Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation which is usually zinc, but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophillic role.
Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site []. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [].This entry contains metallopeptidases belonging to MEROPS peptidase family M50 (S2P protease family, clan MM). Members of the M50 metallopeptidase family include: mammalian sterol-regulatory element binding protein (SREBP) site 2 protease, Escherichia coli protease EcfE, stage IV sporulation protein FB and various hypothetical bacterial and eukaryotic homologues. A number of proteins are classified as non-peptidase homologues as they either have been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for the catalytic activity.
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 family contains chain 3 of the NADH-ubiquinone / plastoquinone oxidoreductase.
The bromodomain and extraterminal (BET) proteins are a class of transcriptional regulators whose members can be found in animals, plants and fungi. BET proteins are involved in diverse cellular phenomena such as meiosis, cell-cycle control, and homeosis and have been suggested to modulate
chromatin structure and affect transcription via a sequence-independent mechanism. BET proteins are defined as having one (plants) or two (animals/yeast) bromodomains and an Extra Terminal (ET)domain. The ET domain consists of three separate regions, only one of which, the N-terminal ET (NET) domain is conserved in all BET proteins. The function of the NET domain is assumed to be protein binding [
,
,
,
].The structure of the NET domain comprises three α-helices and a characteristic loop region of an irregular but well-defined structure. The NET structure has an acidic patch that forms a continuousridge with a hydrophobic cleft. which may interact with other proteins and/or DNA [
].Some proteins known to contain a NET domain include:Human RING3 (now designated Brd2)Murine MCAP (now designated Brd4)Drosophila FshYeast Bdf1 and Bdf2Arabidopsis imbibition-inducible (IMB1), whichplays a role in abscisic acid (ABA) and phytochrome A (phyA) mediated responses of seed germination.
Cobalamin-independent methionine synthase, MetE, catalyses the synthesis of the amino acid methionine by the transfer of a methyl group from methyltetrahydrofolate to homocysteine [
]. The N-terminal and C-terminal domains of MetE together define a catalytic cleft in the enzyme. The N-terminal domain is thought to bind the substrate, in particular, the negatively charged polyglutamate chain. The N-terminal domain is also thought to stabilise a loop from the C-terminal domain.
Methionine synthases catalyse the the final step of methionine biosynthesis. Two apparently unrelated families of proteins catalyse this step: cobalamin-dependent methionine synthase, which catalyses the transfer of a methyl group from N5-methyltetrahydrofolate to L-homocysteine and requires cobalamin as a cofactor (MetH; 5-methyltetrahydrofolate:L-homocysteine S-methyltransferase;
) and cobalamin-independent methionine synthase, which catalyses the transfer of a methyl group from methyltetrahydrofolate to L-homocysteine without using an intermediate methyl carrier (MetE; 5-methyltetrahydropteroyltri-L-glutamate:L-homocysteine S-methyltransferase;
). These enzymes display no detectable sequence homology between them, but both require zinc for activation and binding to L-homocysteine. Organisms that cannot obtain cobalamin (vitamin B12) encode only the cobalamin-independent enzyme. Escherichia coli and many other bacteria express both enzymes [
]. Mammals utilise only cobalamin-dependent methionine synthase, while plants and yeasts utilise only the cobalamin-independent enzyme.The N-terminal half and C-terminal half of MetE in E. coli show some sequence similarity, indicating that the metE gene has evolved from an ancestral metE gene by duplication [
]. This entry represents a the C-terminal domain of cobalamin-independent methionine synthase (MetE) from bacteria and plants, which contains the zinc ion responsible for binding and activating homocysteine []. It also includes archaeal proteins where this domain corresponds to the entire length of the protein [].
Although apparently functionally unrelated, intracellular TRAFs and extracellular meprins share a conserved region of about 180 residues, the meprin and TRAF homology (MATH) domain [
]. Meprins are mammalian tissue-specific metalloendopeptidases of the astacin family implicated in developmental, normal and pathological processes by hydrolysing a variety of proteins. Various growth factors, cytokines, and extracellular matrix proteins are substrates for meprins. They are composed of five structural domains: an N-terminal endopeptidase domain, a MAM domain (see
), a MATH domain, an EGF-like domain (see
) and a C-terminal transmembrane region. Meprin A and B form membrane bound homotetramer whereas homooligomers of meprin A are secreted. A proteolitic site adjacent to the MATH domain, only present in meprin A, allows the release of the protein from the membrane [
].TRAF proteins were first isolated by their ability to interact with TNF receptors [
]. They promote cell survival by the activation of downstream protein kinases and, finally, transcription factors of the NF-kB and AP-1 family. The TRAF proteins are composed of 3 structural domains: a RING finger (see ) in the N-terminal part of the protein, one to seven TRAF zinc fingers (see
) in the middle and the MATH domain in the C-terminal part [
]. The MATH domain is necessary and sufficient for self-association and receptor interaction. From the structural analysis two consensus sequence recognised by the TRAF domain have been defined: a major one, [PSAT]x[QE]E and a minor one, PxQxxD [].The structure of the TRAF2 protein reveals a trimeric self-association of the MATH domain [
]. The domain forms a new, light-stranded antiparallel β-sandwich structure. A coiled-coil region adjacent to the MATH domain is also important for the trimerisation. The oligomerisation is essential for establishing appropriate connections to form signalling complexes with TNF receptor-1. The ligand binding surface of TRAF proteins is located in β-strands 6 and 7 [].
This domain is found in proteins of the peptidase C19 family, which contains ubiquitinyl hydrolases like ubiquitin carboxyl-terminal hydrolase 7 (USP7) [
]. This domain is one of two C-terminal domains on the much longer ubiquitin-specific proteases. It is found to interact with the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110.
Reverse transcriptase, RNA-dependent DNA polymerase
Type:
Domain
Description:
A reverse transcriptase gene is usually indicative of a mobile element such as a retrotransposon or retrovirus. Reverse transcriptases occur in a variety of mobile elements, including retrotransposons, retroviruses, group II introns, bacterial msDNAs, hepadnaviruses, and caulimoviruses. This entry includes reverse transcriptases not recognised by
[
].
O-Glycosyl hydrolases (
) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families [
,
]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.Glycoside hydrolase family 17
comprises enzymes with several known activities; endo-1,3-beta-glucosidase (
); lichenase (
); exo-1,3-glucanase (
). Currently these enzymes have only been found in plants and in fungi.
Hydroxymethylglutaryl-CoA reductase, eukaryotic/archaeal type
Type:
Family
Description:
There are two distinct classes of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase enzymes: class I consists of eukaryotic and most archaeal enzymes (
), while class II consists of prokaryotic enzymes (
) [
,
].Class I HMG-CoA reductases catalyse the NADP-dependent synthesis of mevalonate from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). In vertebrates, membrane-bound HMG-CoA reductase is the rate-limiting enzyme in the biosynthesis of cholesterol and other isoprenoids. In plants, mevalonate is the precursor of all isoprenoid compounds [
]. The reduction of HMG-CoA to mevalonate is regulated by feedback inhibition by sterols and non-sterol metabolites derived from mevalonate, including cholesterol. In archaea, HMG-CoA reductase is a cytoplasmic enzyme involved in the biosynthesis of the isoprenoids side chains of lipids []. Class I HMG-CoA reductases consist of an N-terminal membrane domain (lacking in archaeal enzymes), and a C-terminal catalytic region. The catalytic region can be subdivided into three domains: an N-domain (N-terminal), a large L-domain, and a small S-domain (inserted within the L-domain). The L-domain binds the substrate, while the S-domain binds NADP.Class II HMG-CoA reductases catalyse the reverse reaction of class I enzymes, namely the NAD-dependent synthesis of HMG-CoA from mevalonate and CoA [
]. Some bacteria, such as Pseudomonas mevalonii, can use mevalonate as the sole carbon source. Class II enzymes lack a membrane domain. Their catalytic region is structurally related to that of class I enzymes, but it consists of only two domains: a large L-domain and a small S-domain (inserted within the L-domain). As with class I enzymes, the L-domain binds substrate, but the S-domain binds NAD (instead of NADP in class I).This entry represents class I HMG-CoA reductase enzymes.
There are two distinct classes of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase enzymes: class I consists of eukaryotic and most archaeal enzymes (
), while class II consists of prokaryotic enzymes (
) [
,
].Class I HMG-CoA reductases catalyse the NADP-dependent synthesis of mevalonate from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). In vertebrates, membrane-bound HMG-CoA reductase is the rate-limiting enzyme in the biosynthesis of cholesterol and other isoprenoids. In plants, mevalonate is the precursor of all isoprenoid compounds [
]. The reduction of HMG-CoA to mevalonate is regulated by feedback inhibition by sterols and non-sterol metabolites derived from mevalonate, including cholesterol. In archaea, HMG-CoA reductase is a cytoplasmic enzyme involved in the biosynthesis of the isoprenoids side chains of lipids []. Class I HMG-CoA reductases consist of an N-terminal membrane domain (lacking in archaeal enzymes), and a C-terminal catalytic region. The catalytic region can be subdivided into three domains: an N-domain (N-terminal), a large L-domain, and a small S-domain (inserted within the L-domain). The L-domain binds the substrate, while the S-domain binds NADP.Class II HMG-CoA reductases catalyse the reverse reaction of class I enzymes, namely the NAD-dependent synthesis of HMG-CoA from mevalonate and CoA [
]. Some bacteria, such as Pseudomonas mevalonii, can use mevalonate as the sole carbon source. Class II enzymes lack a membrane domain. Their catalytic region is structurally related to that of class I enzymes, but it consists of only two domains: a large L-domain and a small S-domain (inserted within the L-domain). As with class I enzymes, the L-domain binds substrate, but the S-domain binds NAD (instead of NADP in class I).
