This domain is found in phage proteins, such as
from Acinetobacter phage SH-Ab 15497 and
from cyanophage S-2L, which are associated with PurZ, an enzyme that catalyses the synthesis of diaminopurine (Z), a DNA modification that gives phages an advantage for evading host restriction enzymes activity [
]. This domain has dATP and/or dGTP pyrophosphohydrolase activity; it catalyses the hydrolysis of dATP/dGTP to pyrophosphate and dAMP/dGMP, respectively, with little or no activities for NTPs and pyrimidine dNTPs. In SH-Ab 15497, it has both a dATPase and a dGTPase activities, while in S-2L it is only a dGTPase, suggesting some flexibility in the strategy of these phages to incorporate Z instead of A in their genome []. Enzymes containing this domain supply dGMP as the substrate for PurZ, elevating dZTP level to promote Z incorporation [,
].
This family represents the Gsx factors Gsx1 and Gsx2, also known as GSH1/2. These closely related proteins are among the earliest transcription factors expressed in neuronal progenitors of the lateral ganglionic eminence (LGE) in the ventral telencephalon [
,
]. Both Gsx1 and Gsx2 are expressed in the developing MGE (medial ganglionic eminence) and diencephalon [], Gsx2 is expressed at a high level in progenitors of the dorsal LGE (dLGE), whereas Gsx1 is expressed mainly in the MGE and ventral LGE. Gsx1 and Gsx2 control the choice between excitatory and inhibitory cell fates of the interneurons in the developing spinal cord []. It has been shown that these factors are essential for striatal and olfactory bulb neurogenesis []. Gsx1 also activates the transcription of the GHRH gene and also plays an important role in pituitary development [].
Thioesterase (TE) domains often occur integrated in or associated with peptide synthetases which are involved in the non-ribosomal synthesis of peptide antibiotics [
]. Thioesterases are required for the addition of the last amino acid to the peptide antibiotic, thereby forming a cyclic antibiotic. Next to the operons encoding these enzymes, in almost all cases, are genes that encode proteins that have similarity to the type II fatty acid thioesterases of vertebrates.This domain has a crucial role during fungal polyketide synthesis as it is responsible for the release of the finished polyketide intermediate from the polyketide synthase enzyme (PKS). Most TEs from fungal PKSs catalyse product release by intramolecular C-C bond formation but a small number of PKSs have TE domains that catalyze O-C bond formation through macrolactone closure, hydrolysis, and ester or pyrone formation [
].
O-Glycosyl hydrolases (
) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families [
,
]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.Glycoside hydrolase family 4
comprises enzymes with several known activities; 6-phospho-beta-glucosidase (); 6-phospho-alpha-glucosidase (
); alpha-galactosidase (
).
These enzymes require NAD and a divalent ion for their activity and are proteins of about 50kDa; e.g. 6-phospho-alpha-glucosidase requires both NAD(H) and divalent metal (Mn2+, Fe2+, Co2+, or Ni2+) for activity [
]. The signature pattern is located to a conserved region located in the central section. This region does not contain residues directly shown to be important for the catalytic activity.
Receptor-binding cancer-associated surface antigen (RCAS1) and Estrogen receptor-binding fragment-associated gene 9 (EBAG9) proteins are identical. EBAG9/RCAS1 induces apoptosis and suppresses the growth of several cells such as activated T cells [
]. Defects in EBAG9 may be a cause of breast cancers and adenocarcinomas of the lung as it is present and overexpressed in many patients and the expression correlates with tumor grade, suggesting that it may be involved in cancer immune escape. It may not be a directly tumor-associated antigen, but rather contributes indirectly to the antigenicity of tumor cells. The selective suppression phenomenon of the cytotoxic immune response may be brought about by an increase in sRCAS1 blood serum concentration. Such an increase has been observed during cancer progression. RCAS1 blood serum concentration could be useful in the identification of endometriosis [] and prostatic cancer [].
