encoded by a two-gene operon [
]. |
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| Protein Domain |
| Name: |
CCR4-NOT transcription complex subunit 1 |
| Type: |
Family |
| Description: |
Not1 is the core component of the CCR4/NOT complex, which plays roles in the negative regulation of gene expression at transcriptional and post-transcriptional levels. This entry includes Not1 (also known as Cdc39) and its homologues, such as LET-711 from Caenorhabditis elegans [
]. De novo variants in CNOT1 have been shown to cause neurodevelopmental delay []. The Ccr4-Not complex is a global regulator of gene expression that is conserved from yeast to human. It affects genes positively and negatively and is thought to regulate transcription factor IID function. In Saccharomyces cerevisiae, it exists in two prominent forms and consists of at least nine core subunits: the five Not proteins (Not1 to Not5), Caf1, Caf40, Caf130 and Ccr4 [
]. The Ccr4-Not complex regulates many different cellular functions, including RNA degradation and transcription initiation. It may be a regulatory platform that senses nutrient levels and stress []. Caf1 and Ccr4, are directly involved in mRNA deadenylation, and Caf1p is associated with Dhh1, a putative RNA helicase thought to be a component of the decapping complex []. Pop2, a component of the Ccr4-Not complex, functions as a deadenylase []. |
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| Protein Domain |
| Name: |
DNA fragmentation factor 45kDa, C-terminal |
| Type: |
Homologous_superfamily |
| Description: |
One of the hallmarks of the terminal stages of apoptosis is internucleosomal DNA breakdown. DNA fragmentation factor (DFF) and endonuclease G (Endo G) are responsible for this process. DFF exists in the nucleus as a heterodimer composed of a 45kDa chaperoneand inhibitor subunit (DFF45, also called ICAD-L) and a 40kDa latent nuclease subunit (DFF40/CAD). Apoptotic activation of caspase-3 or -7 results in the cleavage of DFF45 and release of active DFF40 nuclease, which forms
homo-oligomers. DFF40's nucleaseactivity is further activated by proteins such as histone H1, HMGB1/2,
and topoisomerase II []. The C-terminal region of DNA fragmentation factor 45kDa (DFF-C) consists of four α-helices, which are folded in a helix-packing arrangement, with alpha-2 and alpha-3 packing against a long C-terminal helix (alpha-4) [
]. The main function of this region is the inhibition of DFF40 by binding to its C-terminal catalytic domain through ionic interactions, thereby inhibiting the fragmentation of DNA in the apoptotic process. In addition to blocking the DNase activity of DFF40, the C-terminal region of DFF45 is also important for the DFF40-specific folding chaperone activity, as demonstrated by the ability of DFF45 to refold DFF40 []. |
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|
| Protein Domain |
| Name: |
Cytochrome-c3 hydrogenase, C-terminal |
| Type: |
Domain |
| Description: |
This entry represents the C-terminal domain of periplasmic [NiFe] hydrogenase small subunit, hydrogenase-1 small chain and uptake hydrogenase small subunit. Hydrogenases catalyse the reversible oxidation of molecular hydrogen and play a vital role in anaerobic metabolism. Metal-containing hydrogenases are subdivided into three classes: Fe ('iron only') hydrogenases; Ni-Fe hydrogenases; and Ni-Fe-Se hydrogenases [
]. Hydrogen oxidation is coupled to the reduction of electron acceptors (such as oxygen, nitrate, sulphate, carbon dioxide and fumarate), whereas proton reduction (hydrogen evolution) is essential in pyruvate fermentation or in the disposal of excess electrons.The Ni-Fe hydrogenases, when isolated, are found to catalyse both hydrogen evolution and uptake, with low-potential multihaem cytochromes, such as cytochrome c3, acting as either electron donors or acceptors, depending on their oxidation state. Both periplasmic (soluble) and membrane-bound hydrogenases are known.The Ni-Fe hydrogenases are heterodimeric proteins consisting of small (S) and large (L) subunits. The small subunit contains three iron-sulphur clusters (two [4Fe-4S] and one [3Fe-4S]); the large subunit contains a nickel ion [
]. Small subunits of membrane-bound Ni-Fe hydrogenases contain a C-terminal domain of about 40 residues that is absent in periplasmic forms. |
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| Protein Domain |
| Name: |
Spermine synthase, animal |
| Type: |
Family |
| Description: |
