Frataxin is a mitochondrial protein, mutation of which leads to the disease Friedreich's ataxia [
]. Its orthologs are widely distributed in the bacteria, associated with the ISC system for iron-sulphur cluster assembly, and designated CyaY. Friedreich's ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the gene encoding frataxin (FRDA). Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, brown fat and heart). Mouse and yeast frataxin homologues contain a potential N-terminal mitochondrial targeting sequence, and human frataxin has been observed to co-localise with a mitochondrial protein. Furthermore, disruption of the yeast gene has been shown to result in mitochondrial dysfunction. Friedreich's ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat) [,
,
].
The eukaryotic proteins in this entry include frataxin, the protein that is mutated in Friedreich's ataxia [
], and related sequences. Friedreich's ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the gene encoding frataxin (FRDA). Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, brown fat and heart). Mouse and yeast frataxin homologues contain a potential N-terminal mitochondrial targeting sequence, and human frataxin has been observed to co-localise with a mitochondrial protein. Furthermore, disruption of the yeast gene has been shown to result in mitochondrial dysfunction. Friedreich's ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat) [,
,
].The bacterial proteins in this entry are iron-sulphur cluster (FeS) metabolism CyaY proteins homologous to eukaryotic frataxin. Partial Phylogenetic Profiling [
] suggests that CyaY most likely functions as part of the ISC system for FeS cluster biosynthesis, and is supported by expermimental data in some species [,
].
The eukaryotic proteins in this entry include frataxin, the protein that is mutated in Friedreich's ataxia [
], and related sequences. Friedreich's ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the gene encoding frataxin (FRDA). Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, brown fat and heart). Mouse and yeast frataxin homologues contain a potential N-terminal mitochondrial targeting sequence, and human frataxin has been observed to co-localise with a mitochondrial protein. Furthermore, disruption of the yeast gene has been shown to result in mitochondrial dysfunction. Friedreich's ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat) [,
,
].The bacterial proteins in this entry are iron-sulphur cluster (FeS) metabolism CyaY proteins homologous to eukaryotic frataxin. Partial Phylogenetic Profiling [
] suggests that CyaY most likely functions as part of the ISC system for FeS cluster biosynthesis, and is supported by expermimental data in some species [,
]. This conserved site covers a conserved region in the central section of these proteins.
XPB/Ssl2 helicase (also known as Ercc3/RepB/XPB/Rad25/Ssl2/haywire) is a core subunit of the eukaryotic basal transcription factor complex TFIIH which plays a dual role in transcription and DNA repair [
]. It is involved in nucleotide excision repair (NER) of DNA and in RNA transcription by RNA polymerase II []. The TFIIH multiprotein complex consists of a 7-subunit core (XPB, p62, p52, p44, p34, and TTDA) that is associated with a 3-subunit CDK-activating kinase module (MAT1, cyclin H and Cdk7) []. It acts by opening DNA either around the RNA transcription start site or the DNA damage []. Defects in XPB are the cause of xeroderma pigmentosum complementation group B (XP-B); also known as xeroderma pigmentosum II (XP2) or XP group B (XPB) or xeroderma pigmentosum group B combined with Cockayne syndrome (XP-B/CS) [
,
]. Defects in XPB are also a cause of trichothiodystrophy photosensitive (TTDP) [].
This entry represents a domain found in the N terminus of several proteins, including helicases, the R subunit (HsdR) of type I restriction endonucleases (
), the Res subunit of type III endonucleases (
), and the B subunit of the UvrABC system (UvrB) [
,
,
].
This entry represents an N-terminal structural domain which forms an α-helical orthogonal bundle found in fumarate lyase (fumarase) and related proteins, as well as in histidine ammonia-lyase (or histidase) [
]. One member of the fumarate lyase family is L-aspartate ammonia-lyase (aspartase), which catalyses the reversible deamination of the amino acid L-aspartic acid, using a carbanion mechanism to produce fumaric acid and ammonium ion. Aspartases from different organisms show high sequence homology, and this homology extends to functionally related enzymes such as the class II fumarases, the argininosuccinate and adenylosuccinate lyases. The high-resolution structure of aspartase reveals a monomer that is composed of three domains oriented in an elongated S-shape [
].
This entry represents the N-terminal substrate-binding domain of the Lon protease. This ATP-dependent enzyme, a serine peptidase belonging to the MEROPS peptidase family S16, is conserved in archaeal, bacterial and eukaryotic organisms and catalyses rapid turnover of short-lived regulatory proteins and many damaged or denatured proteins. In eukaryotes, the majority of the proteins are located in the mitochondrial matrix [
,
]. In yeast, Pim1, is located in the mitochondrial matrix and required for mitochondrial function. It is constitutively expressed but is increased after thermal stress, suggesting that Pim1 may play a role in the heat shock response [].The structure of this domain has been determined and it represents a general protein and polypeptide interaction domain [
,
,
,
].
Mitochondrial inner membrane protease ATP23 has two roles in the assembly of mitochondrial ATPase. Firstly, it acts as a protease that removes the N-terminal 10 residues of mitochondrial ATPase CF(0) subunit 6 (ATP6) at the intermembrane space side. Secondly, it is involved in the correct assembly of the membrane-embedded ATPase CF(0) particle, probably mediating association of ATP6 with the subunit 9 ring [
,
].
Histone acetyltransferase type B, catalytic subunit
Type:
Family
Description:
This entry represents the catalytic subunit of histone acetyltransferase type B (
) (also known as HAT1), which is the catalytic component of the histone acetylase B (HAT-B) complex [
,
,
]. The HAT-B complex is composed of at least HAT1 and HAT2. In the cytoplasm, this complex binds to the histone H4 tail. In the nucleus, the HAT-B complex has an additional component, the histone H3/H4 chaperone HIF1.This enzyme acetylates soluble but not nucleosomal H4 at Lys-12, which is required for telomeric silencing. HAT1 has intrinsic substrate specificity that modifies lysine in recognition sequence GXGKXG. It is involved in DNA double-strand break repair [
].
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 [
,
].Ribosomal protein L34 is one of the proteins from the large subunit of the prokaryotic ribosome. It is a small basic protein of 44 to 51 amino-acid residues [
]. L34 belongs to a family of ribosomal proteins which, on the basis of sequence similarities, groups: Eubacterial L34, Red algal chloroplast L34 and Cyanelle L34.
This entry represents the N-terminal half of the structure of histone acetyl transferase HAT1. It is often found in association with the C-terminal part of
. It seems to be motifs C and D of the structure. Histone acetyltransferases (HATs) catalyse the transfer of an acetyl group from acetyl-CoA to the lysine E-amino groups on the N-terminal tails of histones. HATs are involved in transcription since histones tend to be hyper-acetylated in actively transcribed regions of chromatin, whereas in transcriptionally silent regions histones are hypo-acetylated [
].
Delta l-pyrroline-5-carboxylate synthetase contains a glutamate 5-kinase (ProB,
) region followed by a gamma-glutamyl phosphate reductase (ProA,
) region and catalyses the first and second steps in proline biosynthesis.
The structure of protein LURP-one-related 15 (At5g01750) has been solved. It comprises a 12-stranded β-barrel with a central C-terminal α-helix. This helix is thought to be a transmembrane helix. It is structurally similar to the C-terminal domain of the Tubby protein [
]. In plants LURP1 plays a role in defense against pathogens [].
This short motif is about 40 amino acids in length and is found in the Fip1 protein that is a component of a Saccharomyces cerevisiae pre-mRNA polyadenylation factor that directly interacts with poly(A) polymerase [
]. This region of Fip1 is needed for the interaction with the Yth1 subunit of the complex and for specific polyadenylation of the cleaved mRNA precursor [].
This family represents beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase (
). This enzyme transfers the bisecting GlcNAc to the core mannose of complex N-glycans. The addition of this residue is regulated during development and has functional consequences for receptor signalling, cell adhesion, and tumour progression [
,
].
This entry represents the RNA-binding domain (also referred to as RNA recognition motif (RRM)) of BRAP2 and its homologues.This entry includes human BRCA1-associated protein (BRAP/BRAP2, also known as impedes mitogenic signal propagation (IMP), RING finger protein 52, or renal carcinoma antigen NY-REN-63) and its homologues from yeast ETP1. BRAP2 is a cytoplasmic protein interacting with the two functional nuclear localization signal (NLS) motifs of BRCA1, a nuclear protein linked to breast cancer. It also binds to the SV40 large T antigen NLS motif and the bipartite NLS motif found in mitosin. BRAP2 serves as a cytoplasmic retention protein and plays a role in the regulation of nuclear protein transport [
,
,
,
,
,
].These proteins contain an N-terminal RNA recognition motif (RRM), also known as RBD (RNA binding domain) or RNP (ribonucleoprotein domain), followed by a C3H2C3-type RING-H2 finger and a UBP-type zinc finger.
Protein Topless is a plant transcriptional co-repressor. It may repress the expression of root-promoting genes in the top half of the embryo to allow proper differentiation of the shoot pole during the transition stage of embryogenesis [
,
,
,
]. This entry represents Topless and related proteins belonging to the same family.