CD8 on thymocytes and thymus-derived T cells consists of disulfide-linked CD8alpha and CD8 beta chains, which are transmembrane proteins containing N-terminal Ig domains, extended and glycosylated hinge and stalk regions and transmembrane and cytoplasmic portions [
]. CD8alphabeta plays important roles in thymic selection, CD8 T-cell differentiation, and antigen recognition []. CD8 also can be expressed as a CD8alphaalpha homodimer. Both CD8alphaalpha and CD8alphabeta bind similarly to MHC class I molecules. However, CD8alphabeta, but not CD8alphaalpha, associates with TCR/CD3, strengthens pMHC binding, and promotes CD8 association with lipid rafts and p56lck (lymphocyte-specific tyrosine kinase, lck) and hence TCR signaling via lck-mediated phosphorylation of CD3 ITAMs []. This entry represents CD8 beta. Disruption of the CD8 beta gene or deletion of the cytoplasmic tail of CD8 beta results in severe reduction of positive selection of CD8 T cells [
,
].
The Ccr4-Not complex is a global regulator of gene expression that is conserved from yeast to human. It affects genes positively and negatively and is thought to regulate transcription factor IID function. In Saccharomyces cerevisiae, it exists in two prominent forms and consists of at least nine core subunits: the five Not proteins (Not1 to Not5), Caf1, Caf40, Caf130 and Ccr4 [
]. The Ccr4-Not complex regulates many different cellular functions, including RNA degradation and transcription initiation. It may be a regulatory platform that senses nutrient levels and stress []. Caf1 and Ccr4, are directly involved in mRNA deadenylation, and Caf1p is associated with Dhh1, a putative RNA helicase thought to be a component of the decapping complex []. Pop2, a component of the Ccr4-Not complex, functions as a deadenylase [].This entry represents a domain of unknown function found in the Not1 subunit of the CCR4-Not complex.
Aminotransferases share certain mechanistic features with other pyridoxal-phosphate dependent enzymes, such as the covalent binding of the pyridoxal-phosphate group to a lysine residue. On the basis of sequence similarity, these various enzymes can be grouped [
] into subfamilies.One of these, called class-IV, currently consists of proteins of about 270 to 415 amino-acid residues that share a few regions of sequence similarity. Surprisingly, the best conserved region does not include the lysine residue to which the pyridoxal-phosphate group is known to be attached, in ilvE, but is located some 40 residues at the C terminus side of the PlP-lysine.Among the class IV aminotransferases are two phylogenetically separable groups of branched-chain amino acid aminotransferase (IlvE) (
). The last common ancestor of the two lineages appears also to have given rise to a family of D-amino acid aminotransferases (DAAT). This model represents the IlvE family more strongly similar to the DAAT family.
The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([intenz:2.4.1.-]) and related proteins into distinct sequence based families has been described [
]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.Glycosyltransferase family 28
comprises enzymes with a number of known activities; 1,2-diacylglycerol 3-beta-galactosyltransferase (
); 1,2-diacylglycerol 3-beta-glucosyltransferase (
); beta-N-acetylglucosamine transferase (
).
Structural analysis suggests the C-terminal domain contains the UDP-GlcNAc binding site.
Glucose-6-phosphate dehydrogenase (
) (G6PDH) is a ubiquitous protein, present in bacteria and all eukaryotic cell types [
]. The enzyme catalyses the the first step in the pentose pathway, i.e. the conversion of glucose-6-phosphate to gluconolactone 6-phosphate in the presence of NADP, producing NADPH. The ubiquitous expression of the enzyme gives it a major role in the production of NADPH for the many NADPH-mediated reductive processes in all cells, and is critical for NADPH homeostasis and redox regulation []. Deficiency of G6PDH is a common genetic abnormality affecting millions of people worldwide. Many sequence variants, most caused by single point mutations, are known, exhibiting a wide variety of phenotypes with the distinctive one being chronic and drug- or food-induced hemolytic anemia, attributed to the inability to produce NADPH and withstand harmful oxidants in erythrocyte cells [,
].This entry represents the NAD-binding domain of glucose-6-phosphate dehydrogenase.