The polyamines putrescine, spermidine and spermine represent a group of naturally occurring compounds exerting a bewildering number of biological effects. Their biosynthesis is accomplished by a concerted action of four different enzymes: ornithine decarboxylase, adenosylmethionine decarboxylase, spermidine synthase and spermine synthase. The development and introduction of specific inhibitors to the biosynthetic enzymes of the polyamines have revealed that an undisturbed synthesis of the polyamines is a prerequisite for animal cell proliferation to occur []. The human spermine synthase gene is involved in polyamine metabolism and is localised to the Xp22 region [
]. From isolated and sequenced cDNA clones that encode human spermine synthase , it was found the total length of the sequenced cDNA was 1,612 nucleotides, containing an open reading frame encoding a polypeptide chain of 368 amino acids. All other sequenced peptide fragments of human and bovine spermine synthase proteins could be located within the coding region derived from the cDNA. Sequence comparisons between human spermine synthase and spermidine synthases from bacterial and mammalian sources revealed a nearly complete lack of similarity between the primary structures of these two enzymes catalyzing almost identical reactions indicating they could have evolved separately [
]. |
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|
| Protein Domain |
| Name: |
[NiFe]-hydrogenase, small subunit, N-terminal domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
This entry represents the N-terminal domain superfamily of periplasmic [NiFe] hydrogenase small subunit, hydrogenase-1 small chain and uptake hydrogenase small subunit. Hydrogenases catalyse the reversible oxidation of molecular hydrogen and play a vital role in anaerobic metabolism. Metal-containing hydrogenases are subdivided into three classes: Fe ('iron only') hydrogenases; Ni-Fe hydrogenases; and Ni-Fe-Se hydrogenases [
]. Hydrogen oxidation is coupled to the reduction of electron acceptors (such as oxygen, nitrate, sulphate, carbon dioxide and fumarate), whereas proton reduction (hydrogen evolution) is essential in pyruvate fermentation or in the disposal of excess electrons.The Ni-Fe hydrogenases, when isolated, are found to catalyse both hydrogen evolution and uptake, with low-potential multihaem cytochromes, such as cytochrome c3, acting as either electron donors or acceptors, depending on their oxidation state. Both periplasmic (soluble) and membrane-bound hydrogenases are known.The Ni-Fe hydrogenases are heterodimeric proteins consisting of small (S) and large (L) subunits. The small subunit contains three iron-sulphur clusters (two [4Fe-4S] and one [3Fe-4S]); the large subunit contains a nickel ion [
]. Small subunits of membrane-bound Ni-Fe hydrogenases contain a C-terminal domain of about 40 residues that is absent in periplasmic forms. |
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•
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| Protein Domain |
| Name: |
Glutaminase |
| Type: |
Family |
| Description: |
Glutaminases (
) deaminate glutamine to glutamate. In Bacillus subtilis, glutaminase is encoded by glnA, which is part of an operon, glnA-glnT (formerly ybgJ-ybgH), where glnT encodes a glutamine transporter. The glnA-glnT operon is regulated by the 2-component system GlnK-GlnL in response to glutamine [
]. This entry represents the core structural motif of a family of glutaminases that include GlnA, which are characterised by their beta-lactamase-like topology, containing a cluster of α-helices and an alpha/beta sandwich.This family describes the enzyme glutaminase, from a larger family that includes serine-dependent beta-lactamases and penicillin-binding proteins. Many bacteria have two isozymes. This model is based on selected known glutaminases and their homologues within prokaryotes, with the exclusion of highly-derived (long branch) and architecturally varied homologues, so as to achieve conservative assignments. A sharp drop in scores occurs below 250, and cutoffs are set accordingly. The enzyme converts glutamine to glutamate, with the release of ammonia. Members tend to be described as glutaminase A (glsA), where B (glsB) is unknown and may not be homologous (as in Rhizobium etli. Some species have two isozymes that may both be designated A (GlsA1 and GlsA2). |
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•