Small G protein signalling modulator 1/2, Rab-binding domain
Type:
Domain
Description:
This domain adopts a PH-like fold. It has been called the Rab-binding domain (RBD) [
]. Small G-protein signalling modulator 1/2 (also known as RUTBC2/1) bind to Rab9A via their Pleckstrin homology (PH) domain [
,
]. RUTBC1 stimulates GTP hydrolysis by Rab32 and Rab33B [], while RUTBC2 appears to be a GAP for Rab36, Rab9A and associated proteins controling the recycling of mannose-6-phosphate receptors from late endosomes to the trans-Golgi [,
,
].
The lipocalins are a diverse, interesting, yet poorly understood family of
proteins composed, in the main, of extracellular ligand-binding proteinsdisplaying high specificity for small hydrophobic molecules [
,
,
]. Functionsof these proteins include transport of nutrients, control of cell regulation, pheromone transport, cryptic colouration, and the enzymatic synthesis
of prostaglandins.The crystal structures of several lipocalins have been solved and show a
novel 8-stranded anti-parallel β-barrel fold well conserved within thefamily. Sequence similarity within the family is at a much lower level and
would seem to be restricted to conserved disulphides and 3 motifs, whichform a juxtaposed cluster that may act as a common cell surface receptor
site []. By contrast, at the more variable end of the fold are found an internal ligand binding site and a putative surface for the formation of macromolecular complexes []. The anti-parallel β-barrel fold is alsoexploited by the fatty acid-binding proteins (which function similarly by
binding small hydrophobic molecules), by avidin and the closely relatedmetalloprotease inhibitors, and by triabin. Similarity at the sequence
level, however, is less obvious, being confined to a single short N-terminal motif.
The lipocalin family can be subdivided into kernal and outlier sets. Thekernal lipocalins form the largest self consistent group. The outlier lipocalins form several smaller distinct subgroups:
the OBPs, the von Ebner's gland proteins, alpha-1-acid glycoproteins, tick histamine binding proteins and the nitrophorins.
Relatively recently, bacterial lipocalins have been described for the
first time [,
,
]. These are lipoproteins anchored to the outer membrane of Gram-negative bacteria and some plants. Their promoters are activated at
the transition between exponential and stationary growth phases. Bacteriallipocalin sequences are quite closely related to apolipoprotein D and may
serve a starvation response function in bacteria. Overexpression, membranefractionation, and metabolic labelling with tritiated palmitate showed
bacterial lipocalins to be globomycin-sensitive outer membrane proteins.The bacterial lipocalins have been found in a small number of species,
raising the possibility that they originated by horizontal transfer. Estimates of the G+C content in the first and third codon positions of
these genes have been calculated. A biased %G+C in the 1st and 3rd codonpositions would suggest horizontal transfer. None of the computed G+C
contents of the bacterial lipocalin genes were outside of the expected limits (between the first and third quartiles). These data provide no
support for a hypothesis in which bacterial lipocalins were recently acquired through horizontal transfer. Further evidence against horizontal
transfer will come from finding more lipocalins in different species, thus making the gene transfer hypothesis more unlikely.
This entry represents ApoD-type lipocalins, including retinol-binding protein 4 as well as other retinol-binding proteins. Apolipoprotein D (ApoD) is mainly associated with high-density lipoproteins (HDL) and appears to be able to transport a variety of ligands in a number of different contexts [
]. Insect Lazarillo is an homologue of ApoD [].The lipocalins are a diverse, interesting, yet poorly understood family of
proteins composed, in the main, of extracellular ligand-binding proteins displaying high specificity for small hydrophobic molecules []. Functions of these proteins include transport of nutrients, control of cell regulation, pheromone transport, cryptic colouration, and the enzymatic synthesis of prostaglandins. For example, retinol-binding protein 4 transfers retinol from the stores in the liver to peripheral tissues [].The crystal structures of several lipocalins have been solved and show a novel 8-stranded anti-parallel β-barrel fold well conserved within the family. Sequence similarity within the family is at a much lower level and would seem to be restricted to conserved disulphides and 3 motifs, which form a juxtaposed cluster that may act as a common cell surface receptor site [
,
]. By contrast, at the more variable end of the fold are found an internal ligand binding site and a putative surface for the formation of macromolecular complexes []. The anti-parallel β-barrel fold is also exploited by the fatty acid-binding proteins, which function similarly by binding small hydrophobic molecules. Similarity at the sequence level, however, is less obvious, being confined to a single short N-terminal motif.
Mediator of RNA polymerase II transcription subunit 22
Type:
Family
Description:
The Mediator complex is a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. The Mediator complex, having a compact conformation in its free form, is recruited to promoters by direct interactions with regulatory proteins and serves for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. On recruitment the Mediator complex unfolds to an extended conformation and partially surrounds RNA polymerase II, specifically interacting with the unphosphorylated form of the C-terminal domain (CTD) of RNA polymerase II. The Mediator complex dissociates from the RNA polymerase II holoenzyme and stays at the promoter when transcriptional elongation begins. The Mediator complex is composed of at least 31 subunits: MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The subunits form at least three structurally distinct submodules. The head and the middle modules interact directly with RNA polymerase II, whereas the elongated tail module interacts with gene-specific regulatory proteins. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation.
The head module contains: MED6, MED8, MED11, SRB4/MED17, SRB5/MED18, ROX3/MED19, SRB2/MED20 and SRB6/MED22. The middle module contains: MED1, MED4, NUT1/MED5, MED7, CSE2/MED9, NUT2/MED10, SRB7/MED21 and SOH1/MED31. CSE2/MED9 interacts directly with MED4. The tail module contains: MED2, PGD1/MED3, RGR1/MED14, GAL11/MED15 and SIN4/MED16. The CDK8 module contains: MED12, MED13, CCNC and CDK8. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.This entry represents subunit Med22 of the Mediator complex. It contains several eukaryotic Surfeit locus protein 5 (SURF5) sequences. The human Surfeit locus has been mapped on chromosome 9q34.1. The locus includes six tightly clustered housekeeping genes (Surf1-6), and the gene organisation is similar in human, mouse and chicken Surfeit loci [
].
Blue (type 1) copper proteins constitute a diverse class of
proteins, including small blue proteins and multicopperoxidases. They bind copper and are characterised by an intense electronic absorption band near 600 nm [
,
].The most well known members of this class of proteins are the small blue proteins, which includes azurins and plastocyanins. It is a group of monomeric
proteins which contain one copper ion per molecule. The plant chloroplastic plastocyanins exchange electrons with cytochrome c6, and the distantly related bacterial azurins exchange electrons with cytochrome c551. This group also includes amicyanin from bacteria such as Methylobacterium extorquens or Paracoccus versutus (Thiobacillus versutus) that can grow on methylamine; auracyanins A and B from Chloroflexus aurantiacus []; blue copper protein from Alcaligenes faecalis; cupredoxin (CPC) from Cucumis sativus (Cucumber) peelings []; cusacyanin (basic blue protein; plantacyanin, CBP) from cucumber; halocyanin from Natronomonas pharaonis (Natronobacterium pharaonis) [], a membrane associated copper-binding protein; pseudoazurin from Pseudomonas; rusticyanin from Thiobacillus ferrooxidans []; stellacyanin from Rhus vernicifera (Japanese lacquer tree); umecyanin from the roots of Armoracia rusticana (Horseradish); and allergen Ra3 from ragweed. This pollen protein is evolutionary related to the above proteins, but seems to have lost the ability to bind copper.Although there is an appreciable amount of divergence in the sequences of all these proteins, the copper ligand sites are conserved. This entry represents a conserved site that includes two of the ligands: a cysteine and a histidine.
Initiation of eukaryotic mRNA transcription requires melting of promoter DNA with the help of the general transcription factors TFIIE and TFIIH. In higher eukaryotes, the general transcription factor TFIIE consists of two subunits: the large alpha subunit (
) and the small beta (
). TFIIE beta has been found to bind to the region where the promoter starts to open to be single-stranded upon transcription initiation by RNA polymerase II. The approximately 120-residue central core domain of TFIIE beta plays a role in double-stranded DNA binding of TFIIE [
].The TFIIE beta central core DNA-binding domain consists of three helices with a beta hairpin at the C terminus, resembling the winged helix proteins. It shows a novel double-stranded DNA-binding activity where the DNA-binding surface locates on the opposite side to the previously reported winged helix motif by forming a positively charged furrow [
].This entry represents the central core DNA-binding domain of the TFIIE beta subunit.Transcription Factor IIE (TFIIE) beta winged-helix (or forkhead) domain is located at the central core region of TFIIE beta. The winged-helix is a form of helix-turn-helix (HTH) domain which typically binds DNA with the 3rd helix. The winged-helix domain is distinguished by the presence of a C-terminal β-strand hairpin unit (the wing) that packs against the cleft of the tri-helical core. Although most winged-helix domains are multi-member families, TFIIE beta winged-helix domain is typically found as a single orthologous group. [
,
,
,
].
Two integral outer envelope GTPases, Toc34 and Toc86, are proposed to regulate the recognition and translocation of nuclear-encoded preproteins during the early stages of protein import into chloroplasts. The cytosolic region of Toc34 reveals 34% α-helical and 26% β-strand structure and is stabilised by intramolecular electrostatic interaction. Toc34 binds both chloroplast preproteins and isolated transit peptides in a guanosine triphosphate- (GTP-) dependent mechanism [
].