Monoamine oxidases (MAO) A and B are encoded by two genes derived from a common ancestral gene [
]. The enzymes catalyse the oxidative deamination of biogenic and xenobiotic amines and have important roles in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues []. MAO-A preferentially oxidises biogenic amines such as 5-hydroxytryptamine, norepinephrine and epinephrine. MAO-A deficiency has been linked to Brunner's syndrome, a form of X-linked nondysmorphic mild mental retardation [].The protein contains two similarly-sized subunits, one of which contains covalently-bound flavin adenine dinucleotide (FAD). The FAD binding site lies near the C terminus; at the N terminus are features characteristic of the ADP-binding fold, suggesting that this region is also involved in FAD binding [
]. The A and B forms of the enzyme share 70% sequence identity; both contain the pentapeptide Ser-Gly-Gly-Cys-Tyr, the cysteine of which binds FAD [].
This superfamily represents a structural domain found in glycoside hydrolase families 38 (
, e.g. alpha-mannosidase) [
].O-Glycosyl hydrolases (
) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families [
,
]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.Glycoside hydrolase family 38
comprises enzymes with only one known activity; alpha-mannosidase (
) (
).
Lysosomal alpha-mannosidase is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover. The enzyme catalyses the hydrolysis of terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides, and can cleave all known types of alpha-mannosidic linkages. Defects in the gene cause lysosomal alpha-mannosidosis (AM), a lysosomal storage disease characterised by the accumulation of unbranched oligo-saccharide chains.
GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. The GST fold contains an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain [,
]. Class Zeta GSTs, also known as maleylacetoacetate (MAA) isomerases, catalyze the isomerization of MAA to fumarylacetoacetate, the penultimate step in tyrosine/phenylalanine catabolism, using GSH as a cofactor [
,
]. They show little GSH-conjugating activity towards traditional GST substrates, but display modest GSH peroxidase activity []. They are also implicated in the detoxification of the carcinogen dichloroacetic acid by catalyzing its dechlorination to glyoxylic acid [].
AP endonucleases can be classified into two families based on sequence similarity. This family contains members of AP endonuclease family 1. They are endonucleases that remove the damaged DNA at cytosines and guanines by cleaving on the 3'-side of the AP site by a beta-elimination reaction [
], []. The proteins contain glutamate which has been shown [] in the Escherichia coli enzyme to bind a divalent metal ion such as magnesium or manganese.DNA damaging agents such as the anti-tumour drugs bleomycin and neocarzinostatin or those that generate oxygen radicals produce a variety of lesions in DNA. Amongst these is base-loss which forms apurinic/apyrimidinic (AP) sites or strand breaks with atypical 3' termini. DNA repair at the AP sites is initiated by specific endonuclease cleavage of the phosphodiester backbone. Such endonucleases are also generally capable of removing blocking groups from the 3' terminus of DNA strand breaks.
Homing endonucleases are rare-cutting enzymes encoded by inteins and introns. They are found inserted within host genes in eukaryotes, bacteria, archaebacteria and viruses [
]. By making a site-specific double-strand break in the intronless or inteinless alleles, these nucleases create recombinogenic ends which engage in a gene conversion process that duplicates the intron or intein [,
]. There are four families of homing endonucleases classified by the conserved sequence motifs LAGLIDADG, GIY-YIG, H-N-H and His-Cys box [,
]. Endonucleases of the DOD family contain one or two copies of the 10-residue sequence known as a dodecapeptide or LAGLIDADG motif. LAGLIDADG endonucleases are either monomers, such as I-SceI, that are composed of two pseudo symmetric subdomains, or homodimers, such as I-CreI. In both cases, the LAGLIDADG endonuclease folds into a β-saddle architecture, a common motif for nucleic acid binding proteins [].This superfamily represents the homing endonuclease domain.