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| Protein Domain |
| Name: |
NADH-ubiquinone oxidoreductase 51kDa subunit, FMN-binding domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
NADH:ubiquinone oxidoreductase (complex I) (
) is a respiratory-chain enzyme that catalyses the transfer of two electrons from NADH to ubiquinone in a reaction that is associated with proton translocation across the membrane (NADH + ubiquinone = NAD+ + ubiquinol) [
]. Complex I is a major source of reactive oxygen species (ROS) that are predominantly formed by electron transfer from FMNH(2). Complex I is found in bacteria, cyanobacteria (as a NADH-plastoquinone oxidoreductase), archaea [], mitochondria, and in the hydrogenosome, a mitochondria-derived organelle. In general, the bacterial complex consists of 14 different subunits, while the mitochondrial complex contains homologues to these subunits in addition to approximately 31 additional proteins [].Among the many polypeptide subunits that make up complex I, there is one with a molecular weight of 51kDa (in mammals), which is the second largest subunit of complex I [
]. The 51kDa subunit, as the corresponding bacterial subunit (Nqo1 in Thermus and NuoF in E. coli) [], contains the NADH-binding site, the primary electron acceptor FMN-binding site, and a 4Fe-4S cluster [].This superfamily represents the FMN-binding domain. Its structure is composed of three layers (alpha/beta/alpha) with parallel β-sheet of four strands. |
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•
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•
|
| Protein Domain |
| Name: |
TFIID subunit TAF5, NTD2 domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
This region is an all-alpha domain associated with the WD40 helical bundle of the TAF5 subunit of transcription factor TFIID. The domain has distant structural similarity to RNA polymerase II CTD interacting factors. It contains several conserved clefts that are likely to be critical for TFIID complex assembly [
]. The TAF5 subunit is present twice in the TFIID complex and is critical for the function and assembly of the complex, and the NTD2 (second N-terminal domain) and N-terminal domain are crucial for homodimerisation []. TAF5 has a paralogue gene (TAF5L) which has a redundant function [].The TATA Binding Protein (TBP) Associated Factor 5 (TAF5) is one of several TAFs that bind TBP and are involved in forming Transcription Factor IID (TFIID) complex. TFIID plays an important role in the recognition of promoter DNA and assembly of the preinitiation complex. TFIID complex is composed of the TBP and at least 13 TAFs. In yeast and human cells, TAFs have been found as components of other complexes besides TFIID [
].The N-terminal domain of TAF5 has a multihelical structure with a C-terminal beta-alpha(2)-beta motif, one central buried helix and parallel β-ribbon. |
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•
•
•
•
|
| Protein Domain |
| Name: |
[NiFe]-hydrogenase, small subunit, C-terminal domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
This entry represents the C-terminal domain superfamily of periplasmic [NiFe] hydrogenase small subunit, hydrogenase-1 small chain and uptake hydrogenase small subunit. Hydrogenases catalyse the reversible oxidation of molecular hydrogen and play a vital role in anaerobic metabolism. Metal-containing hydrogenases are subdivided into three classes: Fe ('iron only') hydrogenases; Ni-Fe hydrogenases; and Ni-Fe-Se hydrogenases [
]. Hydrogen oxidation is coupled to the reduction of electron acceptors (such as oxygen, nitrate, sulphate, carbon dioxide and fumarate), whereas proton reduction (hydrogen evolution) is essential in pyruvate fermentation or in the disposal of excess electrons.The Ni-Fe hydrogenases, when isolated, are found to catalyse both hydrogen evolution and uptake, with low-potential multihaem cytochromes, such as cytochrome c3, acting as either electron donors or acceptors, depending on their oxidation state. Both periplasmic (soluble) and membrane-bound hydrogenases are known.The Ni-Fe hydrogenases are heterodimeric proteins consisting of small (S) and large (L) subunits. The small subunit contains three iron-sulphur clusters (two [4Fe-4S] and one [3Fe-4S]); the large subunit contains a nickel ion [
]. Small subunits of membrane-bound Ni-Fe hydrogenases contain a C-terminal domain of about 40 residues that is absent in periplasmic forms. |
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•