The amidotransferase family of enzymes utilises the ammonia derived from the hydrolysis of glutamine for a subsequent chemical reaction catalyzed by the same enzyme. The ammonia intermediate does not dissociate into solution during the chemical transformations [
].GMP synthetase is a glutamine amidotransferase from the
de novopurine biosynthetic pathway. The C-terminal domain is specific to the GMP synthases
. In prokaryotes this domain mediates dimerisation. Eukaryotic GMP synthases are monomers. This domain in eukaryotes includes several large insertions that may form globular domains [
].
This signature represents the type 1 glutamine amidotransferase (GATase1) domain found in the N-terminal region of GMP synthase
. GMP synthase catalyzes the synthesis of GMP from XMP [
], [].ATP + xanthosine 5'-phosphate + L-glutamine + H(2)O = AMP + diphosphate + GMP + L-glutamate GMP synthetase is a glutamine amidotransferase from the de novo purine biosynthetic pathway. It belongs to the triad family of amidotransferases having a conserved Cys-His-Glu catalytic triad in the glutaminase active site [
].Glutamine amidotransferase (GATase) activity catalyses the transfer of ammonia from the amide side chain of glutamine to an acceptor substrate.
Guanosine 5'-monophosphate synthetase (GMPS) is a widespread enzyme seen in
all domains of life. GMPS is required for the final step of the de novosynthesis of guanine nucleotides, converting xanthosine 5'-monophosphate (XMP)
into guanosine 5'-monophosphate (GMP), a precursor of DNA and RNA. GMPSconsists of two catalytic units, glutamine amidotransferase (GATase) and ATP pyrophosphatase (ATP-PPase). GATase hydrolyzes glutamine
to yield glutamate and ammonia, while ATP-PPase utilises ammonia to convertadenyl xanthosine 5'-monophosphate (adenyl-XMP) into GMP. The two catalytic
units are either encoded by a single gene (two-domain type) in eucaryotes,bacteria, and some archaea, or encoded by two separate genes (two-subunit
type) in other archaea. In two-domain-type GMPS, the GATase domain is locatedin the N-terminal half, and the ATP-PPase domain is located in the C-terminal
half; in two-subunit-type GMPS, these two units exist as separatepolypeptides. ATP-PPase consists of two domains (N-domain and C-domain). The
N-domain contains an ATP-binding platform called P-loop,whereas the C-domain contains the XMP-binding site and also contributes to
homodimerisation [,
,
].The GMP synthetase ATP-PPase ATP-binding domain is a twisted, five-strandedparallel β-sheet sandwiched between helical layers. It
contains a glycine rich ATP-binding motif called the "P-loop motif"located
after the first β-strand [,
].
Mechanosensitive ion channel MscS, transmembrane-2
Type:
Homologous_superfamily
Description:
MscS is a mechanosensitive channel present in the membrane of bacteria, archaea and eukarya that responds both to stretching of the cell membrane and to membrane depolarisation [
,
,
,
]. MscS folds as a homo-heptamer with a cylindrical shape, and can be divided into transmembrane and extramembrane regions: an N-terminal periplasmic region, a transmembrane region, and a C-terminal cytoplasmic region. The MscS family of channels shows diversity in size and sequence between its members; most of the diversity occurs in the size of the transmembrane region, which ranges from three to eleven transmembrane helices, although the three C-terminal helices are conserved. This domain superfamily covers the core transmembrane region, which consists of three transmembrane helices per subunit in an oligomeric fold.
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 [].The M1 family of zinc metallopeptidases contains a number of distinct, well-separated clades of proteins with aminopeptidase activity. Several are designated aminopeptidase N,
, after the Escherichia coli enzyme, suggesting a similar activity profile (see
for a description of catalytic activity).
This group of zinc metallopeptidases belong to MEROPS peptidase family M1 (aminopeptidase N, clan MA); the majority are identified as alanyl aminopeptidases (proteobacteria) that are closely related to E. coli PepN and presumed to have a similar (not identical) function. Nearly all are found in proteobacteria, but members are found also in cyanobacteria, plants, and apicomplexan parasites [
,
]. This family differs greatly in sequence from the family of aminopeptidases typified by Streptomyces lividans PepN () and from the membrane bound aminopeptidase N family in animals.
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 domain, which contains a conserved FSAPV sequence motif, is found in the C-terminal of alanyl aminopeptidases that belong to MEROPS peptidase family M1 (aminopeptidase N, clan MA).
The general transcription factor, TFIID, consists of the TATA-binding protein (TBP) associated with a series of TBP-associated factors (TAFs) that together participate in the assembly of the transcription preinitiation complex. This entry represents a conserved domain found at the C terminus of Transcription initiation factor TFIID subunit 11 from humans (also known as Transcription initiation factor TFIID 28 kDa subunit, TAFII28 [
]). TAF11 interacts with the ligand binding domains of the nuclear receptors for vitamin D3 and thyroid hormone []. It also interacts directly with TFIIA, acting as a bridging factor that stabilises the TFIIA-TBP-DNA complex []. The crystal structure of hTAFII28 with hTAFII18 shows that this region is involved in the binding of these two subunits. The conserved region contains four α-helices and three loops arranged as in histone H3 [,
].
Dihydroneopterin
aldolase catalyzes the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin in the biosynthetic pathway oftetrahydrofolate. The enzyme form a homo-octamers. Aldolase can use L-threo-dihydroneopterin and
D-erythro-dihydroneopterin as substrates for the formation of 6-hydroxymethyldihydropterin, but it can also catalyze the epimerizationof carbon 2' of dihydroneopterin and dihydromonapterin at appreciable velocity [].
Dihydroneopterin aldolase (DHNA or folB) catalyses the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin in the biosynthetic pathway of tetrahydrofolate [
]. Folate derivatives are essential cofactors in the biosynthesis of purines, pyrimidines, and amino acids, as well as formyl-tRNA. Mammalian cells are able to utilize pre-formed folates after uptake by a carrier-mediated active transport system. Most microbes and plants lack this system and must synthesize folates de novo from guanosine triphosphate and DHNA is one enzyme in this pathway. In the opportunistic pathogen Pneumocystis carinii, dihydroneopterin aldolase function is expressed as the N-terminal portion of the multifunctional folic acid synthesis protein (Fas). This region encompasses two domains, FasA and FasB, which are 27% amino acid identical []. FasA and FasB also share significant amino acid sequence similarity with bacterial dihydroneopterin aldolases.This entry also includes 7,8-dihydroneopterin triphosphate epimerase domain (DHNTPE or folX). Though it is known that DHNTPE catalyzes the epimerization of dihydroneopterin triphosphate to dihydromonapterin triphosphate, the biological role of this enzyme is still unclear. It is hypothesized that it is not an essential protein since a folX knockout in E. coli has a normal phenotype and the fact that folX is not present in H. influenza [
,
]. DHNA and DHNTPE have been shown to be able to compensate for the other's activity albeit at slower reaction rates []. The functional enzyme for both is an octamer of identical subunits. Mammals lack many of the enzymes in the folate pathway including, DHNA and DHNTPE.This region consists of two tandem sequences each homologous to folB and which form tetramers [
].
Budding yeast Nob1 is involved in proteasomal and 40S ribosomal subunit biogenesis. It is required for cleavage of the 20S pre-rRNA to generate the mature 18S rRNA [
,
,
].
This is a conserved domain found in deubiquitinating enzymes, MINDY-3 and MINDY-4.Deubiquitinating enzymes (DUBs) remove ubiquitin (Ub) from Ub-conjugated substrates to regulate the functional outcome of ubiquitylation. This entry includes MINDY-3/4. They belong to the MINDY (motif interacting with Ub-containing novel DUB) family (peptidase family C121), whose members are deubiquitinating enzymes releasing Lys48-linked ubiquitin [
].
These sequences represent one of two highly dissimilar forms of glutamate--cysteine ligase (gamma-glutamylcysteine synthetase), an enzyme of glutathione biosynthesis. The other group is represented by
. This form is found in plants (with a probable transit peptide), root nodule and other bacteria, but not Escherichia coli and closely related species.
This entry includes EgtA from Actinobacteria, a glutamate--cysteine ligase involved in the synthesis of ergothioneine (ERG) [
], one of the major redox buffers that protects against redox stressors and in M. tuberculosis is essential for its virulence [].
Also known as gamma-glutamylcysteine synthetase and gamma-ECS (
). This enzyme catalyses the first and rate limiting step in de novo glutathione biosynthesis. Members of this family are found in archaea, bacteria and plants. May and Leaver [
] discuss the possible evolutionary origins of glutamate-cysteine ligase enzymes in different organisms and suggest that it evolved independently in different eukaryotes, from an ancestral bacterial enzyme. They also state that Arabidopsis thaliana (Mouse-ear cress) gamma-glutamylcysteine synthetase is structurally unrelated to mammalian, yeast and Escherichia coli homologues. In plants, there are separate cytosolic and chloroplast forms of the enzyme.
Myeloid leukemia factor is involved in lineage commitment of primary hemopoietic progenitors by restricting erythroid formation and enhancing myeloid formation [
].
This entry includes HemK (also known as PrmC) from Escherichia coli. HemK methylates the class 1 translation termination release factors RF1/PrfA and RF2/PrfB on the glutamine residue of the universally conserved GGQ motif [
,
]. Its homologue in Saccharomyces cerevisiae, Mtq1, is a methyltransferase that methylates MRF1 on 'Gln-287' using S-adenosyl L-methionine as methyl donor []. Homologues are found, usually in a single copy, in nearly all completed genomes, but varying somewhat in apparent domain architecture. Both Escherichia coli and Haemophilus influenzae have two members rather than one. The members from the Mycoplasmas have an additional C-terminal domain.
Synonym(s): RhodaneseThiosulphate sulphurtransferase (
) is an enzyme which catalyses the transfer of the sulphane atom of thiosulphate to cyanide, to form sulphite and thiocyanate. In vertebrates, rhodanese is a mitochondrial enzyme that is involved in forming iron-sulphur complexes and cyanide detoxification. A cysteine residue takes part in the catalytic mechanism [
,
]. Some bacterial proteins may also express sulphotransferase activity. These include, SseA from Mycobacterium leprae and Escherichia coli, Azotobacter vinelandii rhdA, Saccharopolyspora erythraea cysA [] and Synechococcus sp. (strain PCC 7942) rhdA [].
Phosphoglycerate kinase (
) (PGK) is an enzyme that catalyses the formation of ATP to ADP and vice versa. In the second step of the second phase in glycolysis, 1,3-diphosphoglycerate is converted to
3-phosphoglycerate, forming one molecule of ATP. If the reverse were to occur, one molecule of ADP would be formed. This reaction is essential in most cells for the generation of ATP in aerobes, for fermentation in anaerobes and for carbon fixation in plants.PGK is found in all living organisms and its sequence has been highly conserved throughout evolution. The enzyme exists as a monomer containing two nearly equal-sized domains that correspond to the N- and C-termini of the protein (the last 15 C-terminal residues loop back into the N-terminal domain). 3-phosphoglycerate (3-PG) binds to the N-terminal, while the nucleotide substrates, MgATP or MgADP, bind to the C-terminal domain of the enzyme. This extended two-domain structure is associated with large-scale 'hinge-bending' conformational changes, similar to those found in hexokinase [
]. At the core of each domain is a 6-stranded parallel β-sheet surrounded by alpha helices. Domain 1 has a parallel β-sheet of six strands with an order of 342156, while domain 2 has a parallel β-sheet of six strands with an order of 321456. Analysis of the reversible unfolding of yeast phosphoglycerate kinase leads to the conclusion that the two lobes are capable of folding independently, consistent with the presence of intermediates on the folding pathway with a single domain folded []. Phosphoglycerate kinase (PGK) deficiency is associated with haemolytic anaemia and mental disorders in man [
].This entry represents a conserved motif found in the N-terminal region of PGK.
This entry includes inosine-5'-monophosphate dehydrogenases and guanosine 5'-monophosphate (GMP) reductase. Inosine-5'-monophosphate dehydrogenase catalyses the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth [
,
]. GMP catalyses the irreversible NADPH-dependent deamination of GMP to IMP [].
Synonym(s): Inosine-5'-monophosphate dehydrogenase, Inosinic acid dehydrogenase;
Synonym(s): Guanosine 5'-monophosphate oxidoreductase This entry contains two related enzymes: IMP dehydrogenase and GMP reductase. These enzymes adopt a TIM barrel structure.IMP dehydrogenase (
) (IMPDH) catalyses the rate-limiting reaction of
de novoGTP biosynthesis, the NAD-dependent reduction of IMP into XMP [
].Inosine 5-phosphate + NAD++ H
2O = xanthosine 5-phosphate + NADH
IMP dehydrogenase is associated with cell proliferation and is a possible target for cancer chemotherapy. Mammalian and bacterial IMPDHs are tetramers of identical chains. There are two IMP dehydrogenase isozymes in humans []. IMP dehydrogenase nearly always contains a long insertion that has two CBS domains within it.GMP reductase (
) catalyses the irreversible and NADPH-dependent reductive deamination of GMP into IMP [
].NADPH + guanosine 5-phosphate = NADP++ inosine 5-phosphate + NH
3It converts nucleobase, nucleoside and nucleotide derivatives of G to A nucleotides, and maintains intracellular balance of A and G nucleotides.
Synonym(s): Inosine-5'-monophosphate dehydrogenase, Inosinic acid dehydrogenase;
Synonym(s): Guanosine 5'-monophosphate oxidoreductase This entry contains two related enzymes: IMP dehydrogenase and GMP reductase. These enzymes adopt a TIM barrel structure.IMP dehydrogenase (
) (IMPDH) catalyses the rate-limiting reaction of
de novoGTP biosynthesis, the NAD-dependent reduction of IMP into XMP [
].Inosine 5-phosphate + NAD++ H
2O = xanthosine 5-phosphate + NADH
IMP dehydrogenase is associated with cell proliferation and is a possible target for cancer chemotherapy. Mammalian and bacterial IMPDHs are tetramers of identical chains. There are two IMP dehydrogenase isozymes in humans []. IMP dehydrogenase nearly always contains a long insertion that has two CBS domains within it.GMP reductase (
) catalyses the irreversible and NADPH-dependent reductive deamination of GMP into IMP [
].NADPH + guanosine 5-phosphate = NADP++ inosine 5-phosphate + NH
3It converts nucleobase, nucleoside and nucleotide derivatives of G to A nucleotides, and maintains intracellular balance of A and G nucleotides.
The following proteins have been shown [
,
] to be structurally and evolutionary related:Riboflavin synthase alpha chain (
) (RS-alpha) (gene ribC in Escherichia coli, ribB in Bacillus subtilis and Photobacterium leiognathi, RIB5 in yeast. This enzyme synthesises riboflavin from two moles of 6,7- dimethyl-8-(1'-D-ribityl)lumazine (Lum), a pteridine-derivative.
Photobacterium phosphoreum lumazine protein (LumP) (gene luxL). LumP is a protein that modulates the colour of the bioluminescence emission of bacterial luciferase. In the presence of LumP, light emission is shifted to higher energy values (shorter wavelength). LumP binds non-covalently to 6,7-dimethyl-8-(1'-D-ribityl)lumazine.Vibrio fischeri yellow fluorescent protein (YFP) (gene luxY). Like LumP, YFP modulates light emission but towards a longer wavelength. YFP binds non-covalently to FMN.Aliivibrio fischeri blue fluorescence protein. These proteins seem to have evolved from the duplication of a domain of about 100 residues. In its C-terminal section, this domain contains a conserved motif [KR]-V-N-[LI]-E which has been proposed to be the binding site for lumazine (Lum) and some of its derivatives. RS-alpha which binds two molecules of Lum has two perfect copies of this motif, while LumP which binds one molecule of Lum, has a Glu instead of Lys/Arg in the first position of the second copy of the motif. Similarly, YFP, which binds to one molecule of FMN, also seems to have a potentially dysfunctional binding site by substitution of Gly for Glu in the last position of the first copy of the motif.
The lumazine-binding domain is about 100 residues. In its C-terminal section, this domain contains a conserved motif [KR]-V-N-[LI]-E which has been proposed to be the binding site for lumazine (Lum) and some of its derivatives. Riboflavin synthase alpha chain (RS-alpha), which binds two molecules of Lum, has two perfect copies of this motif, while lumazine protein (LumP), which binds one molecule of Lum, has a Glu instead of Lys/Arg in the first position of the second copy of the motif. Similarly, yellow fluorescent protein (YFP), which binds to one molecule of FMN, also seems to have a potentially dysfunctional binding site by substitution of Gly for Glu in the last position of the first copy of the motif.The lumazine-binding domain of RS-alpha forms two Greek-key folds with the topology BBHBBBHB, where most of the substrate binding sites are located in β-strands (B) 4 and 5 and in helix (H) 2 [
,
,
].
ATP synthase subunit alpha, N-terminal domain-like superfamily
Type:
Homologous_superfamily
Description:
In F-ATPases, there are three copies each of the alpha and beta subunits that form the catalytic core of the F1 complex, while the remaining F1 subunits (gamma, delta, epsilon) form part of the stalks. There is a substrate-binding site on each of the alpha and beta subunits, those on the beta subunits being catalytic, while those on the alpha subunits are regulatory. The alpha and beta subunits form a cylinder that is attached to the central stalk. The alpha/beta subunits undergo a sequence of conformational changes leading to the formation of ATP from ADP, which are induced by the rotation of the gamma subunit, itself is driven by the movement of protons through the F0 complex C subunit [
]. In V- and A-ATPases, the alpha/A and beta/B subunits of the V1 or A1 complex are homologous to the alpha and beta subunits in the F1 complex of F-ATPases, except that the alpha subunit is catalytic and the beta subunit is regulatory.The alpha/A and beta/B subunits can each be divided into three regions, or domains, centred around the ATP-binding pocket, and based on structure and function, where the central region is the nucleotide-binding domain (
) [
].This superfamily represents a closed β-barrel domain with Greek-key topology. It is found at the N terminus of the alpha/A subunits. This beta barrel closely resembles folds found in riboflavin synthase [
].
This is the N-terminal domain of fungal and eukaryotic Sec3 proteins. Sec3 is a component of the exocyst complex that is involved in the targeting and tethering of post-Golgi secretory vesicles to fusion sites on the plasma membrane prior to SNARE-mediated fusion. This N-terminal domain contains a cryptic pleckstrin homology (PH) fold, and all six positively charged lysine and arginine residues in the PH domain predicted to bind the phosphatidylinositol 4,5-bisphosphate (PIP2) head group are conserved. In fission yeast, polarised exocytosis for growth relies on the combined action of the exocyst at cell poles and myosin-driven transport along actin cables [
].
This entry represents the C-terminal domain of Sec3 (also known as ExoC1), a component of the exocyst complex (composed of Exoc1, Exoc2, Exoc3, Exoc4, Exoc5, Exoc6, Exoc7 and Exoc8) which mediates the tethering of post-Golgi secretory vesicles to the plasma membrane and promotes the assembly of the SNARE complex for membrane fusion. The exocyst is also involved in other cell processes such as cell polarisation, primary ciliogenesis, cytokinesis, and tumorigenesis and metastasis [
]. This complex has an elongated shape consisting of packed long rods, a structure that is shared among the Complex Associated with Tethering Containing Helical Rods (CATCHRs) proteins from related complexes such as Conserved Oligomeric Golgi complex (COG) and Golgi-Associated Retrograde Protein complex (GARP) [,
,
]. Subunits of these complexes, apart of helical bundles, they usually have a coiled-coil (CC) region at the N-terminal. Sec3 is described as a membrane-anchoring component which serves as a spatial landmark in the plasma membrane for incoming secretory vesicles. Sec3 binds to the C-terminal cytoplasmic domain of GLYT1 (glycine transporter protein 1). Sec3 is recruited to the sites of polarised membrane growth through its interaction with Rho1p, a small GTP-binding protein [].
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 [
,
].Ribosomal protein S9 is one of the proteins from the small ribosomal subunit. It belongs to the S9P family of ribosomal proteins which, on the basis of sequence similarities [
], groups bacterial; algal chloroplast; cyanelle and archaeal S9 proteins; and mammalian, plant, and yeast mitochondrial ribosomal S9 proteins. These proteins adopt a β-α-β fold similar to that found in numerous RNA/DNA-binding proteins, as well as in kinases from the GHMP kinase family [].This entry represents bacterial, plastid and mitochondrial ribosomal S9 proteins. Mitochondrial ribosomal S9 is required for central cell maturation and endosperm development in
Arabidopsis thaliana[
].
COG4 is a component of the conserved oligomeric Golgi (COG) complex which mediates the proper glycosylation of proteins trafficking through the Golgi apparatus. It is included in the CATCHR (complexes associated with tethering containing helical rods) family, which includes components of the exocyst, GARP, and DSL1 complexes and share structural and functional features: the α-helical bundles at the middle/C-terminal (described as domains A-D/E) and a N-terminal coiled-coil region [
,
,
]. This domain is found in the middle region of COG4 and corresponds to domains B and C. Mutations in COG4 cause fatal congenital disorders of glycosylation (CDGs) in humans [,
].
Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway [
]. The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin [].The first stage in tetrapyrrole synthesis is the synthesis of 5-aminoaevulinic acid ALA via two possible routes: (1) condensation of succinyl CoA and glycine (C4 pathway) using ALA synthase (
), or (2) decarboxylation of glutamate (C5 pathway) via three different enzymes, glutamyl-tRNA synthetase (
) to charge a tRNA with glutamate, glutamyl-tRNA reductase (
) to reduce glutamyl-tRNA to glutamate-1-semialdehyde (GSA), and GSA aminotransferase (
) to catalyse a transamination reaction to produce ALA.
The second stage is to convert ALA to uroporphyrinogen III, the first macrocyclic tetrapyrrolic structure in the pathway. This is achieved by the action of three enzymes in one common pathway: porphobilinogen (PBG) synthase (or ALA dehydratase,
) to condense two ALA molecules to generate porphobilinogen; hydroxymethylbilane synthase (or PBG deaminase,
) to polymerise four PBG molecules into preuroporphyrinogen (tetrapyrrole structure); and uroporphyrinogen III synthase (
) to link two pyrrole units together (rings A and D) to yield uroporphyrinogen III.
Uroporphyrinogen III is the first branch point of the pathway. To synthesise cobalamin (vitamin B12), sirohaem, and coenzyme F430, uroporphyrinogen III needs to be converted into precorrin-2 by the action of uroporphyrinogen III methyltransferase (
). To synthesise haem and chlorophyll, uroporphyrinogen III needs to be decarboxylated into coproporphyrinogen III by the action of uroporphyrinogen III decarboxylase (
) [
].Porphobilinogen deaminase (also known as hydroxymethylbilane synthase,
) functions during the second stage of tetrapyrrole biosynthesis. This enzyme catalyses the polymerisation of four PBG molecules into the tetrapyrrole structure, preuroporphyrinogen, with the concomitant release of four molecules of ammonia. This enzyme uses a unique dipyrro-methane cofactor made from two molecules of PBG, which is covalently attached to a cysteine side chain. The tetrapyrrole product is synthesized in an ordered, sequential fashion, by initial attachment of the first pyrrole unit (ring A) to the cofactor, followed by subsequent additions of the remaining pyrrole units (rings B, C, D) to the growing pyrrole chain [
]. The link between the pyrrole ring and the cofactor is broken once all the pyrroles have been added. This enzyme is folded into three distinct domains that enclose a single, large active site that makes use of an aspartic acid as its one essential catalytic residue, acting as a general acid/base during catalysis [,
]. A deficiency of hydroxymethylbilane synthase is implicated in the neuropathic disease, Acute Intermittent Porphyria (AIP) []. This entry represents the N-terminal domains 1 and 2 of porphobilinogen deaminase, an enzyme involved in tetrapyrrole biosynthesis. The structure of this domain consists of a duplication of two similar intertwined domains with three layers of (a/b/a) each. Porphobilinogen deaminase has a three-domain structure. Domains 1 (N-terminal) and 2 are duplications with the same structure, resembling the transferrins and periplasmic binding proteins. The dipyrromethane cofactor is covalently linked to domain 3 (C-terminal), but is bound by extensive salt-bridges and hydrogen-bonds within the cleft between domains 1 and 2, at a position corresponding to the binding sites for small-molecule ligands in the analogous proteins [
]. The enzyme has a single catalytic site, and the flexibility between domains is thought to aid elongation of the polypyrrole product in the active-site cleft of the enzyme.
Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway [
]. The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin [].The first stage in tetrapyrrole synthesis is the synthesis of 5-aminoaevulinic acid ALA via two possible routes: (1) condensation of succinyl CoA and glycine (C4 pathway) using ALA synthase (
), or (2) decarboxylation of glutamate (C5 pathway) via three different enzymes, glutamyl-tRNA synthetase (
) to charge a tRNA with glutamate, glutamyl-tRNA reductase (
) to reduce glutamyl-tRNA to glutamate-1-semialdehyde (GSA), and GSA aminotransferase (
) to catalyse a transamination reaction to produce ALA.
The second stage is to convert ALA to uroporphyrinogen III, the first macrocyclic tetrapyrrolic structure in the pathway. This is achieved by the action of three enzymes in one common pathway: porphobilinogen (PBG) synthase (or ALA dehydratase,
) to condense two ALA molecules to generate porphobilinogen; hydroxymethylbilane synthase (or PBG deaminase, ) to polymerise four PBG molecules into preuroporphyrinogen (tetrapyrrole structure); and uroporphyrinogen III synthase (
) to link two pyrrole units together (rings A and D) to yield uroporphyrinogen III.
Uroporphyrinogen III is the first branch point of the pathway. To synthesise cobalamin (vitamin B12), sirohaem, and coenzyme F430, uroporphyrinogen III needs to be converted into precorrin-2 by the action of uroporphyrinogen III methyltransferase (
). To synthesise haem and chlorophyll, uroporphyrinogen III needs to be decarboxylated into coproporphyrinogen III by the action of uroporphyrinogen III decarboxylase (
) [
].Porphobilinogen deaminase (also known as hydroxymethylbilane synthase,
) functions during the second stage of tetrapyrrole biosynthesis. This enzyme catalyses the polymerisation of four PBG molecules into the tetrapyrrole structure, preuroporphyrinogen, with the concomitant release of four molecules of ammonia. This enzyme uses a unique dipyrro-methane cofactor made from two molecules of PBG, which is covalently attached to a cysteine side chain. The tetrapyrrole product is synthesized in an ordered, sequential fashion, by initial attachment of the first pyrrole unit (ring A) to the cofactor, followed by subsequent additions of the remaining pyrrole units (rings B, C, D) to the growing pyrrole chain [
]. The link between the pyrrole ring and the cofactor is broken once all the pyrroles have been added. This enzyme is folded into three distinct domains that enclose a single, large active site that makes use of an aspartic acid as its one essential catalytic residue, acting as a general acid/base during catalysis [,
]. A deficiency of hydroxymethylbilane synthase is implicated in the neuropathic disease, Acute Intermittent Porphyria (AIP) []. A deficiency of hydroxymethylbilane synthase alters vegetative and reproductive development and causes lesions in Arabidopsis [].
This entry includes phosphomevalonate kinase Erg8 from fungi and plants. Budding yeast Erg8 is involved in step 2 of the subpathway that synthesizes isopentenyl diphosphate from (R)-mevalonate [
,
]. Arabidopsis Erg8 (AT1G31910, also known as PMK) is involved in the mevalonic acid pathway [].
ALG1 (Asparagine-linked glycosylation protein 1) proteins participate in the formation of the lipid-linked precursor oligosaccharide for N-glycosylation. They are also involved in assembling the dolichol-pyrophosphate-GlcNAc(2)-Man5 intermediate on the cytoplasmic surface of the ER [
,
].Defects in human ALG1 are the cause of congenital disorder of glycosylation type 1K (CDG1K). CDGs are characterised by under-glycosylated serum proteins. These multisystem disorders present with a wide variety of clinical features, such as disorders of the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. [
,
,
].Glycosylation and growth of Alg1-deficient PRY56 yeast cells, showing a temperature-sensitive phenotype, could be restored by the human wild-type allele [
].
The TATA-box binding protein (TBP) is required for the initiation of transcription by RNA polymerases I, II and III, from promoters with or without a TATA box [
,
]. TBP associates with a host of factors, including the general transcription factors SL1, TFIIA, -B, -D, -E, and -H, to form huge multi-subunit pre-initiation complexes on the core promoter. Through its association with different transcription factors, TBP can initiate transcription from different RNA polymerases. There are several related TBPs, including TBP-like (TBPL) proteins []. TBP binds directly to the TATA box promoter element, where it nucleates polymerase assembly, thus defining the transcription start site.The C-terminal core of TBP (~180 residues) is highly conserved and contains two 77-amino acid repeats that produce a saddle-shaped structure that straddles the DNA; this region binds to the TATA box and interacts with transcription factors and regulatory proteins [
]. By contrast, the N-terminal region varies in both length and sequence.
The TATA-box binding protein (TBP) is required for the initiation of transcription by RNA polymerases I, II and III, from promoters with or without a TATA box [
,
]. The core of TBP (~180 residues) is highly conserved and contains two 77-amino acid repeats that produce a saddle-shaped structure that straddles the DNA; this region binds to the TATA box, and interacts with transcription factors and regulatory proteins []. TBP shares structural similarity with the C-terminal of beta(2)-adaptin, which is one of four subunits that comprise the clathrin adaptor. This structure can also be found in the N terminus of RNase H3. The N terminus of RNase H3 is suggested to be a substrate binding domain [
].
This enzyme, glucose-1-phosphate adenylyltransferase, is also called ADP-glucose pyrophosphorylase. The plant form is an alpha2, beta2 heterodimer, allosterically regulated in plants [
]. Both subunits are homologous and included in this entry. In bacteria, both homomeric forms of GlgC and more active heterodimers of GlgC and GlgD have been described []. This entry describes the GlgC subunit only. This enzyme appears in variants of glycogen synthesis pathways that use ADP-glucose, rather than UDP-glucose as in animals.
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 [
,
].Ribosomal protein L31 is one of the proteins from the large ribosomal subunit. L31 is a protein of 66 to 97 amino-acid residues which has only been found so far in bacteria and in some plant and algal chloroplasts.
This is a family of inositol-pentakisphosphate 2-kinases (also known as inositol 1,3,4,5,6-pentakisphosphate 2-kinase, Ins(1,3,4,5,6)P5 2-kinase) and InsP5 2-kinase). This enzyme phosphorylates Ins(1,3,4,5,6)P5 to form Ins(1,2,3,4,5,6)P6 (also known as InsP6 or phytate). InsP6 is involved in many processes such as mRNA export, nonhomologous end-joining, endocytosis and ion channel regulation [
].
UV radiation resistance protein/autophagy-related protein 14
Type:
Family
Description:
This entry includes Atg14 (autophagy-related protein 14) from budding yeasts, Vps38 from fission yeasts and their homologues, Atg14L/Bakor (beclin-1-associated autophagy-related key regulator) and UVRAG (UV irradiation resistance-associated gene), from animals. Atg14 is a hydrophilic protein with a coiled-coil motif at the N terminus region. Yeast cells with mutant Atg14 are defective not only in autophagy but also in sorting of carboxypeptidase Y (CPY), a vacuolar-soluble hydrolase, to the vacuole [
].Barkor positively regulates autophagy through its interaction with Beclin-1, with decreased levels of autophagosome formation observed when Barkor expression is eliminated [
]. UVRAG is also a Beclin1 binding protein that positively stimulate starvation-induced autophagy [
]. Autophagy mediates the cellular response to nutrient deprivation, protein aggregation, and pathogen invasion in humans, and malfunction of autophagy has been implicated in multiple human diseases including cancer. Class III phosphatidylinositol 3-kinase (PI3-kinase) regulates multiple membrane trafficking. In yeast, two distinct PI3-kinase complexes are known: complex I (Vps34, Vps15, Vps30/Atg6, and Atg14) is involved in autophagy, andcomplex II (Vps34, Vps15, Vps30/Atg6, and Vps38) functions in the vacuolar protein sorting pathway [
]. In mammals, complex II is also involved in autophagy []. The mammalian counterparts of Vps34, Vps15, and Vps30/Atg6 are Vps34, p150, and Beclin 1, respectively, and UV irradiation resistance-associated gene (UVRAG) has been identified as identical to yeast Vps38 [].
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 [,
].This entry is for the ribosomal protein S30.
UreD is a urease accessory protein. Urease hydrolyses urea into ammonia and carbamic acid [
]. UreD is involved in activation of the urease enzyme via the UreD-UreF-UreG-urease complex [] and is required for urease nickel metallocentre assembly []. This entry includes UreH from Helicobacter pylori, which is an orthologue of UreD [].
The proteins in this entry appear to be important in wyosine base formation in a subset of phenylalanine specific tRNAs. It has been proposed that it participates in converting tRNA(Phe)-m(1)G(37) to tRNA(Phe)-yW [
].
Bacterial prolyl-tRNA synthetases and some smaller paralogues, YbaK and ProX, can hydrolyse misacylated Cys-tRNA(Pro) or Ala-tRNA(Pro) [
]. The small bacterial protein Ybak preferentially hydrolyses Cys-tRNA(Pro) and Cys-tRNA(Cys) [,
]. ProX functions in trans to edit the amino acid moiety from incorrectly charged Ala-tRNA(Pro) []. Prolyl-tRNA synthetases main function is to catalyse the attachment of proline to tRNA(Pro) in a two-step reaction: proline is first activated by ATP to form Pro-AMP and then transferred to the acceptor end of tRNA(Pro) [].This entry represents a domain characteristic of Ybak and ProX, that can also be found with other domains in prolyl-tRNA synthetases.
This group of metallopeptidases belong to the MEROPS peptidase family M8 (leishmanolysin family, clan MA(M)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA. Leishmanolysin (
) is an enzyme found in eukaryotes including Leishmania and related parasitic protozoa [
]. The endopeptidase is the most abundant protein on the cell surface during the promastigote stage of the parasite, and is attached to the membrane by a glycosylphosphatidylinositol anchor []. In the amastigote form, the parasite lives in lysosomes of host macrophages, producing a form of the protease that has an acidic pH optimum []. This differs from most other metalloproteases and may be an adaptation to the environment in which the organism survives [].Tris entry also includes proteins from humans and other chordates, including Leishmanolysin-like peptidase or invadolysin [
] and Ciliated left-right organizer metallopeptidase, CIROP). CIROP plays a role in left-right patterning process [].
The jacalin-like mannose-binding lectin domain has a β-prism fold consisting of three 4-stranded β-sheets, with an internal pseudo 3-fold symmetry. Some proteins with this domain stimulate distinct T- and B- cell functions, such as the plant lectin jacalin, which binds to the T-antigen and acts as an agglutinin. The domain can occur in tandem-repeat arrangements with up to six copies, and in architectures combined with a variety of other functional domains. While the family was initially named after an abundant protein found in the jackfruit seed, taxonomic distribution is not restricted to plants. The domain is also found in the salt-stress induced protein from rice and an animal prostatic spermine-binding protein. Proteins containing this domain include:Jacalin, a tetrameric plant seed lectin and agglutinin from Artocarpus heterophyllus (jackfruit), which is specific for galactose [
].Artocarpin, a tetrameric plant seed lectin from A. heterophyllus [
].Lectin MPA, a tetrameric plant seed lectin and agglutinin from Maclura pomifera (Osage orange), [
].Heltuba lectin, a plant seed lectin and agglutinin from Helianthus tuberosus (Jerusalem artichoke) [
].Agglutinin from Calystegia sepium (Hedge bindweed) [
].Griffithsin, an anti-viral lectin from red algae (Griffithsia species) [
].
Rhamnogalacturonate lyase degrades the rhamnogalacturonan I (RG-I) backbone of pectin [
]. This family contains mainly members from plants, but also contains the plant pathogen Erwinia chrysanthemi.