Acylphosphatase (
) is an enzyme of approximately 98 amino acid residues that specifically catalyses the hydrolysis of the carboxyl-phosphate bond of acylphosphates [
], its substrates including 1,3-diphosphoglycerate and carbamyl phosphate []. The enzyme has a mainly β-sheet structure with 2 short α-helical segments. It is distributed in a tissue-specific manner in a wide variety of species, although its physiological role is as yet unknown []: it may, however, play a part in the regulation of the glycolytic pathway and pyrimidine biosynthesis []. There are two known isozymes. One seems to be specific to muscular tissues, the other, called 'organ-common type', is found in many different tissues. A number of bacterial and archebacterial hypothetical proteins are highly similar to that enzyme and that probably possess the same activity. An acylphosphatase-like domain is also found in some prokaryotic hydrogenase maturation HypF carbamoyltransferases [
,
].
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) [].
NAD+ synthase (
) catalyzes the last step in the biosynthesis of nicotinamide adenine dinucleotide and is induced by stress factors such as heat shock and glucose limitation. The three-dimensional structure of NH3-dependent NAD+ synthetase from Bacillus subtilis, in its free form and in complex with ATP shows that the enzyme consists of a tight homodimer with alpha/beta subunit topology [
].This domain is also found in guanosine 5'-monophosphate (GMP) synthetase. GMP synthase catalyses the synthesis of GMP from XMP. The protein is a homodimer, but in some archaea it is a heterodimer composed of a glutamine amidotransferase subunit and a ATP pyrophosphatase subunit. In eucaryotes, bacteria, and some archaea the two catalytic units are encoded by a single gene, producing a two-domain-type GMP, with a GATase domain in the N-terminal half and a ATP-PPase domain in the C-terminal half. This entry represents the ATP pyrophosphatase domain.
Proliferating cell nuclear antigen, PCNA, conserved site
Type:
Conserved_site
Description:
Proliferating cell nuclear antigen (PCNA), or cyclin, is a non-histone acidic nuclear protein [
] that plays a key role in the control of eukaryotic DNA replication []. It acts as a co-factor for DNA polymerase delta, which is responsible for leading strand DNAreplication [
]. The sequence of PCNA is well conserved between plants and animals, indicating a strong selective pressure for structure conservation, and suggesting that this type of DNA replication mechanism is conserved throughout eukaryotes []. In Saccharomyces cerevisiae (Baker's yeast), POL30, is associated with polymerase III, the yeast analog of polymerase delta.Homologues of PCNA have also been identified in the archaea (known as DNA polymerase sliding clamp) [
,
] and in Paramecium bursaria Chlorella virus 1 (PBCV-1) and in nuclear polyhedrosis viruses. This entry represents two conserved regions located in the N-terminal section. The second one has been proposed to bind DNA.
The beta subunit of archaeal and eukaryotic translation initiation factor 2 (IF2beta) and the N-terminal domain of translation initiation factor 5 (IF5) show significant sequence homology [
]. Archaeal IF2beta contains two independent structural domains: an N-terminal mixed alpha/beta core domain (topological similarity to the common core of ribosomal proteins L23 and L15e), and a C-terminal domain consisting of a zinc-binding C4 finger []. Archaeal IF2beta is a ribosome-dependent GTPase that stimulates the binding of initiator Met-tRNA(i)(Met) to the ribosomes, even in the absence of other factors []. The C-terminal domain of eukaryotic IF5 is involved in the formation of the multi-factor complex (MFC), an important intermediate for the 43S pre-initiation complex assembly []. IF5 interacts directly with IF1, IF2beta and IF3c, which together with IF2-bound Met-tRNA(i)(Met) form the MFC.This entry represents the zinc-binding C4 domain with a zinc-bound β-ribbon motif, which is found in IF2beta and IF5 [
].