|
| Protein Domain |
| Name: |
Allantoicase domain |
| Type: |
Domain |
| Description: |
Allantoicase (also known as allantoate amidinohydrolase) is involved in
purine degradation, facilitating the utilization of purines as secondary nitrogen sources under nitrogen-limiting conditions. While purine degradation converges to uric acid in all vertebrates, its further degradation varies from species to species. Uric acid is excreted by birds, reptiles, and some mammals that do not have a functional uricase gene, whereas other mammals produce allantoin. Amphibians and microorganisms produce ammonia and carbon dioxide using the uricolytic pathway. Allantoicase performs the second step in this pathway catalyzing the conversion of allantoate into ureidoglycolate and urea.allantoate + H(2)0 = (S)-ureidoglycolate + ureaThe structure of allantoicase is best described as being composed of two repeats (the allantoicase repeats: AR1 and AR2), which are connected by a flexible linker. The crystal structure, resolved at 2.4A resolution, reveals that AR1 has a very similar fold to AR2, both repeats being jelly-roll motifs, composed of four-stranded and five-stranded antiparallel β-sheets [
]. Each jelly-roll motif has two conserved surface patches that probably constitute the active site []. The mammalian proteins matched by this entry are thought to be non-functional as mammals do not appear to possess allantoicase activity [
,
]. |
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| Protein Domain |
| Name: |
Bacteriophage T4, Gp11, C-terminal finger domain |
| Type: |
Homologous_superfamily |
| Description: |
The bacteriophage baseplate controls host cell recognition, attachment, tail sheath contraction and viral DNA ejection. The baseplate is a multi-subunit assembly at the distal end of the tail, which is composed of long and short tail fibres [
]. The tail region is responsible for attachment to the host bacteria during infection: long tail fibres enable host receptor recognition, while irreversible attachment is via short tail fibres. Recognition and attachment induce a conformational transition of the baseplate from a hexagonal to a star-shaped structure. In viruses such as Bacteriophage T4, Gp11 acts as a structural protein to connect the short tail fibres to the baseplate, while Gp9 connects the baseplate with the long tail fibres. Both Gp9 and Gp11 are trimers. Each Gp11 monomer consists of three domains, which are entwined together in the trimer: the N-terminal domains of the three monomers form a central, trimeric, parallel coiled coil surrounded by the entwined middle finger domains; the C-terminal domains appear to be responsible for trimerisation [].This superfamily includes the middle finger domain, which is a seven-stranded, antiparallel, skewed β-roll with one α-helix [
]. |
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| Protein Domain |
| Name: |
Dynein heavy chain, linker |
| 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.This entry represents the linker of the dynein heavy chain motor domain. |
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| Protein Domain |
| Name: |
3'5'-cyclic nucleotide phosphodiesterase |
| Type: |
Family |
| 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. |
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| Protein Domain |
| Name: |
SEFIR domain |
| Type: |
Domain |
| Description: |
The SEFIR domain (after SEFs and IL17Rs) is a conserved sequence segment
identified in transmembrane receptors (including SEFs, IL17Rs) and solublefactors (including CIKS/ACT1) in eukaryotes and bacteria. In addition to the
SEFIR sequence homology, SEFs and IL17Rs share the same architecture. Theirextracellular regions are sequentially divergent but appear structurally
similar to a tandem fibronectin 3 (FN3)-like domain arrangement. A singletransmembrane region is followed by a high-complexity sequence region
involving the SEFIR domain and a C-terminal tail that is enriched with polarresidues and, sometimes, with low complexity regions [
].The SEFIR domain is related to the TIR domain. The SEFIR
domain is similar to the TIR domain in length and secondary structure. Thesimilarity between the SEFIR and TIR domains involves the conserved boxes 1
and 2 of the TIR domain that are implicated in homotypic dimerization, butthere is no sequence similarity between SEFIR domains and the TIR sequence box