Hydroxymethylglutaryl-CoA reductase, class I/II, substrate-binding domain superfamily
Type:
Homologous_superfamily
Description:
There are two distinct classes of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase enzymes: class I consists of eukaryotic and most archaeal enzymes (
), while class II consists of prokaryotic enzymes (
) [
,
].Class I HMG-CoA reductases catalyse the NADP-dependent synthesis of mevalonate from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). In vertebrates, membrane-bound HMG-CoA reductase is the rate-limiting enzyme in the biosynthesis of cholesterol and other isoprenoids. In plants, mevalonate is the precursor of all isoprenoid compounds [
]. The reduction of HMG-CoA to mevalonate is regulated by feedback inhibition by sterols and non-sterol metabolites derived from mevalonate, including cholesterol. In archaea, HMG-CoA reductase is a cytoplasmic enzyme involved in the biosynthesis of the isoprenoids side chains of lipids []. Class I HMG-CoA reductases consist of an N-terminal membrane domain (lacking in archaeal enzymes), and a C-terminal catalytic region. The catalytic region can be subdivided into three domains: an N-domain (N-terminal), a large L-domain, and a small S-domain (inserted within the L-domain). The L-domain binds the substrate, while the S-domain binds NADP.Class II HMG-CoA reductases catalyse the reverse reaction of class I enzymes, namely the NAD-dependent synthesis of HMG-CoA from mevalonate and CoA [
]. Some bacteria, such as Pseudomonas mevalonii, can use mevalonate as the sole carbon source. Class II enzymes lack a membrane domain. Their catalytic region is structurally related to that of class I enzymes, but it consists of only two domains: a large L-domain and a small S-domain (inserted within the L-domain). As with class I enzymes, the L-domain binds substrate, but the S-domain binds NAD (instead of NADP in class I).This superfamily represents the substrate-binding L-domain found in class I and II enzymes. The L-domain has the same structural fold in both classes of enzymes, and is unique to HMG-CoA reductases. Its topology resembles a prism, with a central alpha helix surrounded by three alpha/beta subdomains forming three roughly triangular walls [
,
].
Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain superfamily
Type:
Homologous_superfamily
Description:
There are two distinct classes of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase enzymes: class I consists of eukaryotic and most archaeal enzymes (
), while class II consists of prokaryotic enzymes (
) [
,
].Class I HMG-CoA reductases catalyse the NADP-dependent synthesis of mevalonate from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). In vertebrates, membrane-bound HMG-CoA reductase is the rate-limiting enzyme in the biosynthesis of cholesterol and other isoprenoids. In plants, mevalonate is the precursor of all isoprenoid compounds [
]. The reduction of HMG-CoA to mevalonate is regulated by feedback inhibition by sterols and non-sterol metabolites derived from mevalonate, including cholesterol. In archaea, HMG-CoA reductase is a cytoplasmic enzyme involved in the biosynthesis of the isoprenoids side chains of lipids []. Class I HMG-CoA reductases consist of an N-terminal membrane domain (lacking in archaeal enzymes), and a C-terminal catalytic region. The catalytic region can be subdivided into three domains: an N-domain (N-terminal), a large L-domain, and a small S-domain (inserted within the L-domain). The L-domain binds the substrate, while the S-domain binds NADP.Class II HMG-CoA reductases catalyse the reverse reaction of class I enzymes, namely the NAD-dependent synthesis of HMG-CoA from mevalonate and CoA [
]. Some bacteria, such as Pseudomonas mevalonii, can use mevalonate as the sole carbon source. Class II enzymes lack a membrane domain. Their catalytic region is structurally related to that of class I enzymes, but it consists of only two domains: a large L-domain and a small S-domain (inserted within the L-domain). As with class I enzymes, the L-domain binds substrate, but the S-domain binds NAD (instead of NADP in class I).This superfamily represents the NADP or NAD binding S-domain found in class I and II enzymes, respectively. The S-domain has the same structural fold in both classes of enzymes, consisting of an alpha/beta sandwich with antiparallel beta sheets, with a (beta/alpha/beta)x2 topology [
].
Hydroxymethylglutaryl-CoA reductase, class I/II, conserved site
Type:
Conserved_site
Description:
There are two distinct classes of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase enzymes: class I consists of eukaryotic and most archaeal enzymes (
), while class II consists of prokaryotic enzymes (
) [
,
].Class I HMG-CoA reductases catalyse the NADP-dependent synthesis of mevalonate from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). In vertebrates, membrane-bound HMG-CoA reductase is the rate-limiting enzyme in the biosynthesis of cholesterol and other isoprenoids. In plants, mevalonate is the precursor of all isoprenoid compounds [
]. The reduction of HMG-CoA to mevalonate is regulated by feedback inhibition by sterols and non-sterol metabolites derived from mevalonate, including cholesterol. In archaea, HMG-CoA reductase is a cytoplasmic enzyme involved in the biosynthesis of the isoprenoids side chains of lipids []. Class I HMG-CoA reductases consist of an N-terminal membrane domain (lacking in archaeal enzymes), and a C-terminal catalytic region. The catalytic region can be subdivided into three domains: an N-domain (N-terminal), a large L-domain, and a small S-domain (inserted within the L-domain). The L-domain binds the substrate, while the S-domain binds NADP.Class II HMG-CoA reductases catalyse the reverse reaction of class I enzymes, namely the NAD-dependent synthesis of HMG-CoA from mevalonate and CoA [
]. Some bacteria, such as Pseudomonas mevalonii, can use mevalonate as the sole carbon source. Class II enzymes lack a membrane domain. Their catalytic region is structurally related to that of class I enzymes, but it consists of only two domains: a large L-domain and a small S-domain (inserted within the L-domain). As with class I enzymes, the L-domain binds substrate, but the S-domain binds NAD (instead of NADP in class I).This entry represents three conserved sites found in HMG-CoA reductases. The first is located in the centre of the catalytic domain, the second is a glycine-rich region located in the C-terminal section of the same catalytic domain and the third is also located in the C-terminal section and contains an histidine residue that appears to be implicated in the catalytic mechanism as a general base [
].
Hydroxymethylglutaryl-CoA reductase, class I/II, catalytic domain superfamily
Type:
Homologous_superfamily
Description:
There are two distinct classes of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase enzymes: class I consists of eukaryotic and most archaeal enzymes (
), while class II consists of prokaryotic enzymes (
) [
,
].Class I HMG-CoA reductases catalyse the NADP-dependent synthesis of mevalonate from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). In vertebrates, membrane-bound HMG-CoA reductase is the rate-limiting enzyme in the biosynthesis of cholesterol and other isoprenoids. In plants, mevalonate is the precursor of all isoprenoid compounds [
]. The reduction of HMG-CoA to mevalonate is regulated by feedback inhibition by sterols and non-sterol metabolites derived from mevalonate, including cholesterol. In archaea, HMG-CoA reductase is a cytoplasmic enzyme involved in the biosynthesis of the isoprenoids side chains of lipids []. Class I HMG-CoA reductases consist of an N-terminal membrane domain (lacking in archaeal enzymes), and a C-terminal catalytic region. The catalytic region can be subdivided into three domains: an N-domain (N-terminal), a large L-domain, and a small S-domain (inserted within the L-domain). The L-domain binds the substrate, while the S-domain binds NADP.Class II HMG-CoA reductases catalyse the reverse reaction of class I enzymes, namely the NAD-dependent synthesis of HMG-CoA from mevalonate and CoA [
]. Some bacteria, such as Pseudomonas mevalonii, can use mevalonate as the sole carbon source. Class II enzymes lack a membrane domain. Their catalytic region is structurally related to that of class I enzymes, but it consists of only two domains: a large L-domain and a small S-domain (inserted within the L-domain). As with class I enzymes, the L-domain binds substrate, but the S-domain binds NAD (instead of NADP in class I).This superfamily represents the catalytic domain found in both class I and II HMG-CoA reductases. The catalytic domain from both classes share a common overall structural fold, despite low sequence identities of 14-20%.
There are two distinct classes of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase enzymes: class I consists of eukaryotic and most archaeal enzymes (
), while class II consists of prokaryotic enzymes (
) [
,
].Class I HMG-CoA reductases catalyse the NADP-dependent synthesis of mevalonate from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). In vertebrates, membrane-bound HMG-CoA reductase is the rate-limiting enzyme in the biosynthesis of cholesterol and other isoprenoids. In plants, mevalonate is the precursor of all isoprenoid compounds [
]. The reduction of HMG-CoA to mevalonate is regulated by feedback inhibition by sterols and non-sterol metabolites derived from mevalonate, including cholesterol. In archaea, HMG-CoA reductase is a cytoplasmic enzyme involved in the biosynthesis of the isoprenoids side chains of lipids []. Class I HMG-CoA reductases consist of an N-terminal membrane domain (lacking in archaeal enzymes), and a C-terminal catalytic region. The catalytic region can be subdivided into three domains: an N-domain (N-terminal), a large L-domain, and a small S-domain (inserted within the L-domain). The L-domain binds the substrate, while the S-domain binds NADP.Class II HMG-CoA reductases catalyse the reverse reaction of class I enzymes, namely the NAD-dependent synthesis of HMG-CoA from mevalonate and CoA [
]. Some bacteria, such as Pseudomonas mevalonii, can use mevalonate as the sole carbon source. Class II enzymes lack a membrane domain. Their catalytic region is structurally related to that of class I enzymes, but it consists of only two domains: a large L-domain and a small S-domain (inserted within the L-domain). As with class I enzymes, the L-domain binds substrate, but the S-domain binds NAD (instead of NADP in class I).This superfamily represents the N-terminal structural domain of HMGR.
RNA polymerase I specific transcription initiation factor RRN3
Type:
Family
Description:
This family consists of several eukaryotic proteins which are homologous to the Saccharomyces cerevisiae RRN3 protein. RRN3 is one of the RRN genes specifically required for the transcription of rDNA by RNA polymerase I (Pol I) in the S. cerevisiae [] RNA polymerase I complex within the nucleolus.In mammalian cells, the phosphorylation state of Rrn3 regulates rDNA transcription by determining the steady-state
concentration of the Rrn3 [].
The proteins featured in this family are all eukaryotic, and many of them are annotated as being Gryzun. Gryzun is distantly related to, but distinct from, the Trs130 subunit of the TRAPP complex but is absent from S. cerevisiae. RNAi of human Gryzun (
) blocks Golgi exit. Thus the family is likely to be involved with trafficking of proteins through membranes, perhaps as part of the TRAPP complex [
].
This entry represents a domain found in trafficking protein particle complex subunit 11 (Trappc11), which is involved in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage [
]. The C terminus of this region contains TPR repeats.In zebrafish, Trappc11 is also known as protein foie gras. It has been shown to affect development; the mutants develop large, lipid-filled hepatocytes in the liver, resembling those in individuals with fatty liver disease [
].
Serine/threonine-specific protein phosphatase/bis(5-nucleosyl)-tetraphosphatase
Type:
Domain
Description:
Protein phosphorylation plays a central role in the regulation of cell functions [
], causing the activation or inhibition of many enzymes involved in various biochemical pathways [
]. Kinases and phosphatases are the enzymes responsible for this, and may themselves be subject to control through the action of hormones and growth factors [
]. Serine/threonine(S/T) phosphatases (
) catalyse the dephosphorylation of phosphoserine and phosphothreonine residues. In
mammalian tissues four different types of PP have been identified and are known as PP1, PP2A, PP2B and PP2C. Except for PP2C, these enzymes are evolutionary related. The catalytic regions of the proteins are
well conserved and have a slow mutation rate, suggesting that major changes in these regions are highly detrimental [
].Protein phosphatase-1 (PP1) and protein phosphatase-2A (PP2A) have a broad
specificity and there are two closely related isoforms of each, alpha and beta. PP2A is a trimeric enzyme that consists of a core composed of a catalytic subunit associated with a 65kDa regulatory subunit and a
third variable subunit. Protein phosphatase-2B (PP2B or calcineurin), a calcium-dependent enzyme whose activity is stimulated by calmodulin, is composed of two subunits the catalytic A-subunit and the
calcium-binding B-subunit. The specificity of PP2B is restricted. Other serine/threonine specific protein phosphatases that have been characterised include mammalian phosphatase-X (PP-X), and Drosophila
phosphatase-V (PP-V), which are closely related but yet distinct from PP2A; yeast phosphatase PPH3, which is similar to PP2A, but with different enzymatic properties; and Drosophila phosphatase-Y (PP-Y), and yeast
phosphatases Z1 and Z2 which are closely related but yet distinct from PP1.
This family is composed of plant proteins that are similar to FRIGIDA protein expressed by Arabidopsis thaliana (Mouse-ear cress) (
). This protein is probably nuclear and is required for the regulation of flowering time in the late-flowering phenotype. It is known to increase RNA levels of flowering locus C. Allelic variation at the FRIGIDA locus is a major determinant of natural variation in flowering time [
].
This family includes diacylglycerol acyltransferases which catalyse the terminal and only committed step in triacylglycerol (TAG) synthesis using diacylglycerol (DAG) and fatty acyl-CoA as substrates. It is required for synthesis and storage of intracellular triglycerides [
,
,
,
,
]. In yeast, it is involved in lipid particle synthesis from the endoplasmic reticulum, promoting localized TAG production at discrete ER subdomains, and in ergosterol biosynthesis [,
].This family also includes Acyl-CoA wax alcohol acyltransferase 1 and 2 (AWAT1/2), which catalyse the formation of ester bonds between fatty alcohols and fatty acyl-CoAs to form wax monoesters [
,
]. AWAT2 (also known as MFAT) also possesses acyl-CoA retinol acyltransferase (ARAT) activity that catalyses 11-cis-specific retinyl ester synthesis and shows higher catalytic efficiency toward 11-cis-retinol versus 9-cis-retinol, 13-cis-retinol, and all-trans-retinol substrates [].Phytyl ester synthase 1/2, chloroplastic, an acyltransferase involved in fatty acid phytyl ester synthesis in chloroplasts, also belongs to this family. This process is required for the maintenance of the photosynthetic membrane integrity during abiotic stress and senescence [
].
Mannose-6-phosphate receptors (MPRs) are transmembrane proteins involved in the transport of lysosomal enzymes from the Golgi complex and the cell surface to lysosomes [
]. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to MPRs in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelysosomal compartment, where the low pH mediates dissociation of the complex. There are two distinct MPRs that function in the recognition of mannose-6-phosphate-containing proteins: the cation-dependent MPR (CD-MPR) and the cation-independent MPR (CI-MPR). The CI-MPR is also known as the insulin-like growth factor II receptor, a multi-functional protein implicated in tumour suppression. The crystal structure of the N-terminal, extracytoplasmic, receptor-binding domain of bovine CD-MPR (excluding the signal sequence) [
] reveals structural similarity to the fifteen homologous, repeating domains comprising the extracellular region of human CI-MPR []. The structure consists of a partly opened, nine-stranded, β-barrel [,
].
Phosphoribosylaminoimidazole-succinocarboxamide synthase (
) (SAICAR synthetase) catalyses the seventh step in the
de novopurine biosynthetic pathway; the ATP-dependent conversion of 5'-phosphoribosyl-5-aminoimidazole-4-carboxylic acid and aspartic acid to SAICAR [
,
].In bacteria (purC), fungi (ADE1) and plants (Pur7), SAICAR synthetase is a monofunctional protein; in animals it is the N-terminal domain of a bifunctional enzyme that also catalyse phosphoribosylaminoimidazole carboxylase (AIRC) activity (see
).
This domain can be found in budding yeast Fsh1/2/3, fission yeast Dfr1 and the human OVCA2 protein. Fsh1/2/3 are putative serine hydrolases [
]. Dfr1 is a dihydrofolate reductase (DHFR) []. OVCA2 is a putative serine-hydrolase that has been linked to cancers []. Proteins containing this domain also includes Aspergillus terreus esterase LovG, which catalyzes the release of covalently bound dihydromonacolin L from LovB during lovastatin biosynthesis [].
Alg10 (asparagine-linked glycosylation) (
) is a dolichyl-phosphoglucose-dependent glucosyltransferase which adds the terminal alpha-1,2 glucose to the lipid-linked Glc2Man9GlcNAc2 oligosaccharide. The terminal alpha-1,2-linked glucose residue is important for substrate recognition by the oligosaccharyltransferase [
]. In Saccharomyces cerevisiae, Alg10 has a role in regulation of the expression of a myo-inositol transporter, Itr1 (hence the name Die2, standing for derepression of Itr1 expression) []. It also regulates the expression of Ino1, which is an inositol-3-phosphate synthase []. Alg10 is homologous to human and rat potassium channel regulatory protein KCR1, which diminishes the cardiac repolarising current I(Kr) drug response [,
].
The myosin superfamily consists of at least 15 distinct classes of presumed
actin-based molecular motors. All members of the superfamily share a similarmotor domain and a tail portion which is diagnostic of the class [
].Class V myosins are actin-based molecular motors that function in relatively
long-range movements of many intracellular cargoes including organelles,membrane vesicles, and mRNA [
]. These motors are ubiquitously found in alleukaryotes. Class V myosins are characterised by the presence of a conservedglobular domain at the C terminus of the tail portion: the dilute domain [
]. Myosin V moves via attachment of its amino terminal head (motor) domain to actin cables; its carboxyl terminal dilute domain anchors it to cargoes via attachments to organelle-specific receptors [,
].The dilute domain is also found in the afadin family. Afadins are nectin and
actin filament-binding proteins that connect nectin to the actin cytoskeleton[
]. The dilute domain of afadin appears to be responsible for actin stress fibre formation [].
In eukaryotes this family is predicted to play a role in protein secretion and Golgi organisation [
]. In plants this family includes , which is involved in water permeability in the cuticles of fruit [
]. has been found to be expressed during early embryogenesis in mice [
]. This protein contains a conserved NRDE motif. This gene has been characterised in Drosophila melanogaster and named as transport and Golgi organisation 2, hence the name Tango2.
Methionine synthases catalyse the the final step of methionine biosynthesis. Two apparently unrelated families of proteins catalyse this step: cobalamin-dependent methionine synthase, which catalyses the transfer of a methyl group from N5-methyltetrahydrofolate to L-homocysteine and requires cobalamin as a cofactor (MetH; 5-methyltetrahydrofolate:L-homocysteine S-methyltransferase;
) and cobalamin-independent methionine synthase, which catalyses the transfer of a methyl group from methyltetrahydrofolate to L-homocysteine without using an intermediate methyl carrier (MetE; 5-methyltetrahydropteroyltri-L-glutamate:L-homocysteine S-methyltransferase;
). These enzymes display no detectable sequence homology between them, but both require zinc for activation and binding to L-homocysteine. Organisms that cannot obtain cobalamin (vitamin B12) encode only the cobalamin-independent enzyme. Escherichia coli and many other bacteria express both enzymes [
]. Mammals utilise only cobalamin-dependent methionine synthase, while plants and yeasts utilise only the cobalamin-independent enzyme.This group represents cobalamin-independent methionine synthase [
]. A group of archaeal proteins having substantial homology to the C-terminal region of this family is not included (see ).
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [
], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [
].Cyclins contain two domains of similar all-α fold, of which this entry is associated with the N-terminal domain.
This cyclin-like domain is found in cyclins, but it is also found as the core domain in transcription factor IIB (TFIIB) [
] and in the retinoblastoma tumour suppressor []. It consists of a duplication of a fold consisting of 5 helices, one of them surrounded by the others.
DNA primase synthesises the RNA primers for the Okazaki fragments in lagging strand DNA synthesis. DNA primase is a heterodimer of large and small subunits [
].This family represents the small subunit, and also includes baculovirus late expression factor 1 or LEF-1 proteins. Baculovirus LEF-1 is a DNA primase enzyme [
].
DNA primase [
] synthesizes the RNA primers for the Okazaki fragments in lagging strand DNA synthesis. DNA primase is a heterodimer of large (p60) and small (p50) subunits in eukaryotes. This entry represents the eukaryotic and archaeal DNA primase small subunit proteins, and does not include bacterial or viral proteins. Bacterial DNA primase adopts a different fold to archaeal and eukaryotic primases [
].
Ionotropic glutamate receptors (iGluRs) are a highly conserved family of ligand-gated ion channels present in animals, plants, and bacteria, which are best characterised for their roles in synaptic communication in vertebrate nervous systems [
]. A variant subfamily of iGluRs, the Ionotropic Receptors (IRs), consist of non-glutamate-binding chemosensory receptors first identified in Drosophila melanogaster. They function in detecting odors and tastants [].There are three classes of ionotropic glutamate receptors (iGluRs), namely NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid) and kainate receptors. They are believed to play critical roles in synaptic plasticity. At many synapses in the brain, transient activation of NMDA receptors leads to a persistent modification in the strength of synaptic transmission mediated by AMPA receptors and kainate receptors can act as the induction trigger for long-term changes in synaptic transmission [
].
Periplasmic binding protein-like I domains are similar in architecture to the those included in group II, but partly differ in topology. They consist of two similar intertwined globular subdomains, both exhibiting very similar supersecondary structures which consist of a central β-sheet flanked on either side by two or three helices [
].
This describes a ligand binding domain and includes extracellular ligand binding domains of a wide range of receptors, as well as the bacterial amino acid binding proteins of known structure [
].
Synaptobrevin is an intrinsic membrane protein of small synaptic vesicles [
], specialised secretory organelles of neurons that actively accumulate neurotransmitters and participate in their calcium-dependent release by exocytosis. Vesicle function is mediated by proteins in their membranes, although the precise nature of the protein-protein interactions underlying this are still uncertain []. Synaptobrevin may play a role in the molecular events underlying neurotransmitter release and vesicle recycling and may be involved in the regulation of membrane flow in the nerve terminal, a process mediated by interaction with low molecular weight GTP-binding proteins []. Synaptic vesicle-associated membrane proteins (VAMPs) from Torpedo californica (Pacific electric ray) and SNC1 from yeast are related to synaptobrevin.