The beta subunit of archaeal and eukaryotic translation initiation factor 2 (IF2beta) and the N-terminal domain of translation initiation factor 5 (IF5) show significant sequence homology [
]. Archaeal IF2beta contains two independent structural domains: an N-terminal mixed alpha/beta core domain (topological similarity to the common core of ribosomal proteins L23 and L15e), and a C-terminal domain consisting of a zinc-binding C4 finger []. Archaeal IF2beta is a ribosome-dependent GTPase that stimulates the binding of initiator Met-tRNA(i)(Met) to the ribosomes, even in the absence of other factors []. The C-terminal domain of eukaryotic IF5 is involved in the formation of the multi-factor complex (MFC), an important intermediate for the 43S pre-initiation complex assembly. IF5 interacts directly with IF1, IF2beta and IF3c, which together with IF2-bound Met-tRNA(i)(Met) form the MFC [].This entry represents both the N-terminal and zinc-binding domains of IF2, as well as a domain in IF5.
tRNA His molecules are unusual in having an extra 5' GMP residue (G(-1)) that, in eukaryotes, is added after transcription and RNase P cleavage. Incorporation of this G(-1) residue is a rare example of nucleotide addition occurring at an RNA 5' end in a normal phosphodiester linkage. In Saccharomyces cerevisiae, YGR024c (Thg1p) protein is responsible for this guanylyltransferase reaction [
]. It catalyses the guanylyltransferase step of G(-1) addition using a ppp-tRNA His substrate, and appears to catalyse the activation step using p-tRNA His and ATP. Thus, it catalyses phosphodiester bond formation at the 5' end of RNAs, formally in a 3'-5' direction []. Thg1 has also been shown to interact with the origin recognition complex and to be required for the G2/M phase transition [
], and to have polymerase activity []. The polymerase activity has been proposed to be the ancestral activity of this enzyme [].
RNA polymerase II, heptapeptide repeat, eukaryotic
Type:
Repeat
Description:
RNA polymerase II (
) [
,
] is one of the three forms of RNA polymerase that exist in eukaryotic nuclei. The C-terminal region of the largest subunit of this oligomeric enzyme consists of the tandem repeat of a conserved heptapeptide []. The number of repeats varies according to the species (for example there are 17 in Plasmodium, 26 in yeast, 44 in Drosophila, and 52 in mammals). The region containing these repeats is essential for the function of polymerase II. This repeated heptapeptide(called CT7n or CTD) is rich in hydroxyl groups. It probably projects out of the globular catalytic domain and may interact with the acidic activator domains of transcriptional regulatory proteins. It is also known to bind by intercalation to DNA. RNA polymerase II is activated by phosphorylation. The serine and threonine residues in the CT7n repeats are the target of such phosphorylation.
This entry represents 3-oxoacyl-[ACP] reductase, also called 3-ketoacyl-acyl carrier protein reductase, an enzyme of fatty acid biosynthesis found in many plant and bacterial species. This enzyme is involved in type II fatty acid biosynthesis, where the individual metabolic transformations are carried out by different enzymes rather than by a single enzyme as occurs in type I fatty acid biosynthesis []. This family includes Sinorhizobium meliloti NodG, which has been shown to be a 3-oxoacyl-ACP reductase and can play a role in fatty acid synthesis [].Structural studies show that the enzyme is a tetramer which forms a typical Rossman fold [
,
]. Unlike other members of the short-chain dehydrogenase/reductase superfamily, the enzyme undergoes a marked conformational change upon binding of the NADP(H)cofactor. This conformational change aligns the side chains of the catalytic triad at the active site in an active conformation and increases the affinity of the enzyme for its substrate.