3 [].Proteins containing this domain also includes TRAF3IP2 from humans. TRAF3IP2 is a U-box E3 ubiquitin ligase for IL-17 signaling [
]. A mutation (T536I) located in the SEFIR domain, abolished the homotypic interaction of ACT1 with IL-17 receptors, with no effect on homodimerization []. |
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| Protein Domain |
| Name: |
GAF domain |
| Type: |
Domain |
| Description: |
The GAF domain is named after some of the proteins it is found in, including cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA. It is also found in guanylyl cyclases and phytochromes [
,
]. The structure of a GAF domain shows that the domain shares a similar fold with the PAS domain []. Adenylyl and guanylyl cyclases catalyse ATP and GTP to the second messengers cAMP and cGMP respectively, these products up-regulating catalytic activity by binding to the regulatory GAF domain(s). The opposite hydrolysis reaction is catalysed by phosphodiesterase. cGMP-dependent 3',5'-cyclic phosphodiesterase catalyses the conversion of guanosine 3',5'-cyclic phosphate to guanosine 5'-phosphate. Here too, cGMP regulates catalytic activity by GAF-domain binding. Phytochromes are regulatory photoreceptors in plants and bacteria which exist in two thermally stable states that are reversibly inter-convertible by light, the Pr state absorbs maximally in the red region of the spectrum, while the Pfr state absorbs maximally in the far-red region [].The GAF domain is also found in FhlA (formate hydrogen lyase transcriptional activator) and NifA, a transcriptional activator required for activation of most Nif operons, which are directly involved in nitrogen fixation. NifA interacts with sigma-54 [
]. |
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| Protein Domain |
| Name: |
Endonuclease III-like, conserved site-2 |
| Type: |
Conserved_site |
| Description: |
Endonuclease III is a DNA repair enzyme which removes a number of damaged pyrimidines from DNA via its glycosylase activity and also cleaves the phosphodiester backbone at apurinic / apyrimidinic sites via a beta-elimination mechanism [
,
]. The structurally related DNA glycosylase MutYrecognises and excises the mutational intermediate 8-oxoguanine-adenine mispair [
]. The 3-D structures of Escherichia coli endonuclease III [] and catalytic domain of MutY [] have been determined. Thestructures contain two all-alpha domains: a sequence-continuous, six-helix domain (residues 22-132) and a Greek-key,
four-helix domain formed by one N-terminal and three C-terminal helices (residues 1-21 and 133-211) together with theFe4S4 cluster. The cluster is bound entirely within the C-terminal loop by four cysteine residues with a ligation pattern
Cys-(Xaa)6-Cys-(Xaa)2-Cys-(Xaa)5-Cys which is distinct from all other known Fe4S4 proteins. This structural motif isreferred to as a Fe4S4 cluster loop (FCL) [
]. Two DNA-binding motifs have been proposed, one at either end of theinterdomain groove: the helix-hairpin-helix (HhH) (see
) and FCL motifs (see
). The primary role of the iron-sulphur cluster appears to
involve positioning conserved basic residues for interaction with the DNA phosphate backbone by forming the loop ofthe FCL motif [
,
]. |
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| Protein Domain |
| Name: |
AMP nucleosidase |
| Type: |
Family |
| Description: |
AMP nucleosidase (AMN) catalyses the hydrolysis of AMP to form adenine and ribose 5-phosphate. It is only found in prokaryotes, where it plays a role in purine nucleoside salvage and intracellular AMP level regulation [
]. The gene for AMP nucleosidase from Escherichia coli (amn) encodes a protein of 483 amino acids. A comparison of the amino acid sequence for AMP nucleosidase with that for yeast AMP deaminase shows that there is a region where only six out of eight amino acids are identical but there is no other overall homology. AMN also showed little similarity to consensus sequences for adenylate binding sites even though the enzyme is known to have a catalytic site for AMP and regulatory sites for MgATP and phosphate []. The enzyme is a homohexamer, and each monomer has two domains: a catalytic domain and a putative regulatory domain. The overall topology of the catalytic domain and some features of the substrate binding site resemble those of the nucleoside phosphorylases. The structure of the regulatory domain consists of a long helix and a four-stranded sheet, but has a novel topology [
]. |
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| Protein Domain |
| Name: |
Transcription factor PIF1-like, basic helix-loop-helix domain |
| Type: |
Domain |
| Description: |
This entry represents the basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana phytochrome interacting factors (PIFs) and similar transcription factors from plants, including ALC, PIL1, SPATULA, and UNE10 [
,
].PIFs (PIF1/3/4/5/6/7) have been shown to control light-regulated gene expression. They directly bind to the photoactivated phytochromes and are degraded in response to light signals [
,
,
,
,
,
]. ALC, also termed protein ALCATRAZ, is required for the dehiscence of fruit, especially for the separation of the valve cells from the replum. It promotes the differentiation of a strip of labile non-lignified cells sandwiched between layers of lignified cells [,
]. PIL1 is involved in responses to transient and long-term shade. It is required for the light-mediated inhibition of hypocotyl elongation and necessary for rapid light-induced expression of the photomorphogenesis- and circadian-related gene APRR9. PIL1 seems to play a role in multiple PHYB responses, such as flowering transition and petiole elongation [,
]. SPATULA plays a role in floral organogenesis. It promotes the growth of carpel margins and of pollen tract tissues derived from them []. UNE10 is required during the fertilization of ovules by pollen []. |
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| Protein Domain |
| Name: |
Proteasome subunit alpha5 |
| 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 represents the proteasome alpha 5 subunit (MEROPS identifier T01.975) also known as Pup2. |
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| Protein Domain |
| Name: |
Riboflavin kinase domain, CTP-dependent |
| Type: |
Domain |
| Description: |
Riboflavin is converted into catalytically active cofactors (FAD and FMN) by the actions of riboflavin kinase (
), which converts it into FMN, and FAD synthetase (
), which adenylates FMN to FAD. Eukaryotes usually have two separate enzymes, while most prokaryotes have a single bifunctional protein that can carry out both catalyses, although exceptions occur in both cases. While eukaryotic monofunctional riboflavin kinase is orthologous to the bifunctional prokaryotic enzyme [
], the monofunctional FAD synthetase differs from its prokaryotic counterpart, and is instead related to the PAPS-reductase family []. The bacterial FAD synthetase that is part of the bifunctional enzyme has remote similarity to nucleotidyl transferases and, hence, it may be involved in the adenylylation reaction of FAD synthetases [].This entry represents a CTP-dependent riboflavin kinase domain, found primarily in archaea, that catalyses the phosphorylation of riboflavin to form flavin mononucleotide in riboflavin biosynthesis. Its structure resembles a RIFT barrel, structurally similar to but topologically distinct from bacterial and eukaryotic examples [
]. The N-terminal is a winged helix-turn-helix DNA-binding domain, and the C-terminal half is most similar in sequence to a group of cradle-loop barrels. |
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| Protein Domain |
| Name: |
Fungal multicopper oxidase, cupredoxin domain 3 |
| Type: |
Domain |
| Description: |
This domain is found in fungal proteins with similarity to ascorbate oxidase [
]. Ascorbate oxidase catalyzes the oxidation of ascorbic acid to dehydroascorbic acid. It can detect levels of ascorbic acid and eliminate it. The biological function of ascorbate oxidase is still not clear.Ascorbate oxidase belongs to multicopper oxidase (MCO) family which couple oxidation of substrates with reduction of dioxygen to water. MCOs are capable of oxidizing a vast range of substrates, varying from aromatic compounds to inorganic compounds such as metals. Although the members of this family have diverse functions, majority of them have three cupredoxin domain repeats. The copper ions are bound in several sites: Type 1, Type 2, and/or Type 3. The ensemble of types 2 and 3 copper is called a trinuclear cluster. MCOs oxidize their substrate by accepting electrons at a mononuclear copper centre and transferring them to the active site trinuclear copper centre. The cupredoxin domain 3 of 3-domain MCOs contains the Type 1 (T1) copper binding site and part the trinuclear copper binding site, which is located at the interface of domains 1 and 3 [
,
,
,
]. |
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