| Type |
Details |
Score |
| Protein Domain |
| Name: |
Chorismate mutase, periplasmic |
| Type: |
Family |
| Description: |
Chorismate mutase (CM;
) catalyses the reaction at the branch point of the biosynthetic pathway leading to the three aromatic amino acids, phenylalanine, tryptophan and tyrosine (chorismic acid is the last common intermediate, and CM leads to the L-phenylalanine/L-tyrosine branch). It is part of the shikimate pathway, which is present only in bacteria, fungi and plants. Members of this family contain a chorismate mutase domain of the AroQ class (prokaryotic type) that has an all-helical structure.
The three types of CM are AroQ class, prokaryotic type; AroQ class, eukaryotic type; and AroH class. They fall into two structural folds (AroQ class and AroH class) which are completely unrelated [
]. The two types of the AroQ structural class (the Escherichia coli CM dimer and the yeast CM monomer) can be structurally superimposed, and the topology of the four-helix bundle forming the active site is conserved [].Periplasmic chorismate mutases form a subclass of the AroQ class, and are twice the size of cytoplasmic AroQ proteins due to a carboxy-terminal domain of unknown function [
]. This C-terminal domain is so far unique to members of this group.For additional information please see [
,
,
,
]. |
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| Protein Domain |
| Name: |
Cytochrome c/quinol oxidase subunit II |
| Type: |
Family |
| Description: |
Cytochrome c oxidase (
) [
,
] is an oligomeric enzymatic complex which is a component of the respiratory chain and is involved in the transfer of electrons from cytochrome c to oxygen. In eukaryotes this enzyme complex is located in the mitochondrial inner membrane; in aerobic prokaryotes it is found in the plasma membrane. The number of polypeptides in the complex ranges from 3-4 (prokaryotes), up to 13 (mammals). In Archaea, a cytochrome-c-type oxidase from Natronobacterium (cytochrome ba3) has been shown to consists of four subunits [].Subunit 2 (CO II) transfers the electrons from cytochrome c to the catalytic subunit 1. It contains two adjacent transmembrane regions in its N terminus and the major part of the protein is exposed to the periplasmic or to the mitochondrial intermembrane space, respectively. CO II provides the substrate-binding site and contains a copper centre called Cu(A), probably the primary acceptor in cytochrome c oxidase. An exception is the corresponding subunit of the cbb3-type oxidase which lacks the copper A redox-centre. Several bacterial CO II have a C-terminal extension that contains a covalently bound haem c. |
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| Protein Domain |
| Name: |
Double Cache domain 1 |
| Type: |
Domain |
| Description: |
Cache is an extracellular domain that is predicted to have a role in small-molecule recognition in a wide range of proteins, including the animal dihydropyridine-sensitive voltage-gated Ca2 channel alpha-2delta subunit, and various bacterial chemotaxis receptors. The name Cache comes from CAlcium channels and CHEmotaxis receptors. The Cache domain, also known as the extracellular PAS domain, consists of an N-terminal part with three predicted strands and an α-helix, and a C-terminal part with a strand dyad followed by a relatively unstructured region. The N-terminal portion of the Cache domain containing the three predicted strands could form a sheet analogous to that present in the core of the PAS domain structure. Cache domains are particularly widespread in bacteria, such as Vibrio cholerae. The animal calcium channel alpha-2delta subunits might have acquired a part of their extracellular domains from a bacterial source [
]. The Cache domain appears to have arisen from the GAF-PAS fold, despite their divergent functions [,
].This entry represents double cache domain 1, which covers the last three strands from the membrane distal PAS-like domain, the first two strands of the membrane proximal domain, and the connecting elements between the two domains [
]. |
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| Protein Domain |
| Name: |
Transglycosylase SLT domain 2 |
| Type: |
Domain |
| Description: |
This domain is found mainly in proteins from bacteria, such as membrane-bound lytic murein transglycosylase B (mltB, also known as Slt35) from E. coli. MltB is a murein-degrading enzyme that catalyses the cleavage of the glycosidic bonds between N-acetylmuramic acid and N-acetylglucosamine residues in peptidoglycan [
]. This domain is related to the SLT domain 1 ().
Bacterial lytic transglycosylases degrade murein via cleavage of the beta-1,4-glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine, with the concomitant formation of a 1,6-anhydrobond in the muramic acid residue. There are both soluble (Slt enzymes) and membrane-bound (Mlt enzymes) lytic transglycosylases that differ in size, sequence, activity, specificity and location. The multi-domain structure of the 70 Kd soluble lytic transglycosylase Slt70 is known [
]. Slt70 has 3 distinct domains, each rich in alpha helices: an N-terminal superhelical U-shaped domain, a superhelical linker domain (L-domain, ), and a C-terminal catalytic domain (
). Both the U- and L-domain share a similar superhelical structure. These two domains are connected, and together form a closed ring with a large central hole; the catalytic domain is packed on top of, and interacts with, this ring. The catalytic domain has a lysosome-like fold.
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| Protein Domain |
| Name: |
Mediator complex, subunit Med25, PTOV domain |
| Type: |
Domain |
| Description: |
Mediator is a large complex of up to 33 proteins that is conserved from plants to fungi to humans - the number and representation of individual subunits varying with species [
,
]. It is arranged into four different sections, a core, a head, a tail and a kinase-active part, and the number of subunits within each of these is what varies with species. Overall, Mediator regulates the transcriptional activity of RNA polymerase II, but it would appear that each of the four different sections has a slightly different function []. The overall function of the full-length Med25 is efficiently to coordinate the transcriptional activation of RAR/RXR (retinoic acid receptor/retinoic X receptor) in higher eukaryotic cells. Human Med25 consists of several domains with different binding properties, the N-terminal, VWA domain, an SD1 - synapsin 1 - domain from residues 229-381, a PTOV(B) or ACID domain from 395-545, an SD2 domain from residues 564-645 and a C-terminal NR box-containing domain (646-650) from 646-747. The PTOV domain is the domain through which Med25 co-operates with the histone acetyltransferase CBP, which is involved in chromatin remodeling []. |
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| Protein Domain |
| Name: |
NAD-dependent formate dehydrogenase |
| Type: |
Family |
| Description: |
NAD-dependent formate dehydrogenase (FDH) catalyzes the NAD+-dependent oxidation of a formate anion to carbon dioxide coupled with the reduction of NAD+ to NADH. Formate/glycerate and related dehydrogenases of the D-specific 2-hydroxy acid dehydrogenase family have 2 highly similar subdomains of the alpha/beta form, with NAD binding occurring in the cleft between subdomains. NAD contacts are primarily to the Rossmann-fold NAD-binding domain which is inserted within the linear sequence of the more diverse flavodoxin-like catalytic subdomain. Some related proteins have similar structural subdomain but with a tandem arrangement of the catalytic and NAD-binding subdomains in the linear sequence. FDHs of this family contain no metal ions or prosthetic groups. Catalysis occurs though direct transfer of the hydride ion to NAD+ without the stages of acid-base catalysis typically found in related dehydrogenases. FDHs are found in all methylotrophic microorganisms in energy production from C1 compounds such as methanol, and in the stress responses of plants [
,
,
]. NAD-dependent FDH is useful in cofactor regeneration in asymmetrical biocatalytic reduction processes, where FDH irreversibly oxidizes formate to carbon dioxide, while reducing the oxidized form of the cofactor to the reduced form. |
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| Protein Domain |
| Name: |
Restriction endonuclease BfiI C-terminal domain |
| Type: |
Domain |
| Description: |
This entry represents the C-terminal domain of novel type IIs restriction endonuclease BfiI and similar proteins.Type II restriction endonucleases are components of restriction modification (RM) systems that protect bacteria and archaea against invading foreign DNA. They usually function as homodimers or homotetramers that cleave DNA at defined sites of 4 to 8 bp in length, and they require Mg2+, not ATP or GTP, for catalysis. Unlike all other restriction enzymes known to date, BfiI is unique in cleaving DNA at fixed positions downstream of an asymmetric sequence in the absence of Mg2+ [
]. BfiI consists of two discrete domains with distinct functions: an N-terminal catalytic domain with non-specific nuclease activity and dimerization function that is more closely related to Nuc, an EDTA-resistant nuclease from the phospholipase D (PLD) superfamily []; and a C-terminal domain that specifically recognizes its target sequences, 5'-ACTGGG-3' [,
]. BfiI presumably evolved through domain fusion of a DNA recognition domain to the catalytic Nuc-like domain from the PLD superfamily []. BfiI forms a functionally active homodimer which has two DNA-binding surfaces located at the C-terminal domains but only one active site, located at the dimer interface between the two N-terminal catalytic domains [,
]. |
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| Protein Domain |
| Name: |
Membrane-bound lytic murein transglycosylase B-like |
| Type: |
Family |
| Description: |
Bacterial lytic transglycosylases degrade murein via cleavage of the beta-1,4-glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine, with the concomitant formation of a 1,6-anhydrobond in the muramic acid residue. There are both soluble (Slt enzymes) and membrane-bound (Mlt enzymes) lytic transglycosylases that differ in size, sequence, activity, specificity and location. The multi-domain structure of the 70 Kd soluble lytic transglycosylase Slt70 is known []. Slt70 has 3 distinct domains, each rich in alpha helices: an N-terminal superhelical U-shaped domain, a superhelical linker domain (L-domain, ), and a C-terminal catalytic domain (
). Both the U- and L-domain share a similar superhelical structure. These two domains are connected, and together form a closed ring with a large central hole; the catalytic domain is packed on top of, and interacts with, this ring. The catalytic domain has a lysosome-like fold.
This entry includes membrane-bound lytic murein transglycosylase B (mltB, also known as Slt35) from E. coli. MltB is a murein-degrading enzyme that catalyses the cleavage of the glycosidic bonds between N-acetylmuramic acid and N-acetylglucosamine residues in peptidoglycan [
]. This entry also includes uncharacterised proteins that contain the SLT domain 2. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 17 |
| Type: |
Family |
| Description: |
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more
than 20 type-I transmembrane proteins. Family members are defined based onsimilarity in their extracellular domain - a region that contains many
cysteine residues arranged in a specific repetitive pattern []. Thecysteines allow formation of an extended rod-like structure, responsible for
ligand binding [].Upon receptor activation, different intracellular signalling complexes are
assembled for different members of the TNFR superfamily, depending on theirintracellular domains and sequences [
]. Activation of TNFRs can thereforeinduce a range of disparate effects, including cell proliferation,
differentiation, survival, or apoptotic cell death, depending upon thereceptor involved [
].TNFRs are widely distributed and play important roles in many crucial
biological processes, such as lymphoid and neuronal development, innate andadaptive immunity, and maintenance of cellular homeostasis [
]. Drugs that manipulate their signalling have potential roles in the prevention andtreatment of many diseases, such as viral infections, coronary heart
disease, transplant rejection, and immune disease [].TNF receptor 17 acts as a receptor for both a proliferation-inducing ligand
(APRIL) and B cell-activating factor (BAFF) []. It is preferentially expressed by mature B-cells, suggesting a potential role for the receptor in
the B-cell developmental process []. |
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| Protein Domain |
| Name: |
Glutathione S-transferases Phi, C-terminal |
| Type: |
Domain |
| Description: |
This entry represents the C-terminal alpha helical domain found in the Phi subfamily (also known as GSTF) of the glutathione S-transferase (GST) family. GSTF had long been regarded as plant specific but has also been found in basidiomycete fungi [
]. The class Phi GST subfamily has undergone extensive gene duplication. The Arabidopsis and Oryza genomes contain 13 and 16 Tau GSTs, respectively [
,
]. They are primarily responsible for herbicide detoxification together with class Tau GSTs, showing class specificity in substrate preference. Phi enzymes are highly reactive toward chloroacetanilide and thiocarbamate herbicides []. Some Phi GSTs have other functions including transport of flavonoid pigments to the vacuole and shoot regeneration [,
].GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. The GST fold contains an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain [
]. |
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| Protein Domain |
| Name: |
Cobalamin adenosyltransferase-like |
| Type: |
Domain |
| 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: |
Alpha-defensin |
| Type: |
Family |
| Description: |
Mammalian alpha-defensins are expressed primarily in leukocytes and epithelia. They play an important role in the innate and adaptive immune response to microbial infection. There are six cysteine residues and one glycine residue, for an atypical SS-bulge, which are totally conserved in the otherwise diverse sequences of all known mammalian alpha-defensins. There is also a conserved pair of oppositely charged residues (Arg/Glu) that form a salt bridge across a protruding loop in the molecule. The primary function of the salt bridge in HD5 is to ensure correct processing of proHD5 and subsequent stabilisation of mature alpha-defensin in vivo [
].Human neutrophil alpha-defensins (HNPs) are synthesized in vivo as inactive precursor proteins, i.e. preproHNPs. A series of sequential proteolytic events excise the N-terminal inhibitory pro peptide, leading to defensin maturation and storage in azurophilic granules [
]. Human alpha-defensin-1 (HNP1) is a small antimicrobial peptide, which is cytotoxic to tumour cells in vitro and shows inhibitory activity for pathologic neovascularisation in vivo. Intracellularly expressed HNP1 induces tumour cell apoptosis, consequently inhibiting its growth. It might be involved in the host immune response to tumours and as such is a promising basis for HNP1-based gene therapy for cancer []. |
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| Protein Domain |
| Name: |
ResE, histidine kinase sensor domain |
| Type: |
Domain |
| Description: |
The Bacillus subtilis ResD-ResE two-component (TC) regulatory system activates genes involved in nitrate respiration in response to oxygen limitation or nitric oxide (NO). The sensor kinase ResE activates the response regulator ResD through phosphorylation, which then binds to the regulatory region of genes involved in anaerobiosis to activate their transcription. In other words, ResE is involved in sensing signals related to the redox state of the cells. ResE is composed of an N-terminal signal input domain and a C-terminal catalytic domain. The N-terminal domain contains two transmembrane subdomains and a large extra-cytoplasmic loop. Mutational analysis indicate that cytoplasmic ResE lacking the transmembrane segments and the extra-cytoplasmic loop retains the ability to sense oxygen limitation and NO, which leads to transcriptional activation of ResDE-dependent genes. However, it is also proposed that the extra-cytoplasmic region may serve as a second signal-sensing subdomain. This suggests that the extracytoplasmic region could contribute to amplification of ResE activity leading to the robust activation of genes required for anaerobic metabolism in B. subtilis [
]. This entry represents the extracytoplasmic subdomain [
]. Proteins containing this domain also include SrrB found in S. aureus that is similar to ResE of B. subtilis []. |
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| Protein Domain |
| Name: |
Transcription factor GATA-4/5/6 |
| Type: |
Family |
| Description: |
This entry represents the GATA family of transcription factors, such as GATA-4, GATA-5 and GATA-6. These transcription factors regulate critical steps of cellular differentiation during vertebrate development. GATA-4, 5 and 6 each contain two GATA-type zinc fingers, and are known to activate numerous enterocytic genes [
,
]. Loss of GATA-4 and GATA-5 has been reported in human gastric and colon cancer []. GATA-4 binds to the consensus sequence 5'-AGATAG-3', and acts as a transcriptional activator of Anf in cooperation with Nkx2-5 [
]. It interacts with the homeobox domain of Nkx2-5 through its C-terminal zinc finger. It also interacts with Jarid2 which represses its ability to activate transcription of Anf. Defects in GATA-4 are the cause of atrial septal defect type 2 (ASD2) (OMIM:607941)[]. ASD2 is a congenital heart malformation characterised by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria.GATA-5 binds to the functionally important Cef-1 nuclear protein binding site in the cardiac-specific slow/cardiac troponin C transcriptional enhancer [
]. It may play an important role in the transcriptional program(s) that underlies smooth muscle cell diversity. |
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| Protein Domain |
| Name: |
Novel toxin 21 |
| Type: |
Domain |
| 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: |
IC97/Casc1, N-terminal |
| Type: |
Domain |
| Description: |
This domain is found in CASC1 (cancer susceptibility candidate gene 1 protein) from humans and IC97 from Chlamydomonas [
]. There are two completely conserved residues (N and W) that may be functionally important.Dynein-f, also known as dynein I1, is an inner-arm dynein complex comprising two different heavy chains together with a number of intermediate and light chains. In Chlamydomonas, IC97 is the intermediate chain of the Dynein-f complex. This entry includes IC97 (
) and its homologues, including CASC1 (also known as Dnai7) from humans [
]. The CAncer Susceptibility Candidate 1 (CASC1) gene is expressed in lung tissues, and is a strong candidate for the pulmonary adenoma susceptibility 1 (Pas1) locus, the major determinant of strain variation in lung tumour susceptibility [
]. There appears to be a strong correlation between functional polymorphism of CASC1 and lung tumour suspectibility in mice [].Different mouse strains fall into two genotype groups (susceptible and intermediate) according to differences in the 60th codon of the CASC1 gene [
]. The mouse CASC1 gene shares 81% similarity with the human equivalent; the role of CASC1 in human lung-cancer risk may nevertheless differ from that in mice [,
]. |
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| Protein Domain |
| Name: |
Type VIII secretion system, CsgF |
| Type: |
Family |
| Description: |
The extracellular nucleation-precipitation (ENP) pathway or Type VIII secretion system (T8SS) in Gram-negative (diderm) bacteria is responsible for the secretion and assembly of prepilins for fimbiae biogenesis, the prototypical curli. Besides the T2SS that can be involved in the assembly of prototypical Type 4 pilus, the T4SS that can be involved in the biogenesis of the prototypical pilus T, the T3SS involved in the assembly of the injectisome and the T7SS involved in the formation of the prototypical Type 1 pilus, the T8SS differs in that fibre-growth occurs extracellularly. The curli, also called thin aggregative fimbriae (Tafi), are the only fimbriae dependent on the T8SS. Tafi were first identified in Salmonella spp and the controlling operon termed agf; however subsequent isolation of the homologous operon in E coli led to its being called csg. In the absence of extracellular polysaccharides Tafi appear curled, although when expressed with such polysaccharides their morphology appears as a tangled amorphous matrix [
]. CsgF is one of three putative curli assembly factors appearing to act as a nucleator protein. Unlike eukaryotic amyloid formation, curli biogenesis is a productive pathway requiring a specific assembly machinery []. |
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| Protein Domain |
| Name: |
Serine/threonine-protein kinase Atg1-like |
| Type: |
Family |
| Description: |
This entry represents a group of Serine/threonine-protein kinases, including Atg1 from yeasts, Unc-51 from C. elegans, Ulk1-3 from humans and ATG1a/b/c/t from Arabidopsis.Atg1 is required for vesicle formation in autophagy and the cytoplasm-to-vacuole targeting (Cvt) pathway [
].Ulk1-3 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 [].In plants, the ATG1/13 complex is both a regulator and a target of autophagy [
]. |
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| Protein Domain |
| Name: |
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1, catalytic 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 [].This entry represents the catalytic domain of PLC-delta1, a TIM barrel with two highly conserved regions (X,
, and Y,
) split by a highly degenerate linker sequence [
]. |
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| Protein Domain |
| Name: |
Translation initiation factor 2, beta subunit |
| Type: |
Family |
| Description: |
Archaeal transcription initiation factor 2 is, like its eukaryotic homologue, a heterotrimeric protein with alpha, beta and gamma subunits [
]. It is thought play an essential role in the recognition of the correct codon for the start of translation, similar to the role of eukaryotic transcription initiation factor. The eukaryotic factor forms a ternary complex with the methionine initiator tRNA and GTP, which binds to the 40S ribosomal subunit as part of the 43S preinitiation complex []. The beta and gamma subunits are responsible for recruiting the initiator tRNA and GTP, while the alpha subunit is involved in the regulation of the translation initiation process. The beta subunit has also been shown to interact with other transcription factors. All three subunits of the archaeal and eukaryotic factors are well conserved among the diverse species of eukaryotes and archaea, but do not occur in prokaryotes. The archaeal beta subunit has an unfolded N-terminal domain, a mixed alpha/beta core domain and a C-terminal zinc finger [
]. The N-terminal region is thought to interact with the gamma subunit, while the central and C-terminal domains are thought to provide RNA-binding sites. |
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| Protein Domain |
| Name: |
Nitrate transporter NarK/NarU-like |
| Type: |
Family |
| Description: |
This family represents nitrate/nitrite antiporters in bacteria, fungi, algae and marine diatoms. Nitrate transporters in Escherichia coli are involved in excretion of nitrite produced by the dissimilatory reduction of nitrate. NarK is polytopic membrane protein with 12 transmembrane domains which is involved in nitrate uptake and nitrite excretion and is thought to function as a nitrate/nitrite antiporter [
,
]. At low concentrations of nitrate, NarK mediates the electrogenic excretion of nitrite rather than nitrate/nitrite exchange. This process prevents intracellular accumulation of toxic levels of nitrite and allows further detoxification in the periplasm through the action of nitrite reductase [].In the opportunistic fungal pathogen Aspergillus fumigatus the nitrate transporter crnA clusters with nitrite reductase (niiA) and nitrate reductase (niaD). NiaD, niiA and crnA are induced by nitrate and repressed by ammonium at the transcriptional level [
]. In Hebeloma cylindrosporum the nitrate transporter polypeptide (NRT2) is characterised by 12 transmembrane domains and presents both a long putative intracellular loop and a short C-terminal tail, two structural features which distinguish fungal high-affinity transporters from their plant homologues. Transcription is repressed by ammonium and strongly stimulated by nitrate but also by organic nitrogen or nitrogen deficiency. |
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| Protein Domain |
| Name: |
PRDM6, PR/SET domain |
| Type: |
Domain |
| Description: |
This entry represents the PR/SET domain found in PR domain zinc finger protein 6 (PRDM6, also known as PRISM). PRDM6 has been shown to co-localized with histone H4 and methylates H4-K20 [
]. It has also been shown to act as a transcriptional repressor by interacting with class I histone deacetylases and the G9a histone methyltransferase []. It promotes the transition from differentiated to proliferative smooth muscle by suppressing differentiation and maintaining the proliferative potential of vascular smooth muscle cells []. It also plays a role in endothelial cells by inhibiting endothelial cell proliferation, survival and differentiation []. Mutations in the PRDM6 gene have been linked to nonsyndromic patent ductus arteriosus (PDA), which is a common congenital heart defect (CHD) with both inherited and acquired causes [].The PRDM family members are characterised by the presence of a N-terminal PR (PRDI-BF1 and RIZ1 homology) domain followed by multiple zinc fingers which confer DNA binding activity. PR domains are only distantly related to the classical SET methyltransferase domains [
]. They are involved in epigenetic regulation of gene expression through their intrinsic histone methyltransferase activity or via interactions with other chromatin modifying enzymes []. |
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| Protein Domain |
| Name: |
CST complex subunit Ten1, animal and plant type |
| Type: |
Family |
| Description: |
This entry represents the CST complex subunit Ten1 homologue from plants and animals [
]. Even though the protein sequence similarity is very low between budding yeast Ten1 () and animal/plant Ten1, they are evolutionarily related. Ten1 is essential for telomere integrity and it negatively regulates telomerase activity [
].Two distinct telomere capping complexes have evolved: CST complex in budding yeast and shelterin complex in vertebrates. Budding yeast CST is composed of Cdc13, Ten1 and Stn1 [
]. The homologues of Ten1 and Stn1 have been identified in vertebrates and plants. The vertebrate CST complex does not appear to play a primary role in telomere protection, but may complement the function of shelterin complex [].Similar to budding yeast Ten1, mammalian Ten1 forms the CST complex with Stn1 homologue and binds to single strand DNA (ssDNA). However, unlike budding yeast CST, the binding of mammalian CST to ssDNA is not sequence specific. The mammalian CST complex may have both telomeric and non-telomeric functions [
].In plants, the CST complex is structurally analogous to mammalian CST and it plays a role in chromosome end protection [
]. |
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| Protein Domain |
| Name: |
Allantoicase |
| Type: |
Family |
| 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: |
Nuclear RNA export factor |
| Type: |
Family |
| Description: |
Mex67 is involved in the export of mRNA from the nucleus to the cytoplasm in Saccharomyces cerevisiae [
]. Vertebrate TAP (also called NXF1 for nuclear RNA export factor 1) is the orthologue of Mex67 []. TAP belongs to a multigene family with conserved modular architecture []. Other members of the family in humans are NXF2, NXF3, and NFX5. Both TAP(NXF1) and NXF2 bind mRNA and display RNA nuclear export activity []. NXF3 also has the ability to export mRNA from the nucleus to the cytoplasm but it uses a different mechanism []. NXF1 and NXF2 are predominantly nuclear, whereas the cytoplasmic presence of NXF3 and NXF5 suggests that they have a different cellular function [,
].Three functional domains of TAP have been characterised: the RNA-binding domain, the Nuclear Transport Factor 2 (NTF2)-like domain, and the ubiquitin-associated (UBA) domain. The RNA-binding domain (RBD) of TAP is located at its amino terminus and is composed of two RNA recognition motifs (RRMs) and one leucine-rich region [
,
]. Once bound to mRNA, TAP escorts the messenger ribonucleoprotein (mRNP) to the nuclear pore, where TAP interacts with nucleoporins via the NTF2-like (NTF2L) and UBA domains []. |
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| Protein Domain |
| Name: |
Allosteric substrate binding domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
This superfamily represents a domain found at the N terminus of the L-serine dehydratases beta chain and in some but not all D-3-phosphoglycerate dehydrogenases (PGDH) and related enzymes. This domain superfamily covers the intervening domain (also known as the allosteric substrate binding domain) found in D-3-phosphoglycerate dehydrogenase (PGDH) from Mycobacterium tuberculosis [
]. The intervening domain, which serves as an anion binding site, is located between the substrate-binding domain and the regulatory domain (L-serine binding) [,
,
]. The intervening domain may be an allosteric site for the control of enzyme activity []. Interestingly, the intervening domain is found in PGDH from bacteria such as Mycobacterium, Bacillus subtilis, Corynebacterium, plants such as Arabidopsis, and higher order eukaryotes, including mammals. This domain is not present in the PGDH from E. coli and some lower eukaryotes, such as yeast and Neurospora []. L-serine dehydratase is found as a heterodimer of alpha and beta chain or as a fusion of the two chains in a single protein. This domain is found in the beta chain. Similar to PGDH, this domain may serve as a noncatalytic site for L-serine [
]. |
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| Protein Domain |
| Name: |
Alpha/Beta hydrolase fold |
| Type: |
Homologous_superfamily |
| Description: |
This entry represent the α/β hydrolase fold.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 []. |
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| Protein Domain |
| Name: |
Isopenicillin N synthase-like, Fe(2+) 2OG dioxygenase domain |
| Type: |
Domain |
| Description: |
This entry represents the Fe(2) 2-oxoglutarate dioxygenase domain found in isopenicillin N synthase PcbC from fungi and related proteins such as procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) from humans and 1-aminocyclopropane-1-carboxylate oxidase 1 from plants.The iron 2OG dioxygenase domain has a conserved β-barrel structure [
], which forms a double-stranded β-helix core fold that forms the predominant class of the cupin superfamily ('cupa' means a small barrel in Latin) []. Two histidines and an aspartate residue catalytically bind a metal ion, in general iron but in some cases another metal, directly involved in catalysis. A conserved arginine or lysine residue further near the C-terminal part acts as the basic residue that interacts with the acidic substrate.Isopenicillin N synthase (IPNS) catalyses conversion of the linear tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N (IPN), the central step in biosynthesis of the beta-lactam antibiotics [
]. IPNS is a nonhaem-Fe2+-dependent enzyme. It belongs to a class of nonhaem Fe2+-containing enzymes which includes 2-oxoglutarate-dependent dioxygenases, 2-oxoglutarate-dependent hydroxy- lases, and enzymes involved in ethylene formation and anthocyaninidin biosynthesis.The IPNS structure shows that the active site is buried within the hydrophobic pocket of an eight-stranded jelly roll barrel [
,
]. |
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| Protein Domain |
| Name: |
Glial cell line-derived neurotrophic factor receptor, alpha 1/2 |
| Type: |
Family |
| Description: |
Glial cell line-derived neurotrophic factor (GDNF) and its related factors
neurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming
growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific
receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,
cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-1 and 2 are activated by GDNF and NTN respectively, although some degree of ligand promiscuity is thought to occur []. Homologues for these receptor subtypes have been cloned from mammalian and avian tissue. The principal ligand for GFRalpha-3 is artemin. This receptor subtype is currently described only in mammals []. GFRalpha-4 is activated by persephin and has so far only been found in chicken []. This entry is general for types 1 to 3.Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation,
triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and
phospholipase C gamma (PLC gamma) dependent pathways []. |
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| Protein Domain |
| Name: |
Glial cell line-derived neurotrophic factor receptor |
| Type: |
Family |
| Description: |
Glial cell line-derived neurotrophic factor (GDNF) and its related factors
neurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming
growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific
receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,
cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-1 and 2 are activated by GDNF and NTN respectively, although some degree of ligand promiscuity is thought to occur []. Homologues for these receptor subtypes have been cloned from mammalian and avian tissue. The principal ligand for GFRalpha-3 is artemin. This receptor subtype is currently described only in mammals []. GFRalpha-4 is activated by persephin and has so far only been found in chicken []. This entry is general for types 1 to 3.Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation,
triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and
phospholipase C gamma (PLC gamma) dependent pathways []. |
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| Protein Domain |
| Name: |
Ciliary BBSome complex subunit 2, middle region |
| Type: |
Domain |
| Description: |
This entry represents the middle region of the Bardet-Biedl syndrome 2 protein. The BBSome (so-named after the association with Bardet-Biedl syndrome) is a complex of 8 subunits that lies at the base of the flagellar microtubule structure. The precise function of the all the individual components in cilia formation is unclear, however they function to promote loading of cargo to the ciliary axoneme [
]. The primary cilium, a slim microtubule-based organelle that projects from the surface of vertebrate cells has crucial roles in vertebrate development and human genetic diseases. Cilia are required for the response to developmental signals, and evidence is accumulating that the primary cilium is specialised for Hedgehog (Hh) signal transduction. Formation of cilia, in turn, is regulated by other signalling pathways, possibly including the planar cell polarity pathway. The connections between cilia and developmental signalling have begun to clarify the basis of human diseases associated with ciliary dysfunction [].BBS2 is one of the three Bardet-Biedl syndrome subunits that is required for leptin receptor signalling in the hypothalamus [
], and BBS2 and 4 are also required for the localisation of somatostatin receptor 3 and melanin-concentrating hormone receptor 1 into neuronal cilia []. |
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| Protein Domain |
| Name: |
Exopolysaccharide biosynthesis polyprenyl glycosylphosphotransferase |
| Type: |
Family |
| Description: |
Members of this family are generally found near other genes involved in the biosynthesis of a variety of exopolysaccharides. These proteins consist of two fused domains, an N-terminal hydrophobic domain of generally low conservation and a highly conserved C-terminal sugar transferase domain (
). Characterised and partially characterised members of this subfamily include Salmonella WbaP (originally RfbP) [
], Escherichia coli WcaJ [,
], Methylobacillus EpsB [], Xanthomonas GumD [], Vibrio CpsA [], Erwinia AmsG [], Group B Streptococcus CpsE (originally CpsD) [], and Streptococcus suis Cps2E []. Each of these is believed to act in transferring the sugar from, for instance, UDP-glucose or UDP-galactose, to a lipid carrier such as undecaprenyl phosphate as the first (priming) step in the synthesis of an oligosaccharide "block". This function is encoded in the C-terminal domain. The liposaccharide is believed to be subsequently transferred through a "flippase"function from the cytoplasmic to the periplasmic face of the inner membrane by the N-terminal domain. Certain closely related transferase enzymes such as Sinorhizobium ExoY [
] and Lactococcus EpsD [] lack the N-terminal domain and are not identified by this entry. |
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| Protein Domain |
| Name: |
Ciliary BBSome complex subunit 2, N-terminal |
| Type: |
Domain |
| Description: |
This entry represents the N-terminal domain of the Bardet-Biedl syndrome 2 protein. The BBSome (so-named after the association with Bardet-Biedl syndrome) is a complex of 8 subunits that lies at the base of the flagellar microtubule structure. The precise function of the all the individual components in cilia formation is unclear, however they function to promote loading of cargo to the ciliary axoneme [
]. The primary cilium, a slim microtubule-based organelle that projects from the surface of vertebrate cells has crucial roles in vertebrate development and human genetic diseases. Cilia are required for the response to developmental signals, and evidence is accumulating that the primary cilium is specialised for Hedgehog (Hh) signal transduction. Formation of cilia, in turn, is regulated by other signalling pathways, possibly including the planar cell polarity pathway. The connections between cilia and developmental signalling have begun to clarify the basis of human diseases associated with ciliary dysfunction [].BBS2 is one of the three Bardet-Biedl syndrome subunits that is required for leptin receptor signalling in the hypothalamus [
], and BBS2 and 4 are also required for the localisation of somatostatin receptor 3 and melanin-concentrating hormone receptor 1 into neuronal cilia []. |
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| Protein Domain |
| Name: |
Vitamin K epoxide reductase complex subunit 1 |
| Type: |
Family |
| Description: |
This entry represents the vitamin K epoxide reductase complex subunit VKORC1 and VKORC1L1 mostly from animals.VKORC1 is an integral membrane protein that catalyzes the reduction of vitamin K 2,3-epoxide and vitamin K to vitamin K hydroquinone, an essential co-factor subsequently used in the γ-carboxylation of glutamic acid residues in blood coagulation enzymes [,
]. All homologues of VKOR contain an active site CXXC motif, which is switched between reduced and disulfide-bonded states during the reaction cycle []. Warfarin, a widely used oral anticoagulant used in medicine as well as rodenticides, inhibits the activity of VKOR, resulting in decreased levels of reduced vitamin K, which is required for the function of several clotting factors []. However, anticoagulation effect of warfarin is significantly associated with polymorphism of certain genes, including VKORC1. Interestingly, in rodents, an adaptive trait appears to have evolved convergently by selection on new or standing genetic polymorphisms in VKORC1 as well as by adaptive introgressive hybridization between species, likely brought about by human-mediated dispersal []. VKORC1L1, a paralogue of VKORC1, is a vitamin K oxidoreductase, which can support γ-carboxylation in vivo [
,
]. |
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| Protein Domain |
| Name: |
Amidohydrolase 3 |
| Type: |
Domain |
| Description: |
Amidohydrolases are a diverse superfamily of enzymes which catalyse the hydrolysis of amide or amine bonds in a large number of different substrates including urea, cytosine, AMP, formylmethanofuran, etc [
,
]. Also included in this superfamily are the phopshotriesterase enzymes, which hydrolyse P-O bonds. Members participate in a large number of processes including nucleotide metabolism, detoxification and neuronal development. They use a variety of divalent metal cofactors for catalysis: for example adenosine deaminase binds a single zinc ion, phopsphotriesterase binds two, while urease binds nickel. It has been postulated that since some of these proteins, such as those some of those involved in neuronal devlopment, appear to have lost their metal-binding centres, their function may simply be to bind, but not hydrolyse, their target molecules.This entry represents a subset of amidohydrolase domains that participate in different functions including cytosine degradation, atrazine degradation and other metabolic processes. The structure of the domain from Escherichia coli has been studied, and like other amidohydrolases it forms a classical α-β TIM-barrel fold []. The active site is located in the mouth of the enzyme barrel and contains a bound iron ion that coordinates a hydroxyl nucleophile. Substrate binding involves a significant conformational change that sequesters the reaction complex from solvent. |
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| Protein Domain |
| Name: |
Triose phosphate/phosphoenolpyruvate translocator |
| Type: |
Family |
| Description: |
Functionally characterised members of the 6-8 TMS Triose-phosphate Transporter (TPT) family are derived from the inner envelope
membranes of chloroplasts and non-green plastids of plants. Under normal physiological conditions, chloroplast TPTs mediate a strict antiport of substrates, frequently exchanging an organic three carbon compound phosphate ester for inorganic phosphate (Pi) [,
].Normally, a triose-phosphate, 3-phosphoglycerate, or another phosphorylated C3
compound made in the chloroplast during photosynthesis, exits the organelle into thecytoplasm of the plant cell in exchange for Pi. However, experiments with reconstituted translocator in artificial membranes indicate that transport can also occur by a channel-like uniport mechanism with up to 10-fold higher transport rates. Channel opening may be induced by a membrane potential of large magnitude and/or by high substrate concentrations. Non-green plastid and chloroplast carriers, such as those from maize endosperm and root membranes, mediate transport of C3 compounds phosphorylated at carbon atom 2, particularly phosphoenolpyruvate, in exchange for Pi. These are the phosphoenolpyruvate:Pi antiporters (PPT). Glucose-6-P has also been shown to be a substrate of some plastid translocators (GPT). The three types of proteins (TPT, PPT and GPT) are divergent in sequence as well as substrate specificity, but their substrate specificities overlap.TPT paralogues are also present in Saccharomyces cerevisiae, which are functionally uncharacterised. |
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| Protein Domain |
| Name: |
S-adenosylmethionine synthetase, C-terminal |
| Type: |
Domain |
| Description: |
The three domains of S-adenosylmethionine synthetase have the same alpha+beta fold. This entry represents the C-terminal domain of S=adenosylmethionine synthetase and is found in association with
and
.
S-adenosylmethionine synthetase (MAT,
) is the enzyme that catalyzes the formation of S-adenosylmethionine (AdoMet) from methionine and ATP [
]. AdoMet is an important methyl donor for transmethylation and is also the propylamino donor in polyamine biosynthesis.In bacteria there is a single isoform of AdoMet synthetase (gene metK), there are two in budding yeast (genes SAM1 and SAM2) and in mammals while in plants there is generally a multigene family.The sequence of AdoMet synthetase is highly conserved throughout isozymes and species. The active sites of both the Escherichia coli and rat liver MAT reside between two subunits, with contributions from side chains of residues from both subunits, resulting in a dimer as the minimal catalytic entity. The side chains that contribute to the ligand binding sites are conserved between the two proteins. In the structures of complexes with the E. coli enzyme, the phosphate groups have the same positions in the (PPi plus Pi) complex and the (ADP plus Pi) complex and are located at the bottom of a deep cavity with the adenosyl group nearer the entrance []. |
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| Protein Domain |
| Name: |
S-adenosylmethionine synthetase, central domain |
| Type: |
Domain |
| Description: |
The three domains of S-adenosylmethionine synthetase have the same alpha+beta fold. This entry represents the central domain and is found in association with
and
.
S-adenosylmethionine synthetase (MAT,
) is the enzyme that catalyzes the formation of S-adenosylmethionine (AdoMet) from methionine and ATP [
]. AdoMet is an important methyl donor for transmethylation and is also the propylamino donor in polyamine biosynthesis.In bacteria there is a single isoform of AdoMet synthetase (gene metK), there are two in budding yeast (genes SAM1 and SAM2) and in mammals while in plants there is generally a multigene family.The sequence of AdoMet synthetase is highly conserved throughout isozymes and species. The active sites of both the Escherichia coli and rat liver MAT reside between two subunits, with contributions from side chains of residues from both subunits, resulting in a dimer as the minimal catalytic entity. The side chains that contribute to the ligand binding sites are conserved between the two proteins. In the structures of complexes with the E. coli enzyme, the phosphate groups have the same positions in the (PPi plus Pi) complex and the (ADP plus Pi) complex and are located at the bottom of a deep cavity with the adenosyl group nearer the entrance [
]. |
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| Protein Domain |
| Name: |
S-adenosylmethionine synthetase, N-terminal |
| Type: |
Domain |
| Description: |
The three domains of S-adenosylmethionine synthetase have the same alpha+beta fold. This entry represents the N-terminal domain of S-adenosylmethionine synthetase and is found in association with
and
.
S-adenosylmethionine synthetase (MAT,
) is the enzyme that catalyzes the formation of S-adenosylmethionine (AdoMet) from methionine and ATP [
]. AdoMet is an important methyl donor for transmethylation and is also the propylamino donor in polyamine biosynthesis.In bacteria there is a single isoform of AdoMet synthetase (gene metK), there are two in budding yeast (genes SAM1 and SAM2) and in mammals while in plants there is generally a multigene family.The sequence of AdoMet synthetase is highly conserved throughout isozymes and species. The active sites of both the Escherichia coli and rat liver MAT reside between two subunits, with contributions from side chains of residues from both subunits, resulting in a dimer as the minimal catalytic entity. The side chains that contribute to the ligand binding sites are conserved between the two proteins. In the structures of complexes with the E. coli enzyme, the phosphate groups have the same positions in the (PPi plus Pi) complex and the (ADP plus Pi) complex and are located at the bottom of a deep cavity with the adenosyl group nearer the entrance [
]. |
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| Protein Domain |
| Name: |
ERV/ALR sulfhydryl oxidase domain |
| Type: |
Domain |
| Description: |
The ~100-residue ERV/ALR sulphydryl oxidase domain is a versatile module adapted for catalysis of disulphide bond formation in various organelles and biological settings. The ERV/ALR sulphydryl oxidase domain has a Cys-X-X-Cys dithiol/disulphide motif adjacent to a bound FAD cofactor, enabling transfer of electrons from thiol substrates to non-thiol electron acceptors. ERV/ALR family members differ in their N- or C-terminal extensions, which typically contain at least one additional disulphide bond, the hypothesised 'shuttle' disulphide. In yeast ERV1, a mitochondrial enzyme, the shuttle disulphide is N-terminal to the catalytic core; in yeast ERV2, present in the endoplasmic reticulum, it is C-terminal. The N- and C-terminal extensions can be entire domains, such as the thioredoxin-like domains () or short segments that do not seem to be distinct domains. Proteins of the ERV/ALR family are encoded by all eukaryotes and cytoplasmic DNA viruses (poxviruses, African swine fever virus, iridoviruses, and Paramecium bursaria Chlorella virus 1) [
,
,
,
,
].The ERV/ALR sulphydryl oxidase domain contains a four-helix bundle (helices alpha1-alpha4) and an additional single turn of helix (alpha5) packed perpendicular to the bundle [
,
]. The FAD prosthetic group is housed at the mouth of the 4-helix bundle and communicates with the pair of juxtaposed cysteine residues that form the proximal redox active site []. |
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| Protein Domain |
| Name: |
ABC transporter A |
| Type: |
Family |
| Description: |
ATP-binding cassette transporters (ABC) are multipass transmembrane proteins that use the energy of ATP hydrolysis to transport substrates across membrane bilayers. Members of ABC transporter subfamily A are full-length transporters [
], which consist of a single long polypeptide chain organised into two tandemly arranged halves. Each half contains a membrane-spanning domain (MSD) followed by a cytoplasmic nucleotide binding domain (NBD) []. Several members of this group have been shown to mediate the transport of a variety of physiologic lipid compounds, such as sterols, phospholipids and bile acids [,
].ABCA7 plays a role in clearance of apoptotic cells by affecting their phagocytosis [
]. In the human visual cycle, ABCA4 acts as an inward-directed retinoid flipase, retinoid substrates imported by ABCA4 from the extracellular or intradiscal (rod) membrane surfaces to the cytoplasmic membrane surface are all-trans-retinaldehyde (ATR) and N-retinyl-phosphatidyl-ethanolamine (NR-PE). Once transported to the cytoplasmic surface, ATR is reduced to vitamin A by trans-retinol dehydrogenase (tRDH) and then transferred to the retinal pigment epithelium (RPE) where it is converted to 11-cis-retinal. ABCA4 may also play a role in photoresponse, removing ATR/NR-PE from the extracellular photoreceptor surfaces during bleach recovery []. It has been suggested that ABCA9 plays a role in monocyte differentiation and lipid homeostasis []. |
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| Protein Domain |
| Name: |
Glycosyl transferase, family 9 |
| Type: |
Family |
| Description: |
The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([intenz:2.4.1.-]) and related proteins into distinct sequence based families has been described []. This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.Glycosyltransferase family 9
comprises enzymes with two known activity; lipopolysaccharide N-acetylglucosaminyltransferase (
), heptosyltransferase (
).
Heptosyltransferase I is thought to add L-glycero-D-manno-heptose to the inner 3-deoxy-D-manno-octulosonic acid (Kdo) residue of the lipopolysaccharide core [
]. Heptosyltransferase II is a glycosyltransferase involved in the synthesis of the inner core region of lipopolysaccharide []. Lipopolysaccharide is a major component of the outer leaflet of the outer membrane in Gram-negative bacteria. It is composed of three domains; lipid A, Core oligosaccharide and the O-antigen. These enzymes transfer heptose to the lipopolysaccharide core []. |
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| Protein Domain |
| Name: |
Tautomerase/MIF superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Tautomerase superfamily members have a (beta-α-β)2 structure in two layers, and use a similar mechanism of action involving an amino-terminal proline as a general base in a ket-enol tautomerisation reaction [
]. Members of this superfamily include macrophage migration inhibitory factor (MIF) and related proteins such as D-dopachrome tautomerase; 4-oxalocrotonoate tautomerase and related enzymes such as trans-3-chloroacrylic acid dehalogenase; and 5-carboxymethyl-2-hydroxymuconate Delta-isomerase (CHMI).Macrophage migration inhibitory factor (MIF) is a key regulatory cytokine within innate and adaptive immune responses, capable of promoting and modulating the magnitude of the response [
]. MIF is released from T-cells and macrophages, and it can regulate cytokine secretion and the expression of receptors involved in the immune response. MIF has been linked to various inflammatory diseases, such as rheumatoid arthritis and atherosclerosis [].4-Oxalocrotonate tautomerase (4-OT) is a plasmid-encoded enzyme that catalyzes the isomerisation of beta,gamma-unsaturated enones to their alpha,beta-isomers. This enzyme is part of the plasmid-encoded catechol meta-fission pathway, which enables the bacteria to use various aromatic hydrocarbons as their sole sources of carbon and energy [
].5-carboxymethyl-2-hydroxymuconate isomerase (CHMI) is a trimeric enzyme involved in the homoprotocatechuate pathway in Escherichia coli [
]. This enzyme catalyses the isomerisation of 5-carboxymethyl-2-hydroxymuconate (CHM) to 5-carboxymethyl-2-oxo-3-hexene-1,6-dioate (COHED). |
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| Protein Domain |
| Name: |
NADH:ubiquinone oxidoreductase, subunit G, iron-sulphur binding |
| Type: |
Domain |
| Description: |
NADH:ubiquinone oxidoreductase (complex I) (
) is a respiratory-chain enzyme that catalyses the transfer of two electrons from NADH to ubiquinone in a reaction that is associated with proton translocation across the membrane (NADH + ubiquinone = NAD+ + ubiquinol) [
]. Complex I is a major source of reactive oxygen species (ROS) that are predominantly formed by electron transfer from FMNH(2). Complex I is found in bacteria, cyanobacteria (as a NADH-plastoquinone oxidoreductase), archaea [], mitochondria, and in the hydrogenosome, a mitochondria-derived organelle. In general, the bacterial complex consists of 14 different subunits, while the mitochondrial complex contains homologues to these subunits in addition to approximately 31 additional proteins [].This entry describes the G subunit (one of 14 subunits, A to N) of the NADH-quinone oxidoreductase complex I which generally couples NADH and ubiquinone oxidation/reduction in bacteria and mammalian mitochondria while translocating protons, but may act on NADPH and/or plastoquinone in cyanobacteria and plant chloroplasts. This family does not contain related subunits from formate dehydrogenase complexes.This entry represents the iron-sulphur binding domain of the G subunit. This domain consists of just two alpha helices separated by a loop region that coordinates a [4Fe-4S] cluster through an unusual H-x(3)-C-x(2)-C-x(5)-C motif that includes one His and three Cys residues [,
,
]. |
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| Protein Domain |
| Name: |
NADH:ubiquinone oxidoreductase, 51kDa subunit, conserved site |
| Type: |
Conserved_site |
| 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 and is a component of the iron-sulphur (IP) fragment of the enzyme. It seems to bind to NAD, FMN, and a 2Fe-2S cluster. The 51kDa subunit and the bacterial hydrogenase alpha subunit contain three regions of sequence similarities. The first one most probably corresponds to the NAD-binding site, the second to the FMN-binding site, and the third one, which contains three cysteines, to the iron-sulphur binding region. |
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| Protein Domain |
| Name: |
Imidazoleglycerol-phosphate dehydratase, conserved site |
| Type: |
Conserved_site |
| Description: |
Imidazoleglycerol-phosphate dehydratase (IGPD;
) catalyzes the dehydration of imidazole glycerol phosphate to imidazole acetol phosphate, the sixth step of histidine biosynthesis in plants and microorganisms where the histidine is synthesized de novo. There is an internal repeat in the protein domain that is related by pseudo-dyad symmetry, perhaps as a result of an ancient gene duplication. The apo-form of IGPD exists as a catalytically inactive trimer which, in the presence of specific divalent metal cations such as manganese (Mn2+), cobalt (Co2+), cadmium (Cd2+), nickel (Ni2+), iron (Fe2+) and zinc (Zn2+), assembles to form a biologically active high molecular weight metalloenzyme; a 24-mer with 4-3-2 symmetry. Each 24-mer has 24 active sites, and contains around 1.5 metal ions per monomer, each monomer contributing residues to three separate active sites.
IGPD enzymes are monofunctional in fungi, plants, archaea and some eubacteria while they are encoded as bifunctional enzymes in other eubacteria, such that the enzyme is fused to histidinol-phosphate phosphatase, the penultimate enzyme of the histidine biosynthesis pathway. The histidine biosynthesis pathway is a potential target for development of herbicides, and IGPD is a target for the triazole phosphonate herbicides [
,
,
,
,
,
,
,
,
,
,
,
].Both signature patterns in this entry cover two consecutive, conserved histidine residues. |
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| Protein Domain |
| Name: |
Imidazoleglycerol-phosphate dehydratase |
| Type: |
Family |
| Description: |
Imidazoleglycerol-phosphate dehydratase (IGPD;
) catalyzes the dehydration of imidazole glycerol phosphate to imidazole acetol phosphate, the sixth step of histidine biosynthesis in plants and microorganisms where the histidine is synthesized de novo. There is an internal repeat in the protein domain that is related by pseudo-dyad symmetry, perhaps as a result of an ancient gene duplication. The apo-form of IGPD exists as a catalytically inactive trimer which, in the presence of specific divalent metal cations such as manganese (Mn2+), cobalt (Co2+), cadmium (Cd2+), nickel (Ni2+), iron (Fe2+) and zinc (Zn2+), assembles to form a biologically active high molecular weight metalloenzyme; a 24-mer with 4-3-2 symmetry. Each 24-mer has 24 active sites, and contains around 1.5 metal ions per monomer, each monomer contributing residues to three separate active sites.
IGPD enzymes are monofunctional in fungi, plants, archaea and some eubacteria while they are encoded as bifunctional enzymes in other eubacteria, such that the enzyme is fused to histidinol-phosphate phosphatase, the penultimate enzyme of the histidine biosynthesis pathway. The histidine biosynthesis pathway is a potential target for development of herbicides, and IGPD is a target for the triazole phosphonate herbicides [
,
,
,
,
,
,
,
,
,
,
,
]. |
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| Protein Domain |
| Name: |
Alpha/beta hydrolase fold-3 |
| 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 the catalytic domain fold-3 of α/β hydrolase. |
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| Protein Domain |
| Name: |
Pyruvate/Phosphoenolpyruvate kinase-like domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Pyruvate kinase controls the exit from the glysolysis pathway, catalysing the transfer of phosphate from phosphooenolpyruvate (PEP) to ADP. Mammalian pyruvate kinase is a homotetramer, where each polypeptide subunit consists of four domains: N-terminal, A domain, B domain and C-terminal. Activation of the enzyme is believed to occur via the clamping down of the B domain onto the A domain to dehydrate the active site cleft. The N- and C-terminal domains are situated at inter-subunit contact sites, and could be involved in assembly and communication within the complex. The N-terminal domain has a TIM beta/α-barrel structure. Homologous TIM-barrel domains are found in the following proteins:N-terminal of pyruvate kinase (
), which is interrupted by an all-beta domain [
].C-terminal of pyruvate phosphate dikinase (
), which has a similar mode of substrate binding to pyruvate kinase [
].Phosphoenolpyruvate carboxylase (
); this domain has additional helices [
].Phosphenolpyruvate mutase(
)/Isocitrate lyase (
), where it forms a swapped dimer [
].HpcH/HpaI aldolases, such as the beta subunit of citrate lyase, where it forms a swapped dimer, and contains a pyruvate kinase-type metal binding site [
].Ketopantoate hydroxymethyltransferase PanB (
), where a C-terminal helix exchange is observed in some enzymes [
]. |
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| Protein Domain |
| Name: |
Glycosyl transferase, family 43 |
| Type: |
Family |
| Description: |
The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([intenz:2.4.1.-]) and related proteins into distinct sequence based families has been described []. This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.Glycosyltransferase family 43
comprises enzymes with only one known activity: beta-glucuronyltransferase(GlcAT-I;
) [
].GlcAT-I is a key enzyme involved in the initial steps of proteoglycan synthesis [
]. GlcAT-I catalyzes the transfer of a glucuronic acid moiety from the uridine diphosphate-glucuronic acid (UDP-GlcUA) to the common linkage region of trisaccharide Gal-beta-(1-3)-Gal-beta-(1-4)-Xyl of proteoglycans. The enzyme has two subdomains that bind the donor and acceptor substrate separately []. The active site is located at the cleft between both subdomains in which the trisaccharide molecule is oriented perpendicular to the UDP []. |
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| Protein Domain |
| Name: |
Lactate dehydrogenase/glycoside hydrolase, family 4, C-terminal |
| Type: |
Homologous_superfamily |
| Description: |
This entry represents a structural motif found at the C-terminal of lactate dehydrogenase (
)and malate dehydrogenases (
), as well as at the C-terminal of family 4 glycoside hydrolases (
). These domains have an unusual fold consisting of segregated α-helical and β-sheet regions, although they contain predominantly anti-parallel β-sheets [
,
,
].L-lactate dehydrogenases are metabolic enzymes that catalyse the conversion of
L-lactate to pyruvate, the last step in anaerobic glycolysis. L-lactate dehydrogenase is also found as a lens crystallin in bird and crocodile eyes. Malate dehydrogenases catalyse the interconversion of malate to oxaloacetate. The enzyme participates in the citric acid cycle.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) web site. Because the fold of proteins is better conserved than their sequences, some of the families can be grouped in 'clans'. Glycoside hydrolase family 4 comprises enzymes with several known activities; 6-phospho-beta-glucosidase (); 6-phospho-alpha-glucosidase (
); alpha-galactosidase (
).
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| Protein Domain |
| Name: |
Cysteine peptidase, histidine active site |
| Type: |
Active_site |
| Description: |
Thiol (cysteine) proteases (EC 3.4.22.-) [
] are a family of proteolytic enzymes which contain an active site cysteine. Catalysis proceeds through a thioester intermediate and is facilitated by a nearby histidine side chain; an asparagine completes the essential catalytic triad.Cysteine peptidases have characteristic molecular topologies, which can be seen not only in their three-dimensional structures, but commonly also in the two-dimensional structures. These are peptidases in which the nucleophile is the sulphydryl group of a cysteine residue. Cysteine proteases are divided into clans (proteins which are evolutionary related), and further sub-divided into families, on the basis of the architecture of their catalytic dyad (cysteine-histidene) or triad [
].Modification of the catalytic triad, especially of its first amino acid (cysteine), has been postulated as a suitable target for a chemical modulation of enzyme function. This is the case for silicateins, where the cysteine residue has been replaced by a serine [
]. Silicateins represent a group of enzymes possessing bi-functional activity; in addition to the silica-condensing activity, they possess a proteolytic (cathepsin-like) activity [].The sequences around the three active site residues are well conserved. This entry represents the histidine active site. The catalytic triad consists of this entry,
and
. This catalytic triad detects mainly proteases of the C1 family, including papain and several cathepsins.
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| Protein Domain |
| Name: |
Cysteine peptidase, asparagine active site |
| Type: |
Active_site |
| Description: |
Thiol (cysteine) proteases (EC 3.4.22.-) [
] are a family of proteolytic enzymes which contain an active site cysteine. Catalysis proceeds through a thioester intermediate and is facilitated by a nearby histidine side chain; an asparagine completes the essential catalytic triad.Cysteine peptidases have characteristic molecular topologies, which can be seen not only in their three-dimensional structures, but commonly also in the two-dimensional structures. These are peptidases in which the nucleophile is the sulphydryl group of a cysteine residue. Cysteine proteases are divided into clans (proteins which are evolutionary related), and further sub-divided into families, on the basis of the architecture of their catalytic dyad (cysteine-histidene) or triad [
].Modification of the catalytic triad, especially of its first amino acid (cysteine), has been postulated as a suitable target for a chemical modulation of enzyme function. This is the case for silicateins, where the cysteine residue has been replaced by a serine [
]. Silicateins represent a group of enzymes possessing bi-functional activity; in addition to the silica-condensing activity, they possess a proteolytic (cathepsin-like) activity [].The sequences around the three active site residues are well conserved. This entry represents the asparagine active site. The catalytic triad consists of this entry,
and
. This catalytic triad detects mainly proteases of the C1 family, including papain and several cathepsins.
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| Protein Domain |
| Name: |
RuvA domain 2-like |
| Type: |
Homologous_superfamily |
| Description: |
In prokaryotes, RuvA, RuvB, and RuvC process the universal DNA intermediate of homologous recombination, termed Holliday junction. The tetrameric DNA helicase RuvA specifically binds to the Holliday junction and facilitates the isomerization of the junction from the stacked folded configuration to the square-planar structure [
]. In the RuvA tetramer, each subunit consists of three domains, I, II and III, where I and II form the major core that is responsible for Holliday junction binding and base pair rearrangements of Holliday junction executed at the crossover point, whereas domain III regulates branch migration through direct contact with RuvB. Domain 2 has a SAM (sterile alpha motif)-like α-bundle fold that occurs as a duplication containing two helix-hairpin-helix (HhH) motifs.The C-terminal domain (CTD) of the excision repair protein UvrC shows structural similarity to RuvA domain 2. The CTD of UvrC is essential for 5' incision in the prokaryotic nucleotide excision repair process, and acts to mediate structure-specific binding to single-stranded-double-stranded junction DNA [
].Domain III of NAD+-dependent DNA ligase consists of a duplication of two RuvA-like domains (four HhH motifs), and also contains a zinc-finger subdomain. DNA ligases catalyse the crucial step of joining the breaks in duplex DNA during DNA replication, repair and recombination, utilizing either ATP or NAD+ as a cofactor [
]. |
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| Protein Domain |
| Name: |
NAD(+) synthetase |
| Type: |
Family |
| Description: |
This entry represents NAD(+) synthetases, including glutamine-dependent NAD(+) synthetases and NH(3)-dependent NAD(+) synthetases.NAD+ is involved electron transport and redox reactions and in DNA ligation and protein ADP-ribosylation. In yeast and most other organisms, NAD is generated through the de novo pathway and the salvage pathway. In the de novo pathway, quinolinic acid is converted to nicotinic acid mononucleotide (NaMN). In the salvage pathway, NaMN is generated by recycling of nicotinamide. Both pathways converge on NaMN, which is then converted into deamido-NAD+. Subsequently, deamido-NAD+ is converted to NAD+ by NAD+ synthetase [
].NAD+ synthetase has been extensively studied in bacteria. It is encoded by nadE gene in E. coli and by outB gene in B. subtilis [
]. These prokaryotic enzymes are ammonia-dependent (containing an ammonia-utilising domain)[]. However, some pokaryotic NAD(+) synthetases, such as that from Mycobacterium tuberculosis, contain a nitrilase-related domain, are glutamine-dependent []. Eukaryotic NAD+ synthetases are glutamine-dependent. In budding yeast, this enzyme is named as Qns1. It contains an N-terminal nitrilase-related domain (contaiing the nitrilase-related active-site residues) and a C-terminal NAD+ synthetase domain [
]. Both domains are required for its function in vivo. The nitrilase-related domain is the fourth independently evolved glutamine amidotransferase domain to have been identified in nature []. |
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| Protein Domain |
| Name: |
LigD polymerase domain, PaeLigD-type |
| Type: |
Domain |
| Description: |
This entry represents the polymerase (Pol) domain of bacterial LigD proteins similar to Pseudomonas aeruginosa (Pae) LigD.The LigD Pol domain belongs to the archaeal/eukaryal primase (AEP) superfamily. In prokaryotes, LigD along with Ku is required for non-homologous end joining (NHEJ)-mediated repair of DNA double-strand breaks (DSB). NHEJ-mediated DNA DSB repair is error-prone. PaeLigD is monomeric, containing an N-terminal phosphoesterase module, a central polymerase (Pol) domain, and a C-terminal ATP-dependent ligase domain. It has been suggested that LigD Pol contributes to NHEJ-mediated DNA DSB repair in vivo, by filling in short 5'-overhangs with ribonucleotides; the filled in termini would then be sealed by the associated LigD ligase domain, resulting in short stretches of RNA incorporated into the genomic DNA. The PaeLigD Pol domain in vitro, in a manganese-dependent fashion, catalyzes templated extensions of 5'-overhang duplex DNA, and nontemplated single-nucleotide additions to blunt-end duplex DNA; it preferentially adds single ribonucleotides at blunt DNA ends. PaeLigD Pol adds a correctly paired rNTP to the DNA primer termini more rapidly than it does a correctly paired dNTP; it has higher infidelity as an RNA polymerase than it does as a DNA polymerase, which is in keeping with the mutagenic property of NHEJ-mediated DNA DSB repair [
,
,
,
,
,
]. |
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| Protein Domain |
| Name: |
Aromatic amino acid hydroxylase, C-terminal |
| Type: |
Domain |
| Description: |
Hydroxylation of the aromatic amino acids phenylalanine, tyrosine and
tryptophan is carried out by a family of non-heme iron and tetrahydrobiopterin(BH4) dependent enzymes: the aromatic amino acid hydroxylase [
]. Theseenzymes are structurally and functionally similar. The eukaryotic formsinclude a regulatory N-terminal domain, a catalytic domain and a C-terminal
oligomerization motif. The eukaryotic enzymes are all homotetramers [,
].Three-dimensional structures have been determined for the three types of
enzymes. The iron atom is bound to three amino acid residues, two close histidine and a more distant acidic residue. This arrangement of ligands has been observed in a number of metalloproteins with divergent function [].Enzymes that belong to the aromatic amino acid hydroxylase family are listed
below:Phenylalanine-4-hydroxylase (
) (PAH). Catalyzes the conversion
of phenylalanine to tyrosine. In humans, deficiencies [] of PAH are the cause of phenylketonuria, the most common inborn error of amino acid metabolism. In the bacteria Chromobacterium violaceum [], PAH is copper-dependent; it is iron-dependent in Pseudomonas aeruginosa [].Tyrosine 3-hydroxylase (
) (TYH). Catalyzes the rate limiting
step in catecholamine biosynthesis: the conversion of tyrosine to 3,4-dihydroxy-L-phenylalanine.
Tryptophan 5-hydroxylase (
) (TRH). Catalyzes the rate-limiting
step in serotonin biosynthesis: the conversion of tryptophan to 3-hydroxy-anthranilate.
This entry represents a domain containing the catalytic domain and the coiled-coil C-terminal oligomerization motif. |
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| Protein Domain |
| Name: |
Toxin Pg family |
| Type: |
Family |
| Description: |
Proteins in this family are disulphide-rich peptides expressed in Gemmula venom ducts in the gem turrids (venomous snails in the family Turridae) [
].There are more than 10,000 species of predatory marine snail that use venom as their primary weapon for prey capture. Based on shell morphology, they are traditionally divided into 3 groups: cone snails, augers and turrids. Most molluscan taxonomies assign cone snails to a single large genus, Conus, while augers are assigned to several different genera; by contrast, the turrids represent a group that is much more diverse, and is now thought to comprise the vast majority of conoidean biodiversity [
].The venom peptides from several species in the genus Gemmula, the gem turrids, have been characterised. Their translated open reading frames show characteristics typical of the venom peptides from Conus: an N-terminal signal sequence; a C-terminal cysteine-rich mature peptide; and an intervening pro-region. Two of these sequences, Gsp9.1 and Gsp9.2, have highly similar signal and propeptide regions, while their predicted mature peptides are more divergent (although the cysteine residues are completely conserved) [
]. This pattern of highly conserved and more variable regions is characteristic of gene superfamilies encoding the toxin peptides found in Conus venoms. |
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| Protein Domain |
| Name: |
Flavin monooxygenase (FMO) 5 |
| 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 diversecompounds. Five mammalian forms of FMO are now known and have been designated
FMO1-FMO5 [,
,
,
,
].The deduced amino acid sequence of human FM05 includes the putative FAD-
(GxGxxG) and NADP+pyrophosphate-binding (GxGxxA) sites characteristic of
mammalian FMOs [], a 'FATGY' motif that has also been observed in a rangeof siderphore biosynthetic enzymes [
], and a C-terminal hydrophobic segmentthat is believed to anchor the monooxygenase to the microsomal membrane [
].Human and guinea pig FMO5, like other FMOs, are encoded by multipletranscripts. FMO5 has been identified in livers of adult humans, rabbits
and guinea pigs, and foetal livers of humans []. Neither the human nor guinea pig enzyme effectively catalyse the metabolism of methimazole, a
general FMO substrate; however, both are active with n-octylamine []. Theresponses to detergent, ions and elevated temperature are all similar to
those observed in rabbit FMO5, suggesting that these properties are species-independent and that this form of FMO is not readily classified as a drug-
metabolising enzyme []. |
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| Protein Domain |
| Name: |
Imidazole glycerol phosphate dehydratase domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Imidazoleglycerol-phosphate dehydratase (IGPD;
) catalyzes the dehydration of imidazole glycerol phosphate to imidazole acetol phosphate, the sixth step of histidine biosynthesis in plants and microorganisms where the histidine is synthesized de novo. There is an internal repeat in the protein domain that is related by pseudo-dyad symmetry, perhaps as a result of an ancient gene duplication. The apo-form of IGPD exists as a catalytically inactive trimer which, in the presence of specific divalent metal cations such as manganese (Mn2+), cobalt (Co2+), cadmium (Cd2+), nickel (Ni2+), iron (Fe2+) and zinc (Zn2+), assembles to form a biologically active high molecular weight metalloenzyme; a 24-mer with 4-3-2 symmetry. Each 24-mer has 24 active sites, and contains around 1.5 metal ions per monomer, each monomer contributing residues to three separate active sites.
IGPD enzymes are monofunctional in fungi, plants, archaea and some eubacteria while they are encoded as bifunctional enzymes in other eubacteria, such that the enzyme is fused to histidinol-phosphate phosphatase, the penultimate enzyme of the histidine biosynthesis pathway. The histidine biosynthesis pathway is a potential target for development of herbicides, and IGPD is a target for the triazole phosphonate herbicides [
,
,
,
,
,
,
,
,
,
,
,
]. |
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| Protein Domain |
| Name: |
Peptidase C7 domain |
| Type: |
Domain |
| Description: |
This entry represents a peptidase C7 domain, which is found in HAV papain-like proteases p48 and p29 [
,
].Hypoviruses are positive-strand RNA mycoviruses that attenuate virulence of their pathogenic fungal hosts [E1]. They employ a gene expression strategy that involves the autocatalytic processing of the N-terminal portion of encoded polyproteins by papain-like protease domains. The prototypic hypovirus CHV-1/EP713, responsible for virulence attenuation (hypovirulence) of the chestnut blight fungus Cryphonectria parasitica, encodes two contiguous open reading frames (ORFs) designated ORF A and ORF B, which contain N-terminal proteases p29 and p48, respectively. Protease p29 functions as a suppressor of the RNA silencing defense response, while p48 is required for viral RNA replication [,
,
]. The HAV papain-like protease p29 is a cysteine protease, which forms the peptidase family C7 [E2]. A Cys and a His catalytic residue are essential for autocatalytic cleavage at a glycine dipeptide clevage site located at the C- terminus of the domain [,
,
]. The HAV papain-like protease p48 is a cysteine protease, which forms the peptidase family C8 [E3]. A Cys and a His catalytic residue are essential for autocatalytic cleavage between the cleavage site residues Gly and Ala located at the C terminus of the domain [
,
,
]. |
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| Protein Domain |
| Name: |
Methane/phenol monooxygenase, hydroxylase component |
| Type: |
Family |
| Description: |
This group represents the hydroxylase component of aromatic and alkene monooxygenases such as methane monooxygenase (
) phenol 2-monooxygenase (
), toluene-4-monooxygenase (
) from Pseudomonas mendocina, and alkene monooxygenase (
) from Xanthobacter autotrophicus. Aromatic and alkene monooxygenase hydroxylases (AAMH) are composed of two copies each of three subunits (alpha 2 beta 2 gamma 2), and all three subunits are almost completely α-helical, with the exception of two beta hairpin structures in the alpha subunit. The active site of each alpha subunit contains one dinuclear iron centre, housed in a four-helix bundle [
].Methane monooxygenase is a multicomponent enzyme found in methanotrophic bacteria that catalyzes the hydroxylation of methane and higher alkenes (as large as octane). Phenol monooxygenase, found in a diverse group of bacteria, catalyses the hydroxylation of phenol, chloro- and methyl-phenol and naphthol. Both enzyme systems consist of three components: the hydroxylase, a coupling protein and a reductase [
]. The toluene-4-monooxygenase multicomponent enzyme system catalyzes the O2- and NADH-dependent hydroxylation of toluene to form p-cresol [
]. The alkene monooxygenase system catalyzes the O2- and NADH-dependent epoxidation of short chain (C2 to C6) alkenes to their corresponding epoxides [
].Please see the following relevant references: [
,
,
,
]. |
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| Protein Domain |
| Name: |
Photosystem I PsaJ, reaction centre subunit IX superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Oxygenic photosynthesis uses two multi-subunit photosystems (I and II) located in the cell membranes of cyanobacteria and in the thylakoid membranes of chloroplasts in plants and algae. Photosystem II (PSII) has a P680 reaction centre containing chlorophyll 'a' that uses light energy to carry out the oxidation (splitting) of water molecules, and to produce ATP via a proton pump. Photosystem I (PSI) has a P700 reaction centre containing chlorophyll that takes the electron and associated hydrogen donated from PSII to reduce NADP+ to NADPH. Both ATP and NADPH are subsequently used in the light-independent reactions to convert carbon dioxide to glucose using the hydrogen atom extracted from water by PSII, releasing oxygen as a by-product.This superfamily consists of the photosystem I reaction centre subunit IX or PsaJ from various organisms including Synechocystis sp. (strain PCC 6803), Pinus thunbergii (Green pine) and Zea mays (Maize).
PsaJ () is a small 4.4kDa, chloroplast encoded, hydrophobic subunit of the photosystem I reaction complex whose function is not yet fully understood [
]. PsaJ can be cross-linked to PsaF () and has a single predicted transmembrane domain. It has a proposed role in maintaing PsaF in the correct orientation to allow for fast electron transfer from soluble donor proteins to P700+ [
]. |
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| Protein Domain |
| Name: |
Calpastatin |
| Type: |
Family |
| Description: |
Calpain inhibitor (calpastatin) is restricted to the metazoa and specifically inhibits calpain (calcium-dependent cysteine protease) [
]. Calpastatin belongs to MEROPS inhibitor family I27, clan II. It plays a key role in post-mortem tenderisation of meat and may be involved in muscle protein degradation in living tissue.The calpain system originally comprised three molecules: two Ca2+-dependent proteases, mu-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both mu- and m-calpain are heterodimers containing an identical 28kDa subunit and an 80kDa subunit that shares 55-65% sequence homology between the two proteases. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17kDa to 85kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. How calpain activity is regulated in cells is still unclear, but the calpains
ostensibly participate in a variety of cellular processes including remodelling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma []. |
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| Protein Domain |
| Name: |
Aromatic amino acid monoxygenase, C-terminal domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Hydroxylation of the aromatic amino acids phenylalanine, tyrosine and
tryptophan is carried out by a family of non-heme iron and tetrahydrobiopterin(BH4) dependent enzymes: the aromatic amino acid hydroxylase [
]. Theseenzymes are structurally and functionally similar. The eukaryotic formsinclude a regulatory N-terminal domain, a catalytic domain and a C-terminal
oligomerization motif. The eukaryotic enzymes are all homotetramers [,
].Three-dimensional structures have been determined for the three types of
enzymes. The iron atom is bound to three amino acid residues, two close histidine and a more distant acidic residue. This arrangement of ligands has been observed in a number of metalloproteins with divergent function [].Enzymes that belong to the aromatic amino acid hydroxylase family are listed
below:Phenylalanine-4-hydroxylase (
) (PAH). Catalyzes the conversion
of phenylalanine to tyrosine. In humans, deficiencies [] of PAH are the cause of phenylketonuria, the most common inborn error of amino acid metabolism. In the bacteria Chromobacterium violaceum [], PAH is copper-dependent; it is iron-dependent in Pseudomonas aeruginosa [].Tyrosine 3-hydroxylase (
) (TYH). Catalyzes the rate limiting
step in catecholamine biosynthesis: the conversion of tyrosine to 3,4-dihydroxy-L-phenylalanine.
Tryptophan 5-hydroxylase (
) (TRH). Catalyzes the rate-limiting
step in serotonin biosynthesis: the conversion of tryptophan to 3-hydroxy-anthranilate.
This entry represents a domain containing the catalytic domain and the coiled-coil C-terminal oligomerization motif. |
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| Protein Domain |
| Name: |
Angiotensinogen |
| Type: |
Family |
| Description: |
Angiotensinogen is a component of the renin-angiotensin system (RAS), a hormone system that regulates blood pressure and fluid balance. It is also known as the renin substrate, and is a non-inhibitory member of the serpin family of proteinase inhibitors (MEROPS inhibitor family I4, clan ID, MEROPS identifier I04.953).Angiotensinogen is catalytically cleaved by renin to produce angiotensin I in response to lowered blood pressure. Angiotensin converting enzyme (ACE), subsequently removes a dipeptide to produce angiotensin II, the physiologically active peptide, which functions in the regulation of volume and mineral balance of body fluids [
,
]. Angiotensin I and angiotensin II can be further processed to generate angiotensin III, which stimulates aldosterone release [], and angiotensin IV. Angiotensin 1-9 is cleaved from angiotensin-1 by ACE2 [] and can be further processed by ACE to produce angiotensin 1-7, angiotensin 1-5 and angiotensin 1-4 [,
].Angiotensinogen is synthesised in the liver and secreted in plasma [
,
,
,
]. Angiotensinogen appears to be associated with a predisposition to essential hypertension; it is also associated with pregnancy-induced hypertension (pih) (preeclampsia), a heterogeneous disorder that complicates 5-7% of all pregnancies and remains a leading cause of maternal, foetal and neonatal morbidity and mortality [].The entry represents the full precursor sequence of angiotensinogen. |
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| Protein Domain |
| Name: |
Neuropeptide FF receptor family |
| Type: |
Family |
| Description: |
Neuropeptide FF receptors [
] belong to a family of neuropeptides containing an RF-amide motif at their C terminus which have a high affinity for the pain modulatory peptide neuropeptide NPFF (NPFF) []. Neuropeptide FF (NPFF) receptors have two subtypes, neuropeptide FF receptor type 1 (NPFF1) and neuropeptide FF receptor type 2 (NPFF2), they are members of rhodopsin G protein-coupled receptor family. The neuropeptide FF is found at high concentrations in the posterior pituitary, spinal cord, hypothalamus and medulla and is believed to be involved in pain modulation, opioid tolerance, cardiovascular regulation, memory and neuroendocrine regulation [,
,
,
].Comparing the distribution of NPFF1 and NPFF2 receptors in different species reveals important species differences [
]. The NPFF1 receptor is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus, is thought to participate in neuroendocrine functions. Whereas as the NPFF2 receptor is present in high density, particularly in mammals in the superficial layers of the spinal cord [] where it is involved in nociception and modulation of opioid functions [], consistent with a potential role of NPFF in the modulation of sensory inputs, like pain responses [,
,
].This entry represents the neuropeptide FF receptor family. |
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| Protein Domain |
| Name: |
Photosynthetic reaction centre, L subunit |
| Type: |
Family |
| Description: |
The photosynthetic apparatus in non-oxygenic bacteria consists of light-harvesting (LH) protein-pigment complexes LH1 and LH2, which use carotenoid and bacteriochlorophyll as primary donors [
]. LH1 acts as the energy collection hub, temporarily storing it before its transfer to the photosynthetic reaction centre (RC) []. Electrons are transferred from the primary donor via an intermediate acceptor (bacteriopheophytin) to the primary acceptor (quinine Qa), and finally to the secondary acceptor (quinone Qb), resulting in the formation of ubiquinol QbH2. RC uses the excitation energy to shuffle electrons across the membrane, transferring them via ubiquinol to the cytochrome bc1 complex in order to establish a proton gradient across the membrane, which is used by ATP synthetase to form ATP [,
,
]. The core complex is anchored in the cell membrane, consisting of one unit of RC surrounded by LH1; in some species there may be additional subunits [
]. RC consists of three subunits: L (light), M (medium), and H (heavy). Subunits L and M provide the scaffolding for the chromophore, while subunit H contains a cytoplasmic domain []. In Rhodopseudomonas viridis, there is also a non-membranous tetrahaem cytochrome (4Hcyt) subunit on the periplasmic surface. This entry describes the photosynthetic reaction centre L subunit. |
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| Protein Domain |
| Name: |
Ribonuclease T2-like superfamily |
| Type: |
Homologous_superfamily |
| 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.The structure of ribonuclease T2 is composed of an alpha+beta fold. |
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| Protein Domain |
| Name: |
Elongation factor EF1B gamma, C-terminal domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
Translation elongation factors are responsible for two main processes during protein synthesis on the ribosome [
,
,
]. EF1A (or EF-Tu) is responsible for the selection and binding of the cognate aminoacyl-tRNA to the A-site (acceptor site) of the ribosome. EF2 (or EF-G) is responsible for the translocation of the peptidyl-tRNA from the A-site to the P-site (peptidyl-tRNA site) of the ribosome, thereby freeing the A-site for the next aminoacyl-tRNA to bind. Elongation factors are responsible for achieving accuracy of translation and both EF1A and EF2 are remarkably conserved throughout evolution.Elongation factor EF1B (also known as EF-Ts or EF-1beta/gamma/delta) is a nucleotide exchange factor that is required to regenerate EF1A from its inactive form (EF1A-GDP) to its active form (EF1A-GTP). EF1A is then ready to interact with a new aminoacyl-tRNA to begin the cycle again. EF1B is more complex in eukaryotes than in bacteria, and can consist of three subunits: EF1B-alpha (or EF-1beta), EF1B-gamma (or EF-1gamma) and EF1B-beta (or EF-1delta) [
].This entry represents a conserved domain superfamily. This domain is usually found near the C terminus of EF1B-gamma chains, a peptide of 410-440 residues. The gamma chain appears to play a role in anchoring the EF1B complex to the beta and delta chains and to other cellular components. |
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| Protein Domain |
| Name: |
Trehalose operon repressor |
| Type: |
Family |
| Description: |
Trehalose is a non-reducing disaccharide which can be used as both a carbon source and an osmoprotectant in bacteria. Trehalose uptake into the cytoplasm occurs via a trehalose-specific phosphotransferase system which phosphorylates trehalase to trehalose-6-phosphate (Tre6P) during transport into the cytoplasm, and a hydrolase which hydrolyses Tre6P to glucose and glucose-6-phophate[
].This entry represents LacI-type TreR, a transcriptional repressor of trehalose uptake found mainly within the gamma-proteobacteria. It does not include the GntR-type TreR's such as those found in Bacillus species. It is capable of binding both the inducer Tre6P and trehalose. Binding of trehalose does not affect the repressor's affinity for its DNA binding site, while binding Tre6P substantially reduces its affinity. The repression activity of TreR is therefore regulated by the ratio of trehalose to Tre6P within the cell [
]. The protein is composed of two domains, an N-terminal DNA-binding helix-turn-helix domain, and a C-terminal effector-binding domain which is homologous to that of LacI. The effector-binding domain is composed of two subdomains, both of which form an α-β-alpha sandwhich, with the effector binding site located at the interface of these subdomains []. Tre6P and trehalose bind competitively to this site, with the affinty for trehalose substantially lower than that for Tre6P. |
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| Protein Domain |
| Name: |
OLD protein-like, TOPRIM domain |
| Type: |
Domain |
| Description: |
This topoisomerase-primase (TOPRIM) nucleotidyl transferase/hydrolase domain is found in bacterial and archaeal nucleases of the OLD (overcome lysogenization defect) family. The bacteriophage P2 OLD protein, which has DNase as well as RNase activity [
,
], consists of an N-terminal ABC-type ATPase domain [] and a C-terminal Toprim domain []; the nuclease activity of OLD is stimulated by ATP, though the ATPase activity is not DNA-dependent. OLD hologues are divided in two classes based on sequence length and the presence/absence of a unique UvrD/PcrA/Rep-like helicase gene immediately downstream in the genome. Despite degenerate conservation in the C-terminal domain between classes, they conserve the catalytic mechanism for DNA cleavage []. Functional details on OLD are scant and further experimentation is required to define the relationship between the ATPase and Toprim nuclease domains, but in vitro studies on P2 OLD suggest that ATPase and nuclease activities are required for OLD function [].The TOPRIM domain has two conserved motifs, one of which centres at a conserved glutamate and the other one at two conserved aspartates (DxD). The conserved glutamate may act as a general acid in strand cleavage by nucleases. The DXD motif may co-ordinate Mg2+, a cofactor required for full catalytic function []. |
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| Protein Domain |
| Name: |
ERV/ALR sulfhydryl oxidase domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
The ~100-residue ERV/ALR sulphydryl oxidase domain is a versatile module adapted for catalysis of disulphide bond formation in various organelles and biological settings. The ERV/ALR sulphydryl oxidase domain has a Cys-X-X-Cys dithiol/disulphide motif adjacent to a bound FAD cofactor, enabling transfer of electrons from thiol substrates to non-thiol electron acceptors. ERV/ALR family members differ in their N- or C-terminal extensions, which typically contain at least one additional disulphide bond, the hypothesised 'shuttle' disulphide. In yeast ERV1, a mitochondrial enzyme, the shuttle disulphide is N-terminal to the catalytic core; in yeast ERV2, present in the endoplasmic reticulum, it is C-terminal. The N- and C-terminal extensions can be entire domains, such as the thioredoxin-like domains (
) or short segments that do not seem to be distinct domains. Proteins of the ERV/ALR family are encoded by all eukaryotes and cytoplasmic DNA viruses (poxviruses, African swine fever virus, iridoviruses, and Paramecium bursaria Chlorella virus 1) [
,
,
,
,
].The ERV/ALR sulphydryl oxidase domain contains a four-helix bundle (helices alpha1-alpha4) and an additional single turn of helix (alpha5) packed perpendicular to the bundle [
,
]. The FAD prosthetic group is housed at the mouth of the 4-helix bundle and communicates with the pair of juxtaposed cysteine residues that form the proximal redox active site []. |
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| Protein Domain |
| Name: |
Erythropoietin receptor |
| Type: |
Family |
| Description: |
A number of receptors for lymphokines, hematopoietic growth factors and growth hormone-related molecules have been found to share a common binding domain. These receptors are designated as hematopoietin receptors [
] and the corresponding ligands as hematopoietins. Further, hematopoietins have been subdivided into two major structural groups: Large/long and small/short hematopoietins.Several receptor chains for large hematopoietins are structurally related such that their extracellular parts strictly contain the 200 amino-acids hematopoietin domain, duplicated in the thrombopoietin receptor and in avian prolactin receptors. This subgroup of receptor chains contains: Growth hormone receptor (GHR), Prolactin receptor (PRLR), Erythropoietin receptor (EPOR), Thrombopoietin receptor (TPOR).A schematic representation of the structure of these receptors is shown below:+----------------------------------------xxxxxxx-------------------------+
| C C C C Extracellular XXXXXXX Cytoplasmic |+-|-|-------|--|-------------------------xxxxxxx-------------------------+
| | | | Transmembrane+-+ +--+
These receptor chains are single components of receptors that homodimerise upon binding of the cognate cytokine, following the structural model described for the growth hormone-receptor complex [
].This entry describes receptors for erythropoietin (EPO), a plasma glycoprotein, which is the primary physiological mediator of erythrocite production [
]. They are expressed in relatively mature erythroid progenitor cells and in EPO-responsive erythroleukemia cells, and their physiological role is to mediate erythropoietin- induced erythroblast proliferation and differentiation. The receptors dimerise upon stimulation, triggering the JAK2/STAT5 signalling cascade [,
]. |
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| Protein Domain |
| Name: |
Phosphoenolpyruvate phosphomutase, core |
| Type: |
Domain |
| Description: |
Phosphonates are a class of organophosphorus compounds, characterised by a stable C-P bond, which are found in a variety of biologically produced molecules including antiobiotics, lipids, proteins and polysaccharides [
]. The functions of these molecules include phosphorus storage, cell communication, host recognition and chemical warfare. Phosphoenolpyruvate (PEP) phosphomutase catalyses the reversible conversion of PEP to 3-phosphonopyruvate, forming a stable C-P bond, which is the entry point to all known phosphonate biosynthetic pathways [].This entry consists of characterised and predicted PEP phosphomutases found in bacterial and eukayotic species. A closely related enzyme, phosphonopyruvate hydrolase from Variovorax sp. Pal2, is excluded from this entry, and the functional identification of some more distantly related sequences, such as from Bacteroides fragilis, Treponema denticola, and Clostridium tetani E88 is unknown.PEP phosphomutase forms a modified TIM barrel fold where the eighth alpha helix adopts a different conformation than in the classical TIM barrel fold [
]. The substrate binds in the central channel of the barrel and is anchored to the active site by the Mg(2+) cofactor []. In the absence of substrate the active site is acessible to the solvent, while substrate-binding causes a conformational change where a large loop shields the site from solvent []. This shielding appears to be required for catalysis to occur. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 18 |
| Type: |
Family |
| Description: |
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern [
]. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences [
]. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [,
]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis [
]. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 18 is also known as glucocorticoid-induced TNFR family-related gene (GITR) and activation-inducible TNFR family member (AITR). Expression of the receptor by T-lymphocytes has been shown to have an anti-apoptotic effect, indicating that it may play a role in the regulation of T-cell receptor-mediated cell death [
]. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 13B |
| Type: |
Family |
| Description: |
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern [
]. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences [
]. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [,
]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis [
]. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 13B (also known as transmembrane activator and CAML interactor (TACI)) functions as a receptor for B-cell activating factor (BAFF) []. Mutations in TNF receptor 13B cause common variable immunodeficiency (CVID) and IgA deficiency []. |
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| Protein Domain |
| Name: |
Insulin-like growth factor |
| 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 []. IGF2 appears to be induced by placental lactogen and is thought to play a role in foetal development []. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 14 |
| Type: |
Family |
| Description: |
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern [
]. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences [
]. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [
,
]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis [
]. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 14 is also known as herpesvirus entry mediator (HVEM). It plays an important role in the entry of herpes simplex virus into cells, and hence pathogenesis of the virus [
]. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 19-like |
| Type: |
Family |
| Description: |
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern [
]. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences [
]. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [,
]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis [
]. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 19-like, also known as receptor expressed in lymphoid tissues (RELT), is abundantly expressed in hematologic tissues such as spleen, lymph node, and peripheral blood leukocytes, as well as in leukemias and lymphomas [
]. The receptor may play a role in the regulation of immune responses []. |
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| Protein Domain |
| Name: |
3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily |
| Type: |
Homologous_superfamily |
| Description: |
The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They are divided into 11 families. They regulate the localisation, duration and amplitude of cyclic nucleotide signalling within subcellular domains. PDEs are therefore important for signal transduction.PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors include: Roflumilast for chronic obstructive pulmonary disease and asthma [
], Sildenafil for erectile dysfunction [] and Cilostazol for peripheral arterial occlusive disease [], amongst others.Retinal 3',5'-cGMP phosphodiesterase is located in photoreceptor outer segments: it is light activated, playing a pivotal role in signal transduction. In rod cells, PDE is oligomeric, comprising an alpha-, a beta- and 2 gamma-subunits, while in cones, PDE is a homodimer of alpha chains, which are associated with several smaller subunits. Both rod and cone PDEs catalyse the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5' monophosphates, both enzymes also binding cGMP with high affinity. The cGMP-binding sites are located in the N-terminal half of the protein sequence, while the catalytic core resides in the C-terminal portion.This entry represents the C-terminal catalytic domain superfamily of PDE which is multihelical and can be divided into three subdomains. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 7 |
| Type: |
Family |
| Description: |
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern [
]. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences [
]. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [,
]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis [
]. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 7, otherwise known as CD27 antigen, is expressed on discrete subpopulations of T-and B-cells [
]. The receptor plays a vital role in the generation and long-term maintenance of T-cell immunity []. |
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| Protein Domain |
| Name: |
LeuA, N-terminal catalytic TIM barrel domain |
| Type: |
Domain |
| Description: |
Alpha-isopropylmalate synthase (LeuA), a key enzyme in leucine biosynthesis, catalyzes the first committed step in the pathway, converting acetyl-CoA and alpha-ketoisovalerate to alpha-isopropyl malate and CoA [
,
]. Although the reaction catalyzed by LeuA is similar to that of the Arabidopsis thaliana IPMS1 protein, the two fall into phylogenetically distinct families within the same superfamily.LeuA has and N-terminal TIM barrel catalytic domain, a helical linker domain, and a C-terminal regulatory domain. LeuA forms a homodimer in which the linker domain of one monomer sits over the catalytic domain of the other, inserting residues into the active site that may be important for catalysis [
]. Homologues of LeuA are found in bacteria as well as fungi, such as alpha-isopropylmalate synthases I (LEU4) and II (LEU9) from Saccharomyces cerevisiae [,
]. This domain consists of a core beta-alpha motif with the eight parallel beta strands forming an enclosed barrel surrounded by eight alpha helices. The domain has a catalytic centre containing a divalent cation-binding site formed by a cluster of invariant residues that cap the core of the barrel. In addition, the catalytic site includes three invariant residues - an aspartate (D), an arginine (R), and a glutamate (E) - which is the basis for the domain name 'DRE-TIM' [
,
]. |
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| Protein Domain |
| Name: |
PARP-14, RNA recognition motif 2 |
| Type: |
Domain |
| Description: |
This entry represents the RNA recognition motif 2 (RRM2) of poly [ADP-ribose] polymerase 14 (PARP-14), also termed aggressive lymphoma protein 2, a member of the B aggressive lymphoma (BAL) family of macrodomain-containing PARPs []. It is expressed in B lymphocytes and interacts with the IL-4-induced transcription factor Stat6. It plays a fundamental role in the regulation of IL-4-induced B-cell protection against apoptosis after irradiation or growth factor withdrawal. It mediates IL-4 effects on the levels of gene products that regulate cell survival, proliferation, and lymphomagenesis. PARP-14 acts as a transcriptional switch for Stat6-dependent gene activation. In the presence of IL-4, PARP-14 activates transcription by facilitating the binding of Stat6 to the promoter and release of HDACs from the promoter with an IL-4 signal. In contrast, in the absence of a signal, PARP-14 acts as a transcriptional repressor by recruiting HDACs []. Absence of PARP-14 protects against Myc-induced developmental block and lymphoma. Thus, PARP-14 may play an important role in Myc-induced oncogenesis []. Additional research indicates that PARP-14 is also a binding partner with phosphoglucose isomerase (PGI)/autocrine motility factor (AMF). It can inhibit PGI/AMF ubiquitination, thus contributing to its stabilization and secretion [].PARP-14 contains two N-terminal RNA recognition motifs (RRMs), three tandem macro domains, and C-terminal region with sequence homology to PARP catalytic domain. |
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| Protein Domain |
| Name: |
D-galactarate/Altronate dehydratase, C-terminal |
| Type: |
Domain |
| Description: |
This domain is found at the C terminus of D-galactarate dehydratase (GarD,
) [
] and altronate dehydratase () [
]. When purified, both enzymes are catalytically inactive in the absence of added Fe2+, Mn
2+, and beta-mercaptoethanol. Synergistic activation of altronate hydrolase activity is seen in the presence of both iron and manganese ions, suggesting that the enzyme may have two ion binding sites. Mn
2+appears to be part of the enzyme active centre, but the function of the single bound Fe
2+ion is unknown. The hydratase has no Fe-S core [
]. In the crystal structure, GarD forms dimers, each monomer consisting of three domains: the N-terminal β-clip SAF domain connected by a long linker to the second domain which contains three parallel β-strands surrounded by three α-helices and that serves as a dimerisation interface between monomers, and a C-terminal α/β domain with a novel topology resembling a Rossmann fold, with an unusual helix crossover []. This entry represents the second and C-terminal domains, the latter is the core of the protein and may have a catalytic metal binding site [].This domain is also found in (2R)-sulfolactate sulfo-lyase subunit beta (suyB) (
) from Chromohalobacter salexigens [
]. |
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| Protein Domain |
| Name: |
Tumour necrosis factor receptor 9 |
| Type: |
Family |
| Description: |
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern [
]. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [,
].TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis [
]. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease [].TNF receptor 9 (also known as ILA and CD137 antigen) is expressed by activated T and B lymphocytes and monocytes. Stimulation of the receptor inhibits proliferation of activated T lymphocytes and induces programmed cell death [
]. |
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| Protein Domain |
| Name: |
Neurotrophin-4 |
| 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. Neurotrophin-4 (NT-4) exerts its effects by binding to neurotrophic tyrosine kinase receptor type 2 (NTRK2; also called TrkB). NT-4 has been shown to play a crucial role in the development of long-term memory [
]. It has also been implicated in the regulation of appetite and in body weight control []. |
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| Protein Domain |
| Name: |
DNA primase large subunit PriL |
| 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 family consists of DNA primase large subunit PriL from archaea. |
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| Protein Domain |
| Name: |
Transcription factor Otx2 |
| Type: |
Family |
| Description: |
Otx proteins constitute a class of vertebrate homeodomain-containing
transcription factors that have been shown to be essential for anteriorhead formation, including brain morphogenesis. They are orthologous to the
product of the Drosophila head gap gene, orthodenticle (Otd), and appear toplay similar roles in both, since the developmental abnormalities caused by
disruption of these transcription factors in one, can be recovered bysubstitution of the factor(s) from the other. Such studies have provided
strong evidence that there exists a conserved genetic programme for insectand mammalian brain development, which presumably arose in a more primitive
common ancestor [,
].Two vertebrate orthodenticle-related transcription factors have been indentified, Otx1 and Otx2, which have sizes of 355 and 289 residues
respectively. They contain a bicoid-like homeodomain, which features aconserved lysine residue at position 9 of the DNA recognition helix, which
is thought to confer high-affinity binding to TAATCC/T elements on DNA [].Otd-like transcription factors have also been found in zebrafish and
certain lamprey species. Mice completely lacking Otx2 (due to targeted gene disruption) die during
early embryogenesis. Analysis reveals that they lack the neuroectodermthat is destined to become the forebrain, midbrain and rostral hindbrain.
They also show major abnormalities in their body plan. Mice that haveartificially-reduced levels of Otx2 develop head abnormalities reminiscent
of otocephaly []. |
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| Protein Domain |
| Name: |
Coenzyme A pyrophosphatase |
| Type: |
Family |
| Description: |
Coenzyme A pyrophosphatase (CoAse), a member of the Nudix hydrolase superfamily, functions to catalyse the elimination of oxidized inactive CoA, which can inhibit CoA-utilizing enzymes. The need of CoAses mainly arises under conditions of oxidative stress. CoAse has a conserved Nudix fold and requires a single divalent cation for catalysis. In addition to a signature Nudix motif G[X5]E[X7]REUXEEXGU, where U is Ile, Leu, or Val, CoAse contains an additional motif upstream called the NuCoA motif (LLTXT(SA)X3RX3GX3FPGG) which is postulated to be involved in CoA recognition []. CoA plays a central role in lipid metabolism. It is involved in the initial steps of fatty acid synthesis in the cytosol, in the oxidation of fatty acids and the citric acid cycle in the mitochondria, and in the oxidation of long-chain fatty acids in peroxisomes. CoA has the important role of activating fatty acids for further modification into key biological signalling molecules [,
].Proteins in this family include Nudt7 and Nudt8. Nudt7 mediates the cleavage of CoA, CoA esters and oxidized CoA with similar efficiencies, yielding 3',5'-ADP and the corresponding 4'-phosphopantetheine derivative as products. Preferentially hydrolyzes medium-chain acyl-CoAs and bile acid-CoAs [
]. This entry also includes yeast Pcd1, which act as peroxisomal pyrophosphatase with specificity for coenzyme A and CoA derivatives [,
]. |
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| Protein Domain |
| Name: |
S-adenosylmethionine synthetase, domain 2 |
| Type: |
Homologous_superfamily |
| Description: |
S-adenosylmethionine synthetase (MAT,
) is the enzyme that catalyzes the formation of S-adenosylmethionine (AdoMet) from methionine and ATP [
]. AdoMet is an important methyl donor for transmethylation and is also the propylamino donor in polyamine biosynthesis.In bacteria there is a single isoform of AdoMet synthetase (gene metK), there are two in budding yeast (genes SAM1 and SAM2) and in mammals while in plants there is generally a multigene family.The sequence of AdoMet synthetase is highly conserved throughout isozymes and species. The active sites of both the Escherichia coli and rat liver MAT reside between two subunits, with contributions from side chains of residues from both subunits, resulting in a dimer as the minimal catalytic entity. The side chains that contribute to the ligand binding sites are conserved between the two proteins. In the structures of complexes with the E. coli enzyme, the phosphate groups have the same positions in the (PPi plus Pi) complex and the (ADP plus Pi) complex and are located at the bottom of a deep cavity with the adenosyl group nearer the entrance [
].This superfamily represents the second domain found in S-adenosylmethionine synthase. Structurally, this domain consists of 5 beta strands and 3 alpha helices. |
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| Protein Domain |
| Name: |
Gamma-glutamylcyclotransferase |
| Type: |
Family |
| Description: |
This entry contains the human protein C7orf24 (
) which has been used as a cancer marker with a potential role in cell proliferation. It has been characterised as gamma-glutamyl cyclotransferase (GGCT), a homodimer of two 21kDa subunits, that catalyses the formation of 5-oxoproline (2-pyrrolidone-5-carboxylic acid, pyroglutamic acid) from gamma-glutamyl dipeptides (
) [
]. L-gamma-glutamyl-L-amino acid ->5-oxoproline + L-amino acidThe structure of GGCT has been solved. Its topology is unrelated to other enzymes associated with cyclotransferase-like activity and its structure has been termed the GGCT-fold, which appears to be related to the BtrG-like superfamily. A potential active site pocket contains a highly conserved glutamic acid (Glu(98)), which when converted to either Ala or Gln completely inactivates the enzyme without altering the overall fold [
].This entry also includes GGCT gliK, GGCT aclK and GGCT verK from fungi. GGCT gliK is part of the gene cluster that mediates the biosynthesis of gliotoxin, a member of the epipolythiodioxopiperazine (ETP) class of toxins characterised by a disulfide bridged cyclic dipeptide [
,
]. GGCT aclK mediates the biosynthesis of aspirochlorine []. GGCT verK mediates the biosynthesis of 11'-deoxyverticillin A, one of the dimeric epipolythiodioxopiperazines (ETPs) from the verticillin family that act as mycotoxins []. |
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| Protein Domain |
| Name: |
Urocortin/corticotropin-releasing factor |
| Type: |
Family |
| Description: |
Corticotropin-releasing factor (CRF), urotensin-I, urocortin and sauvagine
form a family of related neuropeptides in vertebrates. The family can begrouped into 2 separate paralogous lineages, with urotensin-I, urocortin and
sauvagine in one group and CRF forming the other group. Urocortin andsauvagine appear to represent orthologues of fish urotensin-I in mammals and
amphibians, respectively. The peptides have a variety of physiologicaleffects on stress and anxiety, vasoregulation, thermoregulation, growth and
metabolism, metamorphosis and reproduction in various species, and are allreleased as preprohormones [
].CRF [] is a hormone found mainly in the paraventricular nucleus of the mammalian hypothalamus that regulates the release of corticotropin (ACTH) from the pituitary gland. From here, CRFis transported to the anterior pituitary, stimulating adrenocorticotropic
hormone (ACTH) release via CRF type 1 receptors, thereby activating thehypothalamo-pituitary-adrenocortical axis (HPA) and thus glucocorticoid
release.CRF is evolutionary related to a number of other active peptides. Urocortin acts in vitro to stimulate the secretion of adrenocorticotropic hormone. Urotensin is found in the teleost caudal neurosecretory system and may play a role in osmoregulation and as a corticotropin-releasing factor. Urotensin-I is released
from the urophysis of fish, and produces ACTH and subsequent cortisol release in vivo. The nonhormonal portion of the prohormone is thought to be
the urotensin binding protein (urophysin). |
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| Protein Domain |
| Name: |
MAP3K, TRAFs-binding domain |
| Type: |
Domain |
| Description: |
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [
].This domain corresponds to the TRAFs-binding domain found at the N terminus of some MAP3Ks. This domain includes seven tetratricopeptide repeats (TPRs) and, together with th PH-like domain, constitutes the central regulatory domain of ASK1. |
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| Protein Domain |
| Name: |
Nectin-3/4, second Ig domain |
| Type: |
Domain |
| Description: |
Nectins are single-pass type I membrane glycoproteins belonging to the immunoglobulin superfamily. They are characterised by three Ig-like domains (a distal IgV domain and two IgC domains) in the ectodomain, followed by a transmembrane region and a cytoplasmic tail [
]. Unlike cadherins, nectins are Ca2+-independent cell adhesion molecules that mediate not only homotypic but also heterotypic cell-cell adhesion []. The cytoplasmic tail of nectins possesses a conserved afadin-binding motif, except for nectin-4 which binds the PDZ domain of afadin at its carboxyl terminus. Afadin connects nectins to F-actin and the actin cytoskeleton [,
,
].This entry represents the second Ig domain of nectin-3 and 4. Nectin-3 [
] plays a role in cell-cell adhesion through heterophilic transinteractions with other nectins. Nectin-2 and nectin-3 are expressed in Sertoli cells and spermatids, respectively, and their transinteraction regulates the organization of the Sertoli cell-spermatid junctions that plays a critical role in spermatid development [
,
]. Nectin-3 and nectin-1 interactions play a critical role in selective axo-dendritic adhesion []. Nectin-4 seems to be involved in cell adhesion through trans-homophilic and -heterophilic interactions []. It acts as a receptor for measles virus [,
,
]. Nectin 4 plays a significant role in cancer cell growth and invasion [,
]. |
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| Protein Domain |
| Name: |
Talin-1/2, rod-segment |
| Type: |
Domain |
| Description: |
This entry represents the rod-segment of Talin-1/2. This domain interacts with its N-terminal FERM domain to mask its integrin-binding site and interferes with interactions between the FERM domain and the cellular membrane [
,
].Talin is a cytoskeletal protein that interacts with integrins and lipids. It forms an antiparallel homodimer with an N-terminal globular head and a larger C-terminal rod [
]. The head domain contains a FERM (4.1, ezrin, radixin, moesin) domain, which has been implicated in both integrin and actin-binding. Binding of integrin beta cytoplasmic tails to the FERM domain has been found to induce integrin activation []. The rod domain also appears to mediate binding to both actin and integrins []. The C-terminal rod contains an I/LWEQ domain. It has been shown that the I/LWEQ domains from mouse talin and yeast Sla2p
interact with F-actin [
]. The domain has four conserved blocks, the name of the domain is derived from the initial conserved amino acid of each of the four blocks [].In vivo, talin has been shown to play a critical role in the formation of cell adhesions and regulation of integrin signalling in numerous species [
]. Talin localises to some neuromuscular junction and sites of cell-cell adhesions, as well as to focal adhesions, sites of attachment to the substratum. |
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| Protein Domain |
| Name: |
Tensin/EPS8 phosphotyrosine-binding domain |
| Type: |
Domain |
| Description: |
The phosphotyrosine-binding domain (PTB, also phosphotyrosine-interaction or PI domain) of tensin tends to be found at the C terminus. Tensin is a multi-domain protein that binds to actin filaments and functions as a focal-adhesion molecule (focal adhesions are regions of plasma membrane through which cells attach to the extracellular matrix). Human tensin has actin-binding sites, an SH2 (
) domain and a region similar to the tumour suppressor PTEN [
]. The PTB domain interacts with the cytoplasmic tails of beta integrin by binding to an NPXY motif []. The PTB domain is also found in the epidermal growth factor receptor kinase substrate 8 (EPS8).PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules [
]. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether []. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine []. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains []. |
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| Protein Domain |
| Name: |
Voltage gated sodium channel, alpha-4 subunit, mammalian |
| Type: |
Family |
| Description: |
Voltage-dependent sodium channels are transmembrane (TM) proteins responsible for the depolarising phase of the action potential in most
electrically excitable cells []. They may exist in 3 states []: the resting state, where the channel is closed; the activated state, where the channel is open; and the inactivated state, where the channel is closed and refractory to opening. Several different structurally and functionally distinct isoforms are found in mammals, coded for by a multigene family, these being responsible for the different types of sodium ion currents found in excitable tissues.There are nine pore-forming alpha subunit of voltage-gated sodium channels consisting of four membrane-embedded homologous domains (I-IV), each consisting of six α-helical segments (S1-S6), three cytoplasmic loops connecting the domains, and a cytoplasmic C-terminal tail. The S6 segments of the four domains form the inner surface of the pore, while the S4 segments bear clusters of basic residues that constitute the channel's voltage sensors [
,
,
].This entry represents the voltage-gated sodium channel alpha-4 subunits (Nav1.4, also known as SCN4A) from mammals.Nav1.4 is expressed in skeletal muscle [
]. Mutations in Nav1.4 gene cause several diseases in humans, such as Paramyotonia congenita of von Eulenburg (PMC), Myotonia SCN4A-related (MYOSCN4A) and Periodic paralysis hyperkalemic (HYPP) [,
,
,
,
,
]. |
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| Protein Domain |
| Name: |
Ku70, core domain |
| Type: |
Domain |
| Description: |
This entry represents the central DNA-binding core domain of Ku70, which folds as a β-barrel [
]. 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: |
Transient receptor ion channel domain |
| Type: |
Domain |
| Description: |
Transient receptor potential (TRP) channels can be described as tetramers formed by subunits with six transmembrane domains and containing cation-selective pores, which in several cases show high calcium permeability. The molecular architecture of TRP channels is reminiscent of voltage-gated channels and comprises six putative transmembrane segments (S1-S6), intracellular N- and C-termini, and a pore-forming reentrant loop between S5 and S6 [
].TRP channels represent a superfamily conserved from worms to humans that comprise seven subfamilies [
]: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin or long TRPs), TRPA (ankyrin, whose only member is Transient receptor potential cation channel subfamily A member 1, TrpA1), TRPP (polycystin), TRPML (mucolipin) and TRPN (Nomp-C homologues), which has a single member that can be found in worms, flies, and zebrafish. TRPs are classified essentially according to their primary amino acid sequence rather than selectivity or ligand affinity, due to their heterogeneous properties and complex regulation.
TRP channels are involved in many physiological functions, ranging from pure sensory functions, such as pheromone signalling, taste transduction, nociception, and temperature sensation, over homeostatic functions, such as Ca2+ and Mg2+ reabsorption and osmoregulation, to many other motile functions, such as muscle contraction and vaso-motor control [
].This domain is found in some Trp proteins, and is generally located C-terminal to ankyrin repeats (
).
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