Solute-binding protein family 3/N-terminal domain of MltF
Type:
Domain
Description:
Bacterial high affinity transport systems are involved in active transport of solutes across the cytoplasmic membrane. Most of the bacterial ABC (ATP-binding cassette) importers are composed of one or two transmembrane permease proteins, one or two nucleotide-binding proteins and a highly specific periplasmic solute-binding protein. In Gram-negative bacteria the solute-binding proteins are dissolved in the periplasm, while in archaea and Gram-positive bacteria, their solute-binding proteins are membrane-anchored lipoproteins [
,
]. On the basis of sequence similarities, the vast majority of these solute-binding proteins can be grouped [
] into eight families or clusters, which generally correlate with the nature of the solute bound.This entry represents a domain found in the solute-binding protein family 3 members from Gram-positive bacteria, Gram-negative bacteria and archaea. This domain can also be found in the N-terminal of the membrane-bound lytic murein transglycosylase F (MltF) protein. MltF is a murein-degrading enzyme that degrades murein glycan strands and insoluble, high-molecular weight murein sacculi, with the concomitant formation of a 1,6-anhydromuramoyl product [
].Familiy 3 members include:Histidine-binding protein (gene hisJ) of Escherichia coli and related bacteria. An homologous lipoprotein exists in Neisseria gonorrhoeae. Lysine/arginine/ornithine-binding proteins (LAO) (gene argT) of Escherichia coli and related bacteria are involved in the same transport system than hisJ. Both solute-binding proteins interact with a common membrane-bound receptor hisP of the binding protein dependent transport system HisQMP. Glutamine-binding proteins (gene glnH) of Escherichia coli and Bacillus stearothermophilus.Glutamate-binding protein (gene gluB) of Corynebacterium glutamicum. Arginine-binding proteins artI and artJ of Escherichia coli. Nopaline-binding protein (gene nocT) from Agrobacterium tumefaciens. Octopine-binding protein (gene occT) from Agrobacterium tumefaciens. Major cell-binding factor (CBF1) (gene: peb1A) from Campylobacter jejuni. Bacteroides nodosus protein aabA. Cyclohexadienyl/arogenate dehydratase of Pseudomonas aeruginosa, a periplasmic enzyme which forms an alternative pathway for phenylalanine biosynthesis. Escherichia coli L-cystine-binding protein TcyJ, previously known as protein fliY.Vibrio harveyi protein patH. Bacillus subtilis Probable ABC transporter extracellular-binding protein yckB. Bacillus subtilis L-cystine-binding protein TcyA, also known as yckK.
Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [
,
,
,
,
]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few []. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target. This entry represents ZPR1-type zinc finger domains. An orthologous protein found once in each of the completed archaeal genomes corresponds to a zinc finger-containing domain repeated as the N-terminal and C-terminal halves of the mouse protein ZPR1. ZPR1 is an experimentally proven zinc-binding protein that binds the tyrosine kinase domain of the epidermal growth factor receptor (EGFR); binding is inhibited by EGF stimulation and tyrosine phosphorylation, and activation by EGF is followed by some redistribution of ZPR1 to the nucleus. By analogy, other proteins with the ZPR1 zinc finger domain may be regulatory proteins that sense protein phosphorylation state and/or participate in signal transduction (see also
).
Deficiencies in ZPR1 may contribute to neurodegenerative disorders. ZPR1 appears to be down-regulated in patients with spinal muscular atrophy (SMA), a disease characterised by degeneration of the alpha-motor neurons in the spinal cord that can arise from mutations affecting the expression of Survival Motor Neurons (SMN) [
]. ZPR1 interacts with complexes formed by SMN [], and may act as a modifier that effects the severity of SMA.
This entry represents the C terminus of protein ENHANCED DISEASE RESISTANCE 2 (EDR2) from plants. EDR2 is a negative regulator of the salicylic acid- (SA-) mediated resistance to pathogens, including the biotrophic powdery mildew pathogens Golovinomyces cichoracearum and Blumeria graminis, and the downy mildew pathogen Hyaloperonospora parasitica, probably by limiting the initiation of cell death and the establishment of the hypersensitive response (HR) [
,
].
Members of the zinc (Zn2+)-Iron (Fe2+) permease (ZIP) family consist of proteins with eight putative transmembrane spanners. They are derived from animals, plants and yeast. They comprise a diverse family, with several paralogues in any one organism (e.g., at least five in Caenorhabditis elegans, at least five in Arabidopsis thaliana and two in Saccharomyces cerevisiae (Baker's yeast). The two S. cerevisiae proteins, Zrt1 and Zrt2, both probably transport Zn2+ with high specificity, but Zrt1 transports Zn2+ with ten-fold higher affinity than Zrt2. Some members of the ZIP family have been shown to transport Zn2+ while others transport Fe2+, and at least one transports a range of metal ions. The energy source for transport has not been characterised, but these systems probably function as secondary carriers.
The purine-rich element binding (Pur) protein family protein consists PURalpha/beta/gamma in humans. Pur-alpha is a highly conserved, sequence-specific DNA- and RNA-binding protein involved in diverse cellular and viral functions including transcription, replication, and cell growth. Pur-alpha has a modular structure with alternating three basic aromatic class I and two acidic leucine-rich class II repeats in the central region of the protein [
]. In addition to its involved in basic cellular function, Pur-alpha, has been implicated in the development of blood cells and cells of the central nervous system; it has also been implicated in the inhibition of oncogenic transformation and along with Pur-beta in myelodysplastic syndrome progressing to acute myelogenous leukemia. Pur-alpha can influence viral interaction through functional associations, for example with the Tat protein and TAR RNA of HIV-1, and with large T-antigen and DNA regulatory regions of JC virus. JC virus causes opportunistic infections in the brains of certain HIV-1-infected individuals [
].
The 1,4-beta-glucanase CenC from Cellulomonas fimi contains two
cellulose-binding domains, CBD(N1) and CBD(N2), arranged in tandem at itsN terminus. These homologous CBDs are distinct in their selectivity for binding amorphous and not crystalline cellulose [
].Multidimensional heteronuclear nuclear magnetic resonance (NMR) spectroscopy
was used to determine the tertiary structure of the 152 amino acid N-terminalcellulose-binding domain from C. fimi 1,4-beta-glucanase CenC
(CBDN1) []. The tertiarystructure of CBDN1 is strikingly similar to that of the bacterial
1,3-1,4-beta-glucanases, as well as other sugar-binding proteins with jelly-roll folds.
The transcription factor DP (dimerization partner) forms a heterodimer with E2F and regulates genes involved in cell cycle progression. The transcriptional activity of E2F is inhibited by the retinoblastoma protein which binds to the E2F-DP heterodimer [
] and negatively regulates the G1-S transition. Though originally the role of DP in transcriptional activation was thought to be facilitating the binding of E2F to target DNA, it was latter shown that the C-terminal acidic region of DP1 binds strongly to the PH domain of p62 of TFIIH and acts as a transactivation domain [
].
Proteins in this family are involved in mRNA splicing [
]. This family includes pre-mRNA-splicing factor SPF27, SNT309 and Cwf7. In humans, SPF27 is a component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. It may have a scaffolding role in the spliceosome assembly as it contacts all other components of the core complex [].
GH3 protein was first isolated from Glycine max (soybean) as an early auxin-responsive gene [
,
]. Later, several plant GH3 family proteins have been identified and classified into three groups: group I proteins synthesise JA-amino acid conjugates [], group II proteins produce indole-3-acetic acid (IAA) conjugates [], group III protein are involved in the conjugation of amino acids to 4-substituted benzoate []. This entry also includes proteins from bacteria, fungi and animals.
This entry represents the N-terminal domain of the glucosidase 2 subunit beta, which is also known as protein kinase C substrate 80K-H (PRKCSH). The enzyme catalyses the sequential removal of two alpha-1,3-linked glucose residues in the second step of N-linked oligosaccharide processing [
]. The beta subunit is required for the solubility and stability of the heterodimeric enzyme, and is involved in retaining the enzyme within the endoplasmic reticulum [].
The NusB protein is involved in the regulation of rRNA biosynthesis
by transcriptional antitermination. The antitermination proteins of Escherichia coli are recruited in the replication cycle ofBacteriophage lambda, where they play an important role in switching from the
lysogenic to the lytic cycle. The solution structure indicates that the protein folds into an alpha/α-helicaltopology consisting of six helices; the arginine-rich N terminus appears to be
disordered [].
This domain is found in a number of functionally different proteins:NusB a prokaryotic transcription factor involved in antiterminationTIM44, the mitochondrial inner membrane translocase subunit RsmB, the 16S rRNA m5C967 methyltransferaseNusB is a prokaryotic transcription factor involved in antitermination processes, during which it interacts with the boxA portion of the mRNA nut site. Previous studies have shown that NusB exhibits an all-helical fold, and that the protein from Escherichia coli forms monomers, while Mycobacterium tuberculosis NusB is a dimer. The functional significance of NusB dimerization is unknown.
An N-terminal arginine-rich sequence is the probable RNA binding site, exhibiting aromatic residues as potential stacking partners for the RNA bases. The RNA binding region is hidden in the subunit interface of dimeric NusB proteins, such as NusB from M. tuberculosis, suggesting that such dimers have to undergo a considerable conformational change or dissociate for engagement with RNA. In certain organisms, dimerization may be employed to package NusB in an inactive form until recruitment into antitermination complexes [,
].The antitermination proteins of E. coli are recruited in the replication cycle of
Bacteriophage lambda, where they play an important role in switching from thelysogenic to the lytic cycle.
The X8 domain [
] contains 6 conserved cysteine residues that presumably form three disulphide bridges. The domain is found in an Olive pollen allergen [] as well as at the C terminus of family 17 glycosyl hydrolases []. This domain may be involved in carbohydrate binding.
Glyceraldehyde 3-phosphate dehydrogenase, active site
Type:
Active_site
Description:
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays an important role in glycolysis and gluconeogenesis [
] by reversibly catalysing the oxidation and phosphorylation of D-glyceraldehyde-3-phosphate to 1,3-diphospho-glycerate. The enzyme exists as a tetramer of identical subunits, each containing 2 conserved functional domains: an NAD-binding domain, and a highly conserved catalytic domain []. The enzyme has been found to bind to actin and tropomyosin, and may thus have a role in cytoskeleton assembly. Alternatively, the cytoskeleton may provide a framework for precise positioning of the glycolytic enzymes, thus permitting efficient passage of metabolites from enzyme to enzyme [].GAPDH displays diverse non-glycolytic functions as well, its role depending upon its subcellular location. For instance, the translocation of GAPDH to the nucleus acts as a signalling mechanism for programmed cell death, or apoptosis [
]. The accumulation of GAPDH within the nucleus is involved in the induction of apoptosis, where GAPDH functions in the activation of transcription. The presence of GAPDH is associated with the synthesis of pro-apoptotic proteins like BAX, c-JUN and GAPDH itself.GAPDH has been implicated in certain neurological diseases: GAPDH is able to bind to the gene products from neurodegenerative disorders such as Huntington's disease, Alzheimer's disease, Parkinson's disease and Machado-Joseph disease through stretches encoded by their CAG repeats. Abnormal neuronal apoptosis is associated with these diseases. Propargylamines such as deprenyl increase neuronal survival by interfering with apoptosis signalling pathways via their binding to GAPDH, which decreases the synthesis of pro-apoptotic proteins [
].A cysteine in the middle of the molecule is involved in forming a covalent phosphoglycerol thioester intermediate. The sequence around this cysteine is totally conserved in eubacterial and eukaryotic GAPDHs and is also present, albeit in a variant form, in the otherwise highly divergent archaebacterial GAPDH []. The pattern in this entry represents the active site.
This domain is found in both Yippee-type proteins and Mis18 kinetochore proteins. Yippee are putative zinc-binding/DNA-binding proteins [
]. Mis18 are proteins involved in the priming of centromeres for recruiting CENP-A [,
]. Mis18-alpha and beta form part of a small complex with Mis18-binding protein. Mis18-alpha is found to interact with DNA de-methylases through a Leu-rich region located at its carboxyl terminus []. This domain includes the CULT domain from proteins such as Cereblon [].
This entry represents the C-terminal part of ubiquitin-like proteases
that displays full proteolytic activity [].Deubiquitinating enzymes (DUB) form a large family of cysteine protease that
can deconjugate ubiquitin or ubiquitin-like proteins from ubiquitin-conjugatedproteins. They can be classified in 3 families according to sequence homology
[,
]: ubiquitin carboxyl-terminal hydrolases (UCH),ubiquitin-specific processing proteases (UBP), and
ubiquitin-like proteases (ULP) () specific for deconjugating
ubiquitin-like proteins. In contrast to the UBP pathway, which is veryredundant (16 UBP enzymes in yeast), there is few ubiquitin-like protease
(only one in yeast, ULP1).ULP1 catalyses two critical functions in the SUMO/Smt3 pathway via its
cysteine protease activity. ULP1 processes the Smt3 C-terminal sequence(-GGATY) to its mature form (-GG), and it deconjugates Smt3 from the lysine
ε-amino group of the target protein [].Crystal structure of yeast ULP1 bound to Smt3 [
] revealed that the catalyticand interaction interface is situated in a shallow and narrow cleft where
conserved residues recognise the Gly-Gly motif at the C-terminal extremity ofSmt3 protein. Ulp1 adopts a novel architecture despite some structural
similarity with other cysteine protease. The secondary structure is composedof seven alpha helices and seven beta strands. The catalytic domain includes
the central alpha helix, β-strands 4 to 6, and the catalytic triad(Cys-His-Asp).
A cysteine peptidase is a proteolytic enzyme that hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile. Hydrolysis involves usually a catalytic triad consisting of the thiol group of the cysteine, the imidazolium ring of a histidine, and a third residue, usually asparagine or aspartic acid, to orientate and activate the imidazolium ring. In only one family of cysteine peptidases, is the role of the general base assigned to a residue other than a histidine: in peptidases from family C89 (acid ceramidase) an arginine is the general base. Cysteine peptidases can be grouped into fourteen different clans, with members of each clan possessing a tertiary fold unique to the clan. Four clans of cysteine peptidases share structural similarities with serine and threonine peptidases and asparagine lyases. From sequence similarities, cysteine peptidases can be clustered into over 80 different families [
]. Clans CF, CM, CN, CO, CP and PD contain only one family.Cysteine peptidases are often active at acidic pH and are therefore confined to acidic environments, such as the animal lysosome or plant vacuole. Cysteine peptidases can be endopeptidases, aminopeptidases, carboxypeptidases, dipeptidyl-peptidases or omega-peptidases. They are inhibited by thiol chelators such as iodoacetate, iodoacetic acid,
N-ethylmaleimide or
p-chloromercuribenzoate.
Clan CA includes proteins with a papain-like fold. There is a catalytic triad which occurs in the order: Cys/His/Asn (or Asp). A fourth residue, usually Gln, is important for stabilising the acyl intermediate that forms during catalysis, and this precedes the active site Cys. The fold consists of two subdomains with the active site between them. One subdomain consists of a bundle of helices, with the catalytic Cys at the end of one of them, and the other subdomain is a β-barrel with the active site His and Asn (or Asp). There are over thirty families in the clan, and tertiary structures have been solved for members of most of these. Peptidases in clan CA are usually sensitive to the small molecule inhibitor E64, which is ineffective against peptidases from other clans of cysteine peptidases [
].Clan CD includes proteins with a caspase-like fold. Proteins in the clan have an α/β/α sandwich structure. There is a catalytic dyad which occurs in the order His/Cys. The active site His occurs in a His-Gly motif and the active site Cys occurs in an Ala-Cys motif; both motifs are preceded by a block of hydrophobic residues [
]. Specificity is predominantly directed towards residues that occupy the S1 binding pocket, so that caspases cleave aspartyl bonds, legumains cleave asparaginyl bonds, and gingipains cleave lysyl or arginyl bonds.Clan CE includes proteins with an adenain-like fold. The fold consists of two subdomains with the active site between them. One domain is a bundle of helices, and the other a β-barrel. The subdomains are in the opposite order to those found in peptidases from clan CA, and this is reflected in the order of active site residues: His/Asn/Gln/Cys. This has prompted speculation that proteins in clans CA and CE are related, and that members of one clan are derived from a circular permutation of the structure of the other.Clan CL includes proteins with a sortase B-like fold. Peptidases in the clan hydrolyse and transfer bacterial cell wall peptides. The fold shows a closed β-barrel decorated with helices with the active site at one end of the barrel [
]. The active site consists of a His/Cys catalytic dyad.Cysteine peptidases with a chymotrypsin-like fold are included in clan PA, which also includes serine peptidases. Cysteine peptidases that are N-terminal nucleophile hydrolases are included in clan PB. Cysteine peptidases with a tertiary structure similar to that of the serine-type aspartyl dipeptidase are included in clan PC. Cysteine peptidases with an intein-like fold are included in clan PD, which also includes asparagine lyases.
This family contains a diverse set of enzymes including: enoyl-CoA hydratase, 1,4-dihydroxy-2-naphthoyl-CoA synthase (napthoate synthase), carnitinyl-CoA dehydratase (carnitine racemase), 3-hydroxybutyryl-CoA dehydratase and enoyl-CoA delta isomerase (dodecanoyl-CoA delta-isomerase).
Transthyretin (prealbumin) is a thyroid hormone-binding protein that seems to transport thyroxine (T4) from the bloodstream to the brain. It is a protein of about 130 amino acids that assembles as a homotetramer and forms an internal channel that binds thyroxine. In humans, transthyretin is mainly synthesized in the brain choroid plexus; variants of the protein are associated with distinct forms of amyloidosis. The sequence of transthyretin is highly conserved in vertebrates. A number of uncharacterised proteins also belong to this family: Escherichia coli hypothetical protein YedX. Bacillus subtilis hypothetical protein YunM. Caenorhabditis elegans hypothetical protein R09H10.3. Caenorhabditis elegans hypothetical protein ZK697.8. The signature pattern in this entry is located in the N-terminal extremity and starts with a lysine known to be involved in binding thyroxine binding.
This family includes transthyretin that is a thyroid hormone-binding protein that transports thyroxine from the bloodstream to the brain. However, most of the sequences listed in this family do not bind thyroid hormones. They are actually enzymes of the purine catabolism that catalyse the conversion of 5-hydroxyisourate (HIU) to OHCU [
,
]. HIU hydrolysis is the original function of the family and is conserved from bacteria to mammals; transthyretins arose by gene duplications in the vertebrate lineage [,
]. HIUases are distinguished in the alignment from the conserved C-terminal YRGS sequence.Transthyretin (formerly prealbumin) is one of 3 thyroid hormone-binding proteins found in the blood of vertebrates [
]. It is produced in the liver and circulates in the bloodstream, where it binds retinol and thyroxine (T4) [,
,
]. It differs from the other 2 hormone-binding proteins (T4-binding globulin and albumin) in 3 distinct ways: (1) the gene is expressed at a high rate in the brain choroid plexus; (2) it is enriched in cerebrospinal fluid; and (3) no genetically caused absence has been observed, suggesting an essential role in brain function, distinct from that played in the bloodstream []. The protein consists of around 130 amino acids, which assemble as a homotetramer that contains an internal channel in which T4 is bound. Within this complex, T4 appears to be transported across the blood-brain barrier, where, in the choroid plexus, the hormone stimulates further synthesis of transthyretin. The protein then diffuses back into the bloodstream, where it binds T4 for transport back to the brain [].
Transthyretin (prealbumin) is a thyroid hormone-binding protein that seems to transport thyroxine (T4) from the bloodstream to the brain. It is a protein of about 130 amino acids that assembles as a homotetramer and forms an internal channel that binds thyroxine. In humans, transthyretin is mainly synthesized in the brain choroid plexus; variants of the protein are associated with distinct forms of amyloidosis. The sequence of transthyretin is highly conserved in vertebrates. A number of uncharacterised proteins also belong to this family: Escherichia coli hypothetical protein YedX. Bacillus subtilis hypothetical protein YunM. Caenorhabditis elegans hypothetical protein R09H10.3. Caenorhabditis elegans hypothetical protein ZK697.8. The signature pattern in this entry is located at the C terminus.
This family includes transthyretin that is a thyroid hormone-binding protein that transports thyroxine from the bloodstream to the brain. However, most of the sequences listed in this family do not bind thyroid hormones. They are actually enzymes of the purine catabolism that catalyse the conversion of 5-hydroxyisourate (HIU) to OHCU [
,
]. HIU hydrolysis is the original function of the family and is conserved from bacteria to mammals; transthyretins arose by gene duplications in the vertebrate lineage [,
]. HIUases are distinguished in the alignment from the conserved C-terminal YRGS sequence.Transthyretin (formerly prealbumin) is one of 3 thyroid hormone-binding proteins found in the blood of vertebrates [
]. It is produced in the liver and circulates in the bloodstream, where it binds retinol and thyroxine (T4) [,
,
]. It differs from the other 2 hormone-binding proteins (T4-binding globulin and albumin) in 3 distinct ways: (1) the gene is expressed at a high rate in the brain choroid plexus; (2) it is enriched in cerebrospinal fluid; and (3) no genetically caused absence has been observed, suggesting an essential role in brain function, distinct from that played in the bloodstream []. The protein consists of around 130 amino acids, which assemble as a homotetramer that contains an internal channel in which T4 is bound. Within this complex, T4 appears to be transported across the blood-brain barrier, where, in the choroid plexus, the hormone stimulates further synthesis of transthyretin. The protein then diffuses back into the bloodstream, where it binds T4 for transport back to the brain [].
The proteins in this entry are OHCU decarboxylase, an enzyme of the purine catabolism that catalyses the conversion of OHCU into S(+)-allantoin [
]; it is the third step of the conversion of uric acid (a purine derivative) to allantoin. Step one is catalysed by urate oxidase () and step two is catalysed by hydroxyisourate hydrolase (
).
Members of this family, hydroxyisourate hydrolase, represent a distinct clade of transthyretin-related proteins. Bacterial members typically are encoded next to ureidoglycolate hydrolase and often near either xanthine dehydrogenase or xanthine/uracil permease genes and have been demonstrated to have hydroxyisourate hydrolase activity [
]. In eukaryotes, a clade separate from the transthyretins (a family of thyroid-hormone binding proteins) has also been shown to have HIU hydrolase activity in urate catabolizing organisms []. Transthyretin, then, would appear to be the recently diverged paralog of the more ancient HIUH family.
This group of cysteine peptidases belong to the MEROPS peptidase family C12 (ubiquitin C-terminal hydrolase family, clan CA). Families within the CA clan are loosely termed papain-like as protein fold of the peptidase unit resembles that of papain, the type example for clan CA. The type example is the human ubiquitin C-terminal hydrolase UCH-L1.Ubiquitin is highly conserved, commonly found conjugated to proteins in eukaryotic cells, where it may act as a marker for rapid degradation, or it may have a chaperone function in protein assembly [
]. The ubiquitin is released by cleavage from the bound protein by a protease []. A number of deubiquitinising proteases are known: all are activated by thiol compounds [,
], and inhibited by thiol-blocking agents and ubiquitin aldehyde [,
], and as such have the properties of cysteine proteases [].The deubiquitinsing proteases can be split into 2 size ranges: 20-30kDa (this entry) and 100-200kDa (
) [
]. The 20-30kDa group includes the yeast yuh1, which is known to be active only against small ubiquitin conjugates, being inactive against conjugated beta-galactosidase []. A mammalian homologue, UCH (ubiquitin conjugate hydrolase), is one of the most abundant proteins in the brain []. Only one conserved cysteine can be identified, along with two conserved histidines. The spacing between the cysteine and the second histidine is thought to be more representative ofthe cysteine/histidine spacing of a cysteine protease catalytic dyad [
].A cysteine peptidase is a proteolytic enzyme that hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile. Hydrolysis involves usually a catalytic triad consisting of the thiol group of the cysteine, the imidazolium ring of a histidine, and a third residue, usually asparagine or aspartic acid, to orientate and activate the imidazolium ring. In only one family of cysteine peptidases, is the role of the general base assigned to a residue other than a histidine: in peptidases from family C89 (acid ceramidase) an arginine is the general base. Cysteine peptidases can be grouped into fourteen different clans, with members of each clan possessing a tertiary fold unique to the clan. Four clans of cysteine peptidases share structural similarities with serine and threonine peptidases and asparagine lyases. From sequence similarities, cysteine peptidases can be clustered into over 80 different families [
]. Clans CF, CM, CN, CO, CP and PD contain only one family.Cysteine peptidases are often active at acidic pH and are therefore confined to acidic environments, such as the animal lysosome or plant vacuole. Cysteine peptidases can be endopeptidases, aminopeptidases, carboxypeptidases, dipeptidyl-peptidases or omega-peptidases. They are inhibited by thiol chelators such as iodoacetate, iodoacetic acid,
N-ethylmaleimide or
p-chloromercuribenzoate.
Clan CA includes proteins with a papain-like fold. There is a catalytic triad which occurs in the order: Cys/His/Asn (or Asp). A fourth residue, usually Gln, is important for stabilising the acyl intermediate that forms during catalysis, and this precedes the active site Cys. The fold consists of two subdomains with the active site between them. One subdomain consists of a bundle of helices, with the catalytic Cys at the end of one of them, and the other subdomain is a β-barrel with the active site His and Asn (or Asp). There are over thirty families in the clan, and tertiary structures have been solved for members of most of these. Peptidases in clan CA are usually sensitive to the small molecule inhibitor E64, which is ineffective against peptidases from other clans of cysteine peptidases [
].Clan CD includes proteins with a caspase-like fold. Proteins in the clan have an α/β/α sandwich structure. There is a catalytic dyad which occurs in the order His/Cys. The active site His occurs in a His-Gly motif and the active site Cys occurs in an Ala-Cys motif; both motifs are preceded by a block of hydrophobic residues [
]. Specificity is predominantly directed towards residues that occupy the S1 binding pocket, so that caspases cleave aspartyl bonds, legumains cleave asparaginyl bonds, and gingipains cleave lysyl or arginyl bonds.Clan CE includes proteins with an adenain-like fold. The fold consists of two subdomains with the active site between them. One domain is a bundle of helices, and the other a β-barrel. The subdomains are in the opposite order to those found in peptidases from clan CA, and this is reflected in the order of active site residues: His/Asn/Gln/Cys. This has prompted speculation that proteins in clans CA and CE are related, and that members of one clan are derived from a circular permutation of the structure of the other.Clan CL includes proteins with a sortase B-like fold. Peptidases in the clan hydrolyse and transfer bacterial cell wall peptides. The fold shows a closed β-barrel decorated with helices with the active site at one end of the barrel [
]. The active site consists of a His/Cys catalytic dyad.Cysteine peptidases with a chymotrypsin-like fold are included in clan PA, which also includes serine peptidases. Cysteine peptidases that are N-terminal nucleophile hydrolases are included in clan PB. Cysteine peptidases with a tertiary structure similar to that of the serine-type aspartyl dipeptidase are included in clan PC. Cysteine peptidases with an intein-like fold are included in clan PD, which also includes asparagine lyases.
The band-7 protein family comprises a diverse set of membrane-bound proteins characterised by the presence of a conserved domain, the band-7 domain, also known as SPFH or PHB domain. The exact function of the band-7 domain is not known, but examples from animal and bacterial stomatin-type proteins demonstrate binding to lipids and the ability to assemble into membrane-bound oligomers that form putative scaffolds [
].A variety of proteins belong to the band-7 family. These include the stomatins, prohibitins, flottins and the HflK/C bacterial proteins. Eukaryotic band 7 proteins tend to be oligomeric and are involved in membrane-associated processes. Stomatins are involved in ion channel function, prohibitins are involved in modulating the activity of a membrane-bound FtsH protease and the assembly of mitochondrial respiratory complexes, and flotillins are involved in signal transduction and vesicle trafficking [
].Stomatin, also known as human erythrocyte membrane protein band 7.2b [
], was first identified in the band 7 region of human erythrocyte membrane proteins. It is an oligomeric, monotopic membrane protein associated with cholesterol-rich membranes/lipid rafts. Human stomatin is ubiquitously expressed in all tissues; highly in hematopoietic cells, relatively low in brain. It is associated with the plasma membrane and cytoplasmic vesicles of fibroblasts, epithelial and endothelial cells [].Stomatin is believed to be involved in regulating monovalent cation transport through lipid membranes. Absence of the protein in hereditary stomatocytosis is believed to be the reason for the leakage of Na
+and K
+ions into and from erythrocytes [
]. Stomatin is also expressed in mechanosensory neurons, where it may interact directly with transduction components, including cation channels [].Stomatin proteins have been identified in various organisms, including Caenorhabditis elegans. There are nine stomatin-like proteins in C. elegans, MEC-2 being the one best characterised [
]. In mammals, other stomatin family members are stomatin-like proteins SLP1, SLP2 and SLP3, and NPHS2 (podocin), which display selective expression patterns []. Stomatin family members are oligomeric, they mostly localise to membrane domains, and in many cases have been shown to modulate ion channel activity.The stomatins and prohibitins, and to a lesser extent flotillins, are highly conserved protein families and are found in a variety of organisms ranging from prokaryotes to higher eukaryotes, whereas HflK and HflC homologues are only present in bacteria [
].This entry matches Stomatin, HflK and similar proteins.
This entry represents the MI domain (after MA-3 and eIF4G), it is a protein-protein interaction module of ~130 amino acids [
,
,
]. It appears in several translation factors and is found in:One copy in plant and animal eIF4G 1 and 2 (DAP-5/NAT1/p97)Two copies in the animal programmed cell death protein 4 (PDCD4) or MA-3 that is induced during programmed cell death and inhibits neoplastic transformationFour tandem-repeated copies in a group of uncharacterised plant proteinsThe MI domain consists of seven α-helices, which pack into a globular form. The packing arrangement consists of repeating pairs of antiparallel helices packed one upon the other such that a superhelical axis is generated perpendicular to the α-helical axes [
]. The MI domain has also been named MA3 domain.
This domain is found in proteins that utilise NAD as a cofactor and use nucleotide-sugar substrates for a variety of chemical reactions [
]. One of the best studied of these proteins is UDP-galactose 4-epimerase which catalyses the conversion of UDP-galactose to UDP-glucose during galactose metabolism [,
].
NIPA (nonimprinted in Prader-Willi/Angelman syndrome) is a family of integral membrane proteins which function as magnesium transporters [
,
]. This entry also includes a group of uncharacterised bacterial proteins, such as Cgl0250 (UniProt:P42459) from Corynebacterium glutamicum.
This superfamily represents domains with an immunoglobulin-like (Ig-like) fold, which consists of a β-sandwich of seven or more strands in two sheets with a Greek-key topology. Ig-like domains are one of the most common protein modules found in animals, occurring in a variety of different proteins. These domains are often involved in interactions, commonly with other Ig-like domains via their β-sheets [
,
,
,
]. Domains within this fold-family share the same structure, but can diverge with respect to their sequence. Based on sequence, Ig-like domains can be classified as V-set domains (antibody variable domain-like), C1-set domains (antibody constant domain-like), C2-set domains, and I-set domains (antibody intermediate domain-like). Proteins can contain more than one of these types of Ig-like domains. For example, in the human T-cell receptor antigen CD2, domain 1 (D1) is a V-set domain, while domain 2 (D2) is a C2-set domain, both domains having the same Ig-like fold [].Domains with an Ig-like fold can be found in many, diverse proteins in addition to immunoglobulin molecules. For example, Ig-like domains occur in several different types of receptors (such as various T-cell antigen receptors), several cell adhesion molecules, MHC class I and II antigens, as well as the hemolymph protein hemolin, and the muscle proteins titin, telokin and twitchin.
The many different actin cross-linking proteins share a common architecture, consisting of a globular actin-binding domain and an extended rod. Whereas their actin-binding domains consist of two calponin homology domains (see
), their rods fall into three families.
The rod domain of the family including the Dictyostelium discoideum (Slime mould) gelation factor (ABP120) and human filamin (ABP280) is constructed from tandem repeats of a 100-residue motif that is glycine and proline rich [
]. The gelation factor's rod contains 6 copies of the repeat, whereas filamin has a rod constructed from 24 repeats. The resolution of the 3D structure of rod repeats from the gelation factor has shown that they consist of a β-sandwich, formed by two β-sheets arranged in an immunoglobulin-like fold [,
]. Because conserved residues that form the core of the repeats are preserved in filamin, the repeat structure should be common to the members of the gelation factor/filamin family.The head to tail homodimerisation is crucial to the function of the ABP120 and ABP280 proteins. This interaction involves a small portion at the distal end of the rod domains. For the gelation factor it has been shown that the carboxy-terminal repeat 6 dimerises through a double edge-to-edge extension of the β-sheet and that repeat 5 contributes to dimerisation to some extent [
,
,
].
The many different actin cross-linking proteins share a common architecture, consisting of a globular actin-binding domain and an extended rod. Whereas their actin-binding domains consist of two calponin homology domains (see
), their rods fall into three families.
The rod domain of the family including the Dictyostelium discoideum (Slime mould) gelation factor (ABP120) and human filamin (ABP280). It is constructed from tandem repeats of a 100-residue motif that is glycine and proline rich [
]. The gelation factor's rod contains 6 copies of the repeat, whereas filamin has a rod constructed from 24 repeats. The resolution of the 3D structure of rod repeats from the gelation factor has shown that they consist of a β-sandwich, formed by two β-sheets arranged in an immunoglobulin-like fold [,
]. The repeat structure is common to the members of the gelation factor/filamin family.This entry represents the entire filamin/ABP280 repeat.
Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites [
,
]. About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to - the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits. Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome [
,
].Evidence suggests that, in prokaryotes, the peptidyl
transferase reaction is performed by the large subunit 23S rRNA, whereasproteins probably have a greater role in eukaryote ribosomes. Most of the
proteins lie close to, or on the surface of, the 30S subunit, arrangedperipherally around the rRNA [
]. The small subunit ribosomal proteins canbe categorised as primary binding proteins, which bind directly and
independently to 16S rRNA; secondary binding proteins, which display nospecific affinity for 16S rRNA, but its assembly is contingent upon the
presence of one or more primary binding proteins; and tertiary bindingproteins, which require the presence of one or more secondary binding
proteins and sometimes other tertiary binding proteins.The small ribosomal subunit protein S21 contains 55-70 amino acid residues,
and has only been found in eubacteria to date, though it has been reported that plant chloroplasts and mammalian mitochondria contain ribosomal subunit protein S21. Experimental evidence hasrevealed that S21 is well exposed on the surface of the Escherichia coli
ribosome [], and is one of the 'split proteins': these are a discrete groupthat are selectively removed from 30S subunits under low salt conditions
and are required for the formation of activated 30S reconstitutionintermediate (RI*) particles.
The PCI (for Proteasome, COP9, Initiation factor 3) domain (sometimes also
referred to as the PINT domain, for Proteasome subunits, Int-6, Nip-1, andTrip-15) is present in six different subunits of 26 proteasome lid, COP9
signalosome (CSN) and eukaryotic translation initiation factor-3 (eIF3)complexes, as well as in subunits of certain other multiprotein complexes. The
PCI domain mediates and stabilizes protein-protein interactions within thecomplexes. The role of the PCI domains is most likely that of a scaffold for
the other complex subunits and other binding partners. The PCI domain couldplay a role as a universal binding domain supporting intra-complex
interactions as well as recruitments of additional ligands [,
,
,
,
,
].PCI is an ~190-amino acid domain, not well conserved in its primary sequence,
usually located near the C terminus of the protein. It does not contain anyinvariant residues or any conserved pattern of charged residues that would
suggest a catalytic activity. The PCI domain is comprised of two subdomainsthat are intimately connected, an N-terminal helical bundle (HB) subdomain and
a C-terminal globular winged helix (WH) subdomain. The C-terminal half of the PCI domain is much better conserved than the N-terminal
half [,
,
].
This entry includes 26S proteasome regulatory subunit Rpn7 and COP9 signalosome complex subunit 1 (Csn1) and fungal CSN11.
The 26S proteasome plays a major role in ATP-dependent degradation of ubiquitinated proteins. Substrate specificity is conferred by the regulatory particle (RP), which can dissociate into stable lid and base subcomplexes. The regulatory subunit RPN7 is one of the lid subunits of the 26S proteasome and has been shown in Saccharomyces cerevisiae to be required for structural integrity [
].The COP9 signalosome is a conserved protein complex composed of eight subunits, where individual subunits of the complex have been linked to various signal transduction pathways leading to gene expression and cell cycle control [
]. The overall organisation and the amino acid sequences of the COP9 signalosome subunits resemble the lid subcomplex of the 19 S regulatory particle for the 26 S proteasome []. COP9 subunit 1 (CSN1 or GPS1) of the COP9 complex is an essential subunit of the complex with regard to both structural integrity and functionality. The N-terminal region of subunit 1 (CSN1-N) can inhibit c-fos expression from either a transfected template or a chromosomal transgene (fos-lacZ), and may contain the activity domain that confers most of the repression functions of CSN1. The C-terminal region of subunit 1 (CSN1-C) allows integration of the protein into the COP9 signalosome.
Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids - lysine, threonine, methionine and isoleucine - in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not posses this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see [
].Homoserine dehydrogenase (
) catalyses the third step in the aspartate pathway; the NAD(P)-dependent reduction of aspartate beta-semialdehyde into homoserine [
,
]. Homoserine is an intermediate in the biosynthesis of threonine, isoleucine, and methionine. The enzyme can be found in a monofunctional form, in some bacteria and yeast, or a bifunctional form consisting of an N-terminal aspartokinase domain and a C-terminal homoserine dehydrogenase domain, as found in bacteria such as Escherichia coli and in plants. Structural analysis of the yeast monofunctional enzyme () indicates that the enzyme is a dimer composed of three distinct regions; an N-terminal nucleotide-binding domain, a short central dimerisation region, and a C-terminal catalytic domain [
]. The N-terminal domain forms a modified Rossman fold, while the catalytic domain forms a novel α-β mixed sheet.This entry represents the catalytic domain of homoserine dehydrogenase.
This entry contains proteins with various specificities and includes the aspartate, glutamate and uridylate kinase families. In prokaryotes and plants the synthesis of the essential amino acids lysine and threonine is predominantly regulated by feed-back inhibition of aspartate kinase (AK) and dihydrodipicolinate synthase (DHPS). In Escherichia coli, thrA, metLM, and lysC encode aspartokinase isozymes that show feedback inhibition by threonine, methionine, and lysine, respectively [
]. The lysine-sensitive isoenzyme of aspartate kinase from spinach leaves has a subunit composition of 4 large and 4 small subunits []. In plants although the control of carbon fixation and nitrogen assimilation has been studied in detail, relatively little is known about the regulation of carbon and nitrogen flow into amino acids. The metabolic regulation of expression of an Arabidopsis thaliana aspartate kinase/homoserine dehydrogenase (AK/HSD) gene, which encodes two linked key enzymes in the biosynthetic pathway of aspartate family amino acids has been studied [
]. The conversion of aspartate into either the storage amino acid asparagine or aspartate family amino acids may be subject to a coordinated, reciprocal metabolic control, and this biochemical branch point is a part of a larger, coordinated regulatory mechanism of nitrogen and carbon storage and utilization.
Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids - lysine, threonine, methionine and isoleucine - in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not posses this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see [
].Aspartate kinase (
) (AK) catalyzes the first reaction in the aspartate pathway; the phosphorylation of aspartate. The product
of this reaction can then be used in the biosynthesis of lysine or in the pathway leading to homoserine, which participates in the biosynthesis of threonine, isoleucine
and methionine [].In bacteria there are three different aspartate kinase isozymes which differ in sensitivity to repression and inhibition by Lys, Met and Thr. AK1 and AK2 are bifunctional enzymes which both consist of an N-terminal AK domain and a C-terminal homoserine dehydrogenase domain. AK1 is involved in threonine biosynthesis and AK2, in that of methionine. The third isozyme, AK3 is monofunctional and involved in lysine synthesis. In archaea and plants there may be a single isozyme of AK which in plants is multifunctional.
Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids - lysine, threonine, methionine and isoleucine - in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not posses this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see [
].This entry represents the bifunctional enzyme aspartokinase/homoserine dehydrogenase (AK-HSDH) found in bacteria and plant chloroplasts, which catalyses the first and third steps of the aspartate pathway. Homoserine dehydrogenase (
) catalyses the conversion of L-homoserine to L-aspartate-4-semialdehyde using NAD(P), while aspartate kinase (
) catalyses the phosphorylation of L-aspartate to 4-phospho-L-aspartate. There are two genes encoding different isoforms of this bifunctional enzymes; one isoform is threonine-sensitive, while the other is methionine-sensitive [
,
].Bifunctional enzymes that catalyse consecutive reactions offer the advantages of efficient channelling and protection of potentially reactive intermediates. AK-HSDH is unusual in its ability to catalyse two non-consecutive reactions. The enzyme that catalyses the intermediary step, aspartate semialdehyde dehydrogenase, is thought to provide a bridge to channel the intermediates between the non-consecutive reactions of AK-HSDH [
].This entry also includes homoserine dehydrogenase from fungi, which catalyses the third step in the aspartate pathway and it is found in a monofunctional form in yeast. Structural analysis of this monofunctional form (
) indicates that the enzyme is a dimer composed of an N-terminal nucleotide-binding domain that forms a modified Rossman fold, a short central dimerisation region, and a C-terminal catalytic domain which forms a novel α-β mixed sheet [
].
Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids - lysine, threonine, methionine and isoleucine - in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not posses this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see [
].Homoserine dehydrogenase (
) catalyses the third step in the aspartate pathway; the NAD(P)-dependent reduction of aspartate beta-semialdehyde into homoserine [
,
]. Homoserine is an intermediate in the biosynthesis of threonine, isoleucine, and methionine. The enzyme can be found in a monofunctional form, in some bacteria and yeast, or a bifunctional form consisting of an N-terminal aspartokinase domain and a C-terminal homoserine dehydrogenase domain, as found in bacteria such as Escherichia coli and in plants. Structural analysis of the yeast monofunctional enzyme () indicates that the enzyme is a dimer composed of three distinct regions; an N-terminal nucleotide-binding domain, a short central dimerisation region, and a C-terminal catalytic domain [
]. The N-terminal domain forms a modified Rossman fold, while the catalytic domain forms a novel α-β mixed sheet.This entry represents the NAD(P)-binding domain of aspartate and homoserine dehydrogenase. Asparate dehydrogenase (
) is strictly specific for L-aspartate as substrate and catalyses the first step in NAD biosynthesis from aspartate. The enzyme has a higher affinity for NAD+ than NADP+ [
].Note that the C terminus of the protein contributes a helix to this domain that is not covered by this model.
Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids - lysine, threonine, methionine and isoleucine - in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not posses this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see [
].Homoserine dehydrogenase (
) catalyses the third step in the aspartate pathway; the NAD(P)-dependent reduction of aspartate beta-semialdehyde into homoserine [
,
]. Homoserine is an intermediate in the biosynthesis of threonine, isoleucine, and methionine. The enzyme canbe found in a monofunctional form, in some bacteria and yeast, or a bifunctional form consisting of an N-terminal aspartokinase domain and a C-terminal homoserine dehydrogenase domain, as found in bacteria such as Escherichia coli and in plants. Structural analysis of the yeast monofunctional enzyme (
) indicates that the enzyme is a dimer composed of three distinct regions; an N-terminal nucleotide-binding domain, a short central dimerisation region, and a C-terminal catalytic domain [
]. The N-terminal domain forms a modified Rossman fold, while the catalytic domain forms a novel α-β mixed sheet.The signature pattern of this entry is 23 to 24 residues in length, is located in the central region and contains two conserved aspartate residues.
Aspartate kinase (
) (AK) catalyzes the first reaction in the aspartate pathway; the phosphorylation of aspartate. The product
of this reaction can then be used in the biosynthesis of lysine or in the pathway leading to homoserine, which participates in the biosynthesis of threonine, isoleucine
and methionine [].In bacteria there are three different aspartate kinase isozymes which differ in sensitivity to repression and inhibition by Lys, Met and Thr. AK1 and AK2 are bifunctional enzymes which both consist of an N-terminal AK domain and a C-terminal homoserine dehydrogenase domain. AK1 is involved in threonine biosynthesis and AK2, in that of methionine. The third isozyme, AK3 is monofunctional and involved in lysine synthesis. In archaea and plants there may be a single isozyme of AK which in plants is multifunctional.This entry represents a region encoding aspartate kinase activity found in both the monofunctional and bifunctional enzymes.Synonym(s): Aspartokinase
The ACT domain is a structural motif of 70-90 amino acids that functions in the control of metabolism, solute transport and signal transduction. They are thus found in a variety of different proteins in a variety of different arrangements [
]. In mammalian phenylalanine hydroxylase the domain forms no contacts but promotes an allosteric effect despite the apparent lack of ligand binding [].This ACT domain is found in CASTOR proteins
and C-terminal in some aspartate kinases.
This family consists of selenium binding proteins from eukaryotes, bacteria and archaea. Human selenium-binding protein 1 (SELENBP1) is a methanethiol oxidase (MTO) that converts methanethiol to H2O2, formaldehyde, and H2S [
]. Bovine SBP56 has been shown to participate in late stages of intra-Golgi protein transport []. The Lotus japonicus homologue of SBP56, LjSBP is thought to have more than one physiological role, and can be implicated in controlling the oxidation/reduction status of target proteins in vesicular Golgi transport [
].
This entry represents the C terminus (approximately 300 residues) of eukaryotic micro-fibrillar-associated protein 1, which is a component of elastin-associated microfibrils in the extracellular matrix [
].
Proteins in this group are involved in the transport system that mediates the uptake of a number of sugar phosphates as well as the regulatory components that are responsible for induction of this transport system by external glucose 6-phosphate. In Escherichia coli its role in transmembrane signalling may involve sugar-phosphate-binding sites and transmembrane orientations similar to those of the transport protein [
]. The following proteins in this entry, involved in the uptake of phosphorylated metabolites,are evolutionary related [
,
]:E. coli, Bacillus subtilis and Haemophilus influenzae glycerol-3- phosphate transporter (gene glpT).Salmonella typhimurium phosphoglycerate transporter (gene pgtP).E. coli and S. typhimurium hexose-6-phosphate transporter (gene uhpT).E. coli and S. typhimurium protein uhpC. UhpC is necessary for the expression of uhpT and seems to act jointly with the uhpB sensor/kinase protein.Human glucose 6-phosphate translocase [
].These proteins of about 50kDa apparently contain 12 transmembrane regions.
ATP synthase, F1 complex, delta/epsilon subunit, N-terminal
Type:
Domain
Description:
Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP. There are several different types of transmembrane ATPases, which can differ in function (ATP hydrolysis and/or synthesis), structure (e.g., F-, V- and A-ATPases, which contain rotary motors) and in the type of ions they transport [
,
]. The different types include:F-ATPases (ATP synthases, F1F0-ATPases), which are found in mitochondria, chloroplasts and bacterial plasma membranes where they are the prime producers of ATP, using the proton gradient generated by oxidative phosphorylation (mitochondria) or photosynthesis (chloroplasts).V-ATPases (V1V0-ATPases), which are primarily found in eukaryotes and they function as proton pumps that acidify intracellular compartments and, in some cases, transport protons across the plasma membrane [
]. They are also found in bacteria [].A-ATPases (A1A0-ATPases), which are found in Archaea and function like F-ATPases, though with respect to their structure and some inhibitor responses, A-ATPases are more closely related to the V-ATPases [
,
].P-ATPases (E1E2-ATPases), which are found in bacteria and in eukaryotic plasma membranes and organelles, and function to transport a variety of different ions across membranes.E-ATPases, which are cell-surface enzymes that hydrolyse a range of NTPs, including extracellular ATP.F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (
) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the alpha(3)beta(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis [
]. These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.This family represents subunits called delta (in mitochondrial ATPase) or epsilon (in bacteria or chloroplast ATPase). The interaction site of subunit C of the F0 complex with the delta or epsilon subunit of the F1 complex may be important for connecting the rotor of F1 (gamma subunit) to the rotor of F0 (C subunit) [
]. In bacterial species, the delta subunit is the equivalent of the Oligomycin sensitive subunit (OSCP, ) in metazoans. The C-terminal domain of the epsilon subunit appears to act as an inhibitor of ATPase activity [
].
Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP. There are several different types of transmembrane ATPases, which can differ in function (ATP hydrolysis and/or synthesis), structure (e.g., F-, V- and A-ATPases, which contain rotary motors) and in the type of ions they transport [
,
]. The different types include:F-ATPases (ATP synthases, F1F0-ATPases), which are found in mitochondria, chloroplasts and bacterial plasma membranes where they are the prime producers of ATP, using the proton gradient generated by oxidative phosphorylation (mitochondria) or photosynthesis (chloroplasts).V-ATPases (V1V0-ATPases), which are primarily found in eukaryotes and they function as proton pumps that acidify intracellular compartments and, in some cases, transport protons across the plasma membrane [
]. They are also found in bacteria [].A-ATPases (A1A0-ATPases), which are found in Archaea and function like F-ATPases, though with respect to their structure and some inhibitor responses, A-ATPases are more closely related to the V-ATPases [
,
].P-ATPases (E1E2-ATPases), which are found in bacteria and in eukaryotic plasma membranes and organelles, and function to transport a variety of different ions across membranes.E-ATPases, which are cell-surface enzymes that hydrolyse a range of NTPs, including extracellular ATP.F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (
) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the alpha(3)beta(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis [
]. These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.This family represents subunits called delta (in mitochondrial ATPase) or epsilon (in bacteria or chloroplast ATPase). The interaction site of subunit C of the F0 complex with the delta or epsilon subunit of the F1 complex may be important for connecting the rotor of F1 (gamma subunit) to the rotor of F0 (C subunit) [
]. In bacterial species, the delta subunit is the equivalent of the Oligomycin sensitive subunit (OSCP, ) in metazoans. The C-terminal domain of the epsilon subunit appears to act as an inhibitor of ATPase activity [
].
This entry represents the C-terminal long α-helix domain of ATPase subunit epsilon (in bacteria or chloroplast ATPase) from bacteria and plants [
].The interaction site of subunit C of the F0 complex with the delta or epsilon subunit of the F1 complex may be important for connecting the rotor of F1 (gamma subunit) to the rotor of F0 (C subunit) [
]. In bacterial species, the delta subunit is the equivalent of the Oligomycin sensitive subunit (OSCP, ) in metazoans. The C-terminal domain of the epsilon subunit appears to act as an inhibitor of ATPase activity [
].
This family includes the pre-mRNA-splicing factor BUD31, also known as G10 protein, and its homologues. BUD31 is involved in the pre-mRNA splicing process [
,
,
] and it is highly conserved in a wide range of eukaryotic species. Human BUD31 may play a role as regulator of androgen receptor (AR) transcriptional activity, probably, increasing the AR transcriptional activity [].
A Xenopus protein known as G10 [
] and alternatively as BUD31-homologue has been found to be highly conserved in a wide range of eukaryotic species. The function of G10 is still unknown. G10 is a protein of about 17 to 18kDa (143 to 157 residues) which is hydrophilic and whose C-terminal half is rich in cysteines and could be involved in metal-binding.
Heat shock factor (HSF) is a transcriptional activator of heat shock genes [
,
]: it binds specifically to heat shock promoter elements, which are palindromic sequences rich with repetitive purine and pyrimidine motifs []. Under normal conditions, HSF is a homo-trimeric cytoplasmic protein, but heat shock activation results in relocalisation to the nucleus []. Each HSF monomer contains one C-terminal and three N-terminal leucine zipper repeats []. Point mutations in these regions result in disruption of cellular localisation, rendering the protein constitutively nuclear []. Two sequences flanking the N-terminal zippers fit the consensus of a bi-partite nuclear localisation signal (NLS). Interaction between the N- and C-terminal zippers may result in a structure that masks the NLS sequences: following activation of HSF, these may then be unmasked, resulting in relocalisation of the protein to the nucleus []. The DNA-binding component of HSF lies to the N terminus of the first NLS region, and is referred to as the HSF domain.
In eukaryotes heat shock factors (HSFs) induce transcription of heat shock genes following stress and in response to developmental signals [
]. HSFs recognise cis-acting promoter elements composed of variations of an inverted repeat called heat shock elements (HSE) []. Both HSF and HSEs are conserved in their fundamental structures from yeast to humans.In general, HSFs contain an N-terminal DNA-binding domain of the helix-turn-winged helix type, one or more coiled-coil trimerisation domains, nuclear localisation domains, and a C-terminal trans-activation domain [
]. HSF is present in a latent state under normal conditions; it is activated upon heat stress by induction of trimerisation and high-affinity binding to DNA and by exposure of domains for transcriptional activity [].