This domain is found in mitochondrial ubiquitin ligase activator of NFKB 1 (MULAN, also known as MUL1) from animals and ubiquitin E3 Ligase SP1/SP2/SPL1/SPL2 from Arabidopsis.MUL1 is a multifunctional E3 ubiquitin ligase anchored in the outer mitochondrial membrane with its RING finger domain facing the cytoplasm. Mul1 functions as a ubiquitin ligase to ubiquitinate molecules such as mitofusin2 (Mfn2), Akt, p53 and ULK1, through its RING finger domain, leading to proteins degradation. Moreover, Mul1 can also act as a small ubiquitin-like modifiers (SUMO) E3 ligase to sumoylate proteins such as dynamin-related protein 1 (Drp1), enhancing protein stabilization [
]. It plays a role in the control of mitochondrial morphology, promotes mitochondrial fragmentation and influences mitochondrial localisation []. When over-expressed in human cells, it activates JNK through MAP3K7/TAK1 and induces caspase-dependent apoptosis []. MUL1 has also been shown to regulate RIG-I mediated antiviral response []. Ubiquitin E3 ligase SP1 associates with TOC (translocon at the outer envelope membrane of chloroplasts) complexes and mediates ubiquitination of TOC components, promoting their degradation. SP1-mediated regulation of chloroplast protein import contributes to the organellar proteome changes that occur during plant development [
]. It is also important for stress tolerance in plants [].
This family consists of several bacterial and plant proteins of around 400 residues in length. One member of this family has been characterised in Pseudomonas citronellolis as AtuA, a member of a gene cluster that is essential for the acyclic terpene utilisation (Atu) pathway [
].
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 [
,
].This entry represents a mitochondrial ribosomal subunit annotated as S27 in yeast and S33 in humans [
,
]. It is a small 106 residue protein. The evolutionary history of the mitoribosomal proteome that is encoded by a diverse subset of eukaryotic genomes, reveals an ancestral ribosome of alpha-proteobacterial descent that more than doubled its protein content in most eukaryotic lineages. Several new MRPs have originated via duplication of existing MRPs as well as by recruitment from outside of the mitoribosomal proteome [].
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 zinc finger appears to be common in activating signal cointegrator 1/thyroid receptor interacting protein 4.
Trm112 is required for tRNA methylation in Saccharomyces cerevisiae (Baker's yeast) and is found in complexes with 2 tRNA methylases (Trm9 and Trm11) also with putative methyltransferase Ydr140w [
]. Trm112 from S. cerevisiae (Ynr046w) is plurifunctional and a component of the eRF1 methyltransferase []. The crystal structure of Ynr046w has been determined to 1.7 A resolution. It comprises a zinc-binding domain built from both the N- and C-terminal sequences and an inserted domain, absent from bacterial and archaeal orthologs of the protein, composed of three α-helices [].Trm112 has also been described in archaea (UPF0434 protein from Haloferax volcanii). UPF0434 proteins are found both in bacteria and archaea, and the study of interacting partners from the H. volcanii member appears to indicate that Trm112 is a general partner for methyltransferases in all organisms [
].This entry also includes mitochondrial protein preY, an uncharacterized protein from vertebrates.
Tyrosine-specific protein phosphatase, PTPase domain
Type:
Domain
Description:
This entry represents the PTPase domain found in several tyrosine-specific protein phosphatases (PTPases).Structurally, all known receptor PTPases, are made up of a variable length extracellular domain, followed by a transmembrane region and a C-terminal catalytic cytoplasmic domain. Some of the receptor PTPases contain fibronectin type III (FN-III) repeats, immunoglobulin-like domains, MAM domains or carbonic anhydrase-like domains in their extracellular region. The cytoplasmic region generally contains two copies of the PTPase domain. The first seems to have enzymatic activity, while the second is inactive. The inactive domains of tandem phosphatases can be divided into two classes. Those which bind phosphorylated tyrosine residues may recruit multi-phosphorylated substrates for the adjacent active domains and are more conserved, while the other class have accumulated several variable amino acid substitutions and have a complete loss of tyrosine binding capability. The second class shows a release of evolutionary constraint for the sites around the catalytic centre, which emphasises a difference in function from the first group. There is a region of higher conservation common to both classes, suggesting a new regulatory centre [
]. PTPase domains consist of about 300 amino acids. There are two conserved cysteines, the second one has been shown to be absolutely required for activity. Furthermore, a number of conserved residues in its immediate vicinity have also been shown to be important.Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;
) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation [
,
]. The PTP superfamily can be divided into four subfamilies []:(1) pTyr-specific phosphatases(2) dual specificity phosphatases (dTyr and dSer/dThr)(3) Cdc25 phosphatases (dTyr and/or dThr)(4) LMW (low molecular weight) phosphatasesBased on their cellular localisation, PTPases are also classified as:Receptor-like, which are transmembrane receptors that contain PTPase domains [
]
Non-receptor (intracellular) PTPases [
]
All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif [
]. Functional diversity between PTPases is endowed by regulatory domains and subunits.
Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;
) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation [
,
]. The PTP superfamily can be divided into four subfamilies []:(1) pTyr-specific phosphatases(2) dual specificity phosphatases (dTyr and dSer/dThr)(3) Cdc25 phosphatases (dTyr and/or dThr)(4) LMW (low molecular weight) phosphatasesBased on their cellular localisation, PTPases are also classified as:Receptor-like, which are transmembrane receptors that contain PTPase domains [
]
Non-receptor (intracellular) PTPases [
]
All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif [
]. Functional diversity between PTPases is endowed by regulatory domains and subunits. This entry represents the PTP-signature motif that characterises the catalytic site, and which encompasses only part of the PTPase domain structure.
Helicobacter pylori is a prevalent bacterial, gastroduodenal pathogen of humans that can express Lewis (Le) and related antigens in the O-chains of its surface lipopolysaccharide. The alpha1,3-fucosyltransferase VI (FUT VI) protein is a key enzyme for synthesis of sialyl Lewis X and Lewis X in epithelial cells [
]. Despite striking functional similarity, there is low sequence homology between the bacterial and mammalian alpha(1,3/4)- and alpha(1,2)-fucosyltransferases. Le antigen expression and fucosylation have multiple biological effects on pathogenesis and disease outcome of H. pylori [
]. The sialyl-Lewis X (SLe(x)) determinant is important in leukocyte extravasation, metastasis and bacterial adhesion []. Changes in enzyme activity and the expression levels of alpha(1,6)fucosyltransferase [alpha(1,6)FT]occur in certain types of malignant transformations. Alpha(1,6)FT activity is higher in tumour tissue than in healthy tissue. Increased alpha(1,6)FT expression is also found in tumour tissues as compared to healthy and transitional tissues, inflammatory lesions and adenomas [
].This group represents an alpha-(1,3)-fucosyltransferase/alpha-(1,4)-fucosyltransferase found in plants.
These sucrose/proton symporters, found in plants, are from the Glycoside-Pentoside-Hexuronide (GPH)/cation symporter family. These proteins are predicted to have 12 transmembrane domains. Members may export sucrose (e.g. SUT1, SUT4) from green parts to the phloem for long-distance transport or import sucrose (e.g SUT2) to sucrose sinks such as the tap root of the carrot [
].
This entry represents the Solute carrier family 40 member 1 (SLC40A) family of proteins, also known as Ferroportin 1 (or simply ferroportin (FPN), the major iron transporter key in cellular and systemic iron levels balance. In mammals, it mediates the absorption of dietary iron by transporting ferrous iron across the basolateral surface of duodenal enterocytes and can also recycle iron from hepatocytes and macrophages. FPN is also involved in iron transfer between maternal and fetal circulation [,
,
]. FPN synthesis is transcriptionally regulated by cellular hypoxia, iron and heme concentrations, and inflammatory signalling, while cell surface FPN is negatively regulated by hepcidin, which, under elevated serum iron levels, it blocks iron transport and induces FPN ubiquitination, internalization, and degradation []. Structural studies in Bdellovibrio bacteriovorous suggest that the putative substrate-binding site is localized deep in the N-terminal domain and demonstrated that Ca facilitates a conformational change critical to the transport cycle []. In humans, mutations in this transporter leads to nonclassical ferroportin disease (FD), a form of hereditary hemochromatosis [].
This entry represents a domain is found in proteins from eukaryotes. It is typically between 140 and 163 amino acids in length. It is found at the C terminus of GPALPP motifs-containing protein 1 (GPAM1).
This entry represents a group of abhydrolase domain-containing proteins, including mammalian ABHD1/2/3/15 and budding yeast Eht1, Eeb1 and YMR210W.Human ABHD3 is a phospholipase that may play a role in phospholipids remodeling. It may selectively cleave myristate (C14)-containing phosphatidylcholines through its predominant phospholipase 1 activity, cleaving preferentially acyl groups in sn1 position [
]. Mouse ABHD2 may play a role in smooth muscle cells migration []. Yeast Eht1 and its paralogue, Eeb1, are Acyl-coenzymeA:ethanol O-acyltransferases involved in medium-chain fatty acid ethyl ester biosynthesis during fermentation [
]. YMR210W does not seem to play an important role in medium-chain fatty acid ethyl ester formation []. This entry also includes bacterial putative esterases, such as yheT from E. coli.
PIN domains are small protein domains identified by the presence of three strictly conserved acidic residues. Apart from these three residues, there is poor sequence conservation [
]. PIN domains are found in eukaryotes, eubacteria and archaea. In eukaryotes they are ribonucleases involved in nonsense mediated mRNA decay [] and in processing of 18S ribosomal RNA []. In prokaryotes, they are the toxic components of toxin-antitoxin (TA) systems, their toxicity arising by virtue of their ribonuclease activity. The PIN domain TA systems are now called VapBC TAs(virulence associated proteins), where VapB is the inhibitor and VapC, the PIN-domain ribonuclease toxin [].
Prokaryotes contain a single DNA-dependent RNA polymerase (RNAP;
) that is responsible for the transcription of all genes, while eukaryotes have three classes of RNAPs (I-III) that transcribe different sets of genes. Each class of RNA polymerase is an assemblage of ten to twelve different polypeptides. Certain subunits of RNAPs, including RPB5 (POLR2E in mammals), are common to all three eukaryotic polymerases. RPB5 plays a role in the transcription activation process. Eukaryotic RPB5 has a bipartite structure consisting of a unique N-terminal region (
), plus a C-terminal region that is structurally homologous to the prokaryotic RPB5 homologue, subunit H (gene rpoH) [
,
,
,
].This entry represents a conserved site of RNA polymerase, subunit H/Rpb5.
Assembly of a robust microtubule-based mitotic spindle is essential for accurate segregation of chromosomes to progeny [
]. Spindle assembly relies on the concerted action of centrosomes, spindle microtubules, molecular motors and non-motor spindle proteins []. A number of novel regulators of spindle assembly have been identified: one of these is HAUS, an 8-subunit protein complex that shares similarity with Drosophila Augmin [,
]. Plants also have a augmin complex consisting of eight subunits. Subunits AUG1 to AUG6 can be aligned with the human HAUS1 to HAUS6 proteins [].HAUS localises to interphase centrosomes and to mitotic spindle micro- tubules; its disruption induces microtubule-dependent fragmentation of centrosomes, and an increase in centrosome size. HAUS disruption results in the destabilisation of kinetochore microtubules and eventual formation of multipolar spindles. Such severe mitotic defects are alleviated by co-depletion of NuMA, indicating that both factors regulate opposing activities. HAUS disruption alters NuMA localisation, suggesting that mis-localised NuMA activity contributes to the observed spindle and centrosome defects. The Augmin complex (HAUS) is thus a critical, evolutionarily conserved multi-subunit protein complex that regulates centrosome and spindle integrity [
].The HAUS (Homologous to AUgmin Subunits) individual subunits have been designated HAUS1 to HAUS8 [
]. HAUS augmin-like complex subunit 1 (also known as enhancer of invasion-cluster, HEI-C [], and coiled-coil domain-containing protein 5) is a coiled-coil protein required for passage through mitosis [].
Rpb8 is a subunit common to the three yeast RNA polymerases, pol I, II and III. Rpb8 interacts with the largest subunit Rpb1, and with Rpb3 and Rpb11, two smaller subunits.
This entry represent LIN37 and related proteins from animals and plants. In humans, LIN37 is a component of the DREAM (MuvB/DRM) complex, which represses cell cycle-dependent genes in quiescent cells and plays a role in the cell cycle-dependent activation of G2/M genes [
,
].
The Cfx genes in Ralstonia eutropha (Alcaligenes eutrophus) encode a number of Calvin cycle enzymes. The observed sizes of two
of the gene products, CfxX and CfxY, are 35kDa and 27kDa respectively []. No functions couldbe assigned to CfxX and CfxY, but CfxQ is required for the expression of rubisco. These proteins show a
high degree of similarity to the Bacillus subtilis stage V sporulation protein K [].
This entry includes SDHF4 from animals, Sdh8 from budding yeasts and some uncharacterised proteins from bacteria. Sdh8 is required for assembly of succinate dehydrogenase (SDH). It interacts with the catalytic Sdh1 subunit in the mitochondrial matrix, facilitating its association with Sdh2 and the subsequent assembly of the SDH holocomplex [
].
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 [
,
].L6 is a protein from the large (50S) subunit. In Escherichia coli, it is located in the aminoacyl-tRNA binding
site of the peptidyltransferase centre, and is known to bind directly to 23S rRNA. It belongs to a family of ribosomal proteins, including L6 from bacteria, cyanelles (structures that perform similar functions to chloroplasts, but have structural and biochemical characteristics of Cyanobacteria) and mitochondria; and L9 from mammals, Drosophila, plants and yeast. L6 contains two domains with almost identical folds, suggesting that is was derived by the duplication of anancient RNA-binding protein gene. Analysis reveals several sites on the protein surface where interactions with other ribosome components may occur, the N terminus being involved in protein-protein interactions and the C terminus containing possible RNA-binding sites [
].
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 [
,
].A number of eukaryotic and archaeabacterial ribosomal proteins can be grouped on the basis of sequence similarities. One of these families includes mammalian ribosomal protein L6 (L6 was previously known as TAX-responsive enhancer element binding protein 107); Caenorhabditis elegans ribosomal protein L6 (R151.3); Saccharomyces cerevisiae (Baker's yeast) ribosomal protein YL16A/YL16B; and Mesembryanthemum crystallinum (Common ice plant) ribosomal protein
YL16-like. These proteins have 175 (yeast) to 287 (mammalian) amino acids.
SUMT, an enzyme of the cobalamin and siroheme biosynthetic pathway, catalyses the transformation of uroporphyrinogen III into precorrin-2. It transfers two methyl groups from S-adenosyl-L-methionine to the C-2 and C-7 atoms of uroporphyrinogen III to yield precorrin-2 via the intermediate formation of precorrin-1. SUMT is the first enzyme committed to the biosynthesis of siroheme or cobalamin (vitamin B12), and precorrin-2 is a common intermediate in the biosynthesis of corrinoids such as vitamin B12, siroheme and coenzyme F430 [,
]. In some organisms, the SUMT domain is fused to the precorrin-2 oxidase/ferrochelatase domain to form siroheme synthase or to uroporphyrinogen-III synthase to form bifunctional uroporphyrinogen-III methylase/uroporphyrinogen-III synthase.
Uroporphiryn-III C-methyltransferase, conserved site
Type:
Conserved_site
Description:
Uroporphyrin-III C-methyltransferase (
)(SUMT) [
,
] catalyses the transfer of two methyl groups from S-adenosyl-L-methionine to the C-2 and C-7 atoms of uroporphyrinogen III to yield precorrin-2 via the intermediate formation of precorrin-1. SUMT is the first enzyme specific to the cobalamin pathway and precorrin-2 is a common intermediate in the biosynthesis of corrinoids such as vitamin B12, siroheme and coenzyme F430.The sequences of SUMT from a variety of eubacterial and archaebacterial species are currently available. In species such as Bacillus megaterium (gene cobA), Pseudomonas denitrificans (cobA) or Methanobacterium ivanovii (gene corA) SUMT is a protein of about 25 to 30 Kd. In Escherichia coli and related bacteria, the cysG protein, which is involved in the biosynthesis of siroheme, is a multifunctional protein composed of a N-terminal domain, probably involved in transforming precorrin-2 into siroheme, and a C-terminal domain which has SUMT activity.The sequence of SUMT is related to that of a number of P. denitrificans and Salmonella typhimurium enzymes involved in the biosynthesis of cobalamin which also seem to be SAM-dependent methyltransferases [
,
]. The similarity is especially strong with two of these enzymes: cobI/cbiL which encodes S-adenosyl-L-methionine--precorrin-2 methyltransferase and cobM/cbiF whose exactfunction is not known.
This entry includes the beta subunit of geranylgeranyl transferase type-2 (GGTase-II), which is also known as Rab geranyl-geranyltransferase subunit beta, Bet2 and Ptb1. GGTase-II catalyses the transfer of a geranyl-geranyl moiety from geranyl-geranyl pyrophosphate to proteins having the C-terminal -XCC or -XCXC [
,
,
]. GGTase-IIs are a subgroup of protein prenyltransferases (PTases) of lipid-modifying enzymes. PTases catalyze the carboxyl-terminal lipidation of Ras, Rab, and several other cellular signal transduction proteins, facilitating membrane associations and specific protein-protein interactions. Prenyltransferases employ a Zn2+ ion to alkylate a thiol group catalyzing the formation of thioether linkages between cysteine residues at or near the C terminus of protein acceptors and the C1 atom of isoprenoid lipids (geranylgeranyl (20-carbon) in the case of GGTase-II). GGTase-II catalyzes alkylation of both cysteine residues in Rab proteins containing carboxy-terminal "CC", "CXCX"or "CXC"motifs. PTases are heterodimeric with both alpha and beta subunits required for catalytic activity. The beta subunit has an alpha 6 - alpha 6 barrel fold. In contrast to other prenyltransferases, GGTas-II requires an escort protein to bring the substrate protein to the catalytic heterodimer and to escort the geryanylgeranylated product to the membrane [
,
].