Glutamyl-tRNA(Gln) amidotransferase, subunit B, conserved site
Type:
Conserved_site
Description:
Glutamyl-tRNA(Gln) amidotransferase (Gat; [intenz:EC 6.3.5]) provides a means of producing correctly charged Gln-tRNA(Gln) through the transamidation of mis-acylated Glu-tRNA(Gln) in organisms which lack glutaminyl-tRNA synthetase []. The reaction takes place in the presence of glutamine and ATP through an activated gamma-phospho-Glu-tRNA(Gln). The enzyme is composed of three subunits: A (an amidase), B and C. It also exists in eukaryotes as a protein targeted to the mitochondria.The heterotrimer GatABC is involved in converting Glu to Gln and/or Asp to Asn, when the amino acid is attached to the appropriate tRNA. In Lactobacillus, GatABC is responsible for producing tRNA(Gln). In Archaea, GatABC is responsible for producing tRNA(Asn), while GatDE is responsible for producing tRNA(Gln). In lineages that include Thermus, Chlamydia, or Acidithiobacillus, the GatABC complex catalyses both tRNA(Gln) and tRNA(Asn).This entry represents a conserved region located in the N-terminal of the B subunit of glutamyl-tRNA(Gln) amidotransferase.
Aspartyl/glutamyl-tRNA(Asn/Gln) amidotransferase, B subunit
Type:
Family
Description:
Aspartyl/glutamyl-tRNA(Asn/Gln) amidotransferase ([intenz:6.3.5.-]) allows the formation of correctly charged Asn-tRNA(Asn) or Gln-tRNA(Gln) through the transamidation of misacylated Asp-tRNA(Asn) or Glu-tRNA(Gln) in organisms which lack either or both of asparaginyl-tRNA or glutaminyl-tRNA synthetases. The reaction takes place in the presence of glutamine and ATP through an activated phospho-Asp-tRNA(Asn) or phospho-Glu-tRNA(Gln) []. The enzyme is composed of three subunits: A (an amidase), B and C. It also exists in eukaryotes as a protein targeted to the mitochondria.The heterotrimer GatABC is involved in converting Glu to Gln and/or Asp to Asn, when the amino acid is attached to the appropriate tRNA. In Lactobacillus, GatABC is responsible for producing tRNA(Gln). In Archaea, GatABC is responsible for producing tRNA(Asn), while GatDE is responsible for producing tRNA(Gln). In lineages that include Thermus, Chlamydia, or Acidithiobacillus, the GatABC complex catalyses both tRNA(Gln) and tRNA(Asn).This entry represents the B subunit of aspartyl/glutamyl-tRNA(Asn/Gln) amidotransferase.
The many different actin cross-linking proteins share a common architecture, consisting of a globular actin-binding domain and an extended rod. Whereas their actin-binding domains consist of two calponin homology domains (see
), their rods fall into three families.
The rod domain of the family including the Dictyostelium discoideum (Slime mould) gelation factor (ABP120) and human filamin (ABP280). It is constructed from tandem repeats of a 100-residue motif that is glycine and proline rich [
]. The gelation factor's rod contains 6 copies of the repeat, whereas filamin has a rod constructed from 24 repeats. The resolution of the 3D structure of rod repeats from the gelation factor has shown that they consist of a β-sandwich, formed by two β-sheets arranged in an immunoglobulin-like fold [,
]. The repeat structure is common to the members of the gelation factor/filamin family.This entry represents the entire filamin/ABP280 repeat.
Certain aminoacyl-tRNA synthetases prevent potential errors in protein synthesis through deacylation of mischarged tRNAs. The close homologues isoleucyl-tRNA synthetase (IleRS) and valyl-tRNA synthetase (ValRS) deacylate Val-tRNAIle and Thr-tRNAVal, respectively. These reactions strictly require the presence of the cognate tRNA. In the absence of tRNA, the enzymatically generated misactivated adenylates remain in the active site, sequestered from hydrolysis. Upon addition of cognate tRNA the misactivated amino acids are hydrolysed, regenerating the free tRNA and amino acid, while converting 1 equivalent of ATP to AMP. A prominent mechanism for editing misactivated amino acids is the rapid hydrolysis of transiently mischarged tRNA. This reaction is catalysed at a second active site on IleRS and ValRS. This site is located within a large insertion (termed CP1) into the canonical class I aminoacyl-tRNA synthetase active-site fold [
,
]. The CP1 domain as an isolated polypeptide hydrolyses its cognate mischarged tRNA [].
Sequences containing this domain belong to the terpene synthase family [
]. It has been suggested that this gene family be designated tps (for terpene synthase). Sequence comparisons reveal similarities between the monoterpene (C10) synthases, sesquiterpene (C
15) synthases and the diterpene (C
20) synthases. It has been split into six subgroups on the basis of phylogeny, called Tpsa-Tpsf [
].Tpsa includes vetispiradiene synthase
, 5-epi- aristolochene synthase,
and (+)-delta-cadinene synthase
.
Tpsb includes (-)-limonene synthase,
.
Tpsc includes copalyl diphosphate synthase (kaurene synthase A),
.
Tpsd includes taxadiene synthase,
, pinene synthase,
and myrcene synthase,
.
Tpse includes ent-kaurene synthase B
.
Tpsf includes linalool synthase
.
In the fungus Phaeosphaeria sp. (strain L487) the synthesis of ent-kaurene from geranylgeranyl diphosphate is promoted by a single bifunctional protein [
].This domain is involved in the cyclization of linear terpenes [
,
,
,
,
,
].
The misato protein contains three distinct, conserved domains, segments I, II and III and is involved in the regulation of mitochondrial distribution and morphology [
]. This entry represents misato segment II.Segments I and III are common to tubulins (
), but segment II aligns with myosin heavy chain sequences from Drosophila melanogaster (Fruit fly,
), rabbit (
), and human.
Segment II of misato is a major contributor to its greater length compared with the various tubulins. The most significant sequence similarities to this 54-amino acid region are from a motif found in the heavy chains of myosins from different organisms. A comparison of segment II with the vertebrate myosin heavy chains reveals that it shares homology with a myosin peptide in the hinge region linking the S2 and LMM domains. Segment II also contains heptad repeats which are characteristic of the myosin tail α-helical coiled-coils [
].
This family contains both lactate and malate dehydrogenases. Malate dehydrogenases catalyse the interconversion of malate to oxaloacetate. The enzyme participates in the citric acid cycle.L-lactate dehydrogenase (
) (LDH) [
] catalyses the reversible NAD-dependent interconversion of pyruvate to L-lactate. In vertebrate muscles and in lactic acid bacteria it represents the final step in anaerobic glycolysis. This tetrameric enzyme is present in prokaryotic and eukaryotic organisms. In vertebrates there are three isozymes of LDH: the M form (LDH-A), found predominantly in muscle tissues; the H form (LDH-B), found in heart muscle and the X form (LDH-C), found only in the spermatozoa of mammals and birds. In birds and crocodilian eye lenses, LDH-B serves as a structural protein and is known as epsilon-crystallin [].L-2-hydroxyisocaproate dehydrogenase (
) (L-hicDH) [
] catalyses the reversible and stereospecific interconversion between 2-ketocarboxylic acids and L-2-hydroxy-carboxylic acids. L-hicDH is evolutionary related to LDH's.
O-Glycosyl hydrolases (
) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families [
,
]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.Glycoside hydrolase family 3
comprises enzymes with a number of known activities; beta-glucosidase (
); beta-xylosidase (
); N-acetyl beta-glucosaminidase (
); glucan
beta-1,3-glucosidase (); cellodextrinase (
); exo-1,3-1,4-glucanase (
).
These enzymes are two-domain globular proteins that are N-glycosylated at three sites []. This domain is oftenN-terminal to the glycoside hydrolase family 3, C-terminal domain
.
The signature pattern in these enzymes is centred on a conserved aspartic acid residue which has been shown [
], in Aspergillus wentii beta-glucosidase A3, to be implicated in the catalytic mechanism.
Aspartate carbamoyltransferase (ATCase) catalyses the formation of
carbamoyl-aspartate in the pyrimidine biosynthesis pathway, by the association of aspartate and carbamoyl-phosphate. This is the commitment
step in the Escherichia coli pathway and is regulated by feedback inhibition by CTP, the final product of the pathway [
].The structural organisation of the ATCase protein varies considerably
between different organisms. In bacteria such as E. coli, Salmonella typhimurium andSerratia marcescens, the ATCase is a dodecamer of 2 catalytic (c) trimers
and 3 regulatory (r) dimers. The catalytic domains are coded for by thepyrB gene [
], and the regulatory domains by pyrI []. In Gram-positive bacteriasuch as Bacillus subtilis, ATCase exists as a trimer of catalytic subunits, but
unlike in E. coli, it neither contains nor binds to regulatory subunits. Ineukaryotes, ATCase is found as a single domain in a multifunctional enzyme
that contains activity for glutamine amidotransferase, carbamoylphosphatesynthetase, dihydroorotase, and aspartate carbamoyltransferase.
Porins are found in the outer membranes of Gram-negative bacteria,
mitochondria and chloroplasts, where they form ion-selective channels forsmall hydrophilic molecules (up to ~600 D) [
,
]. X-ray structureanalyses of several bacterial porins [
,
,
] have revealed a large 16-strandedanti-parallel β-barrel structure enclosing the transmembrane pore, by
contrast with all other integral membrane proteins described to date,which are α-helical. Three subunits form a trimer; the 3-fold axis is
approximately parallel to the barrel axes and is assumed to beperpendicular to the membrane plane.
From the range of porins now known, similarities have been observed between
porins from different species, and between porins of different specificitywithin the same species. But most porins cannot be related to each other on
the basis of sequence alone, and this is reflected in the lengths of theknown porin sequences, which range from 282-483 residues/monomer.This superfamily represents the structural domain found in porins.
This entry represents the β-propeller domain found at the N-terminal of prolyl oligopeptidase from the MEROPS peptidase family S9A. The prolyl oligopeptidase family consist of a number of evolutionary related peptidases whose catalytic activity seems to be provided by a charge relay system similar to that of the trypsin family of serine proteases, but which evolved by independent convergent evolution. The N-terminal domain of prolyl oligopeptidases form an unusual 7-bladed β-propeller consisting of seven 4-stranded β-sheet motifs.Prolyl oligopeptidase is a large cytosolic enzyme involved in the maturation and degradation of peptide hormones and neuropeptides, which relate to the induction of amnesia. The enzyme contains a peptidase domain, where its catalytic triad (Ser554, His680, Asp641) is covered by the central tunnel of the N-terminal β-propeller domain. In this way, large structured peptides are excluded from the active site, thereby protecting larger peptides and proteins from proteolysis in the cytosol [
].
This conserved region is found in four-carbon acid sugar kinases from a range of Proteobacteria as well as the Gram-positive Oceanobacillus iheyensis. These four-carbon acid sugar kinases are composed of two domains: an N-terminal domain and a C-terminal domain connected by a variable linker sequence. The N-terminal domain exhibits an α/β-fold composed of an eight-stranded parallel β-sheet. The C-terminal domain also exhibits an α/β-fold composed of a seven-stranded mixed β-sheet. The acid sugar is bound by the N-terminal domain, while nucleotide by the C-terminal domain [
].Proteins containing this domain include D-threonate kinase from Salmonella typhimurium (DtnK), 3-oxo-tetronate kinase from Methylobacterium radiotolerans, 3-oxo-isoapionate kinase from Paraburkholderia graminis and D-erythronate kinase from Heliobacterium modesticaldum. DtnK catalyzes the ATP-dependent phosphorylation of D-threonate to D-threonate 4-phosphate and is also able to phosphorylate 4-hydroxy-L-threonine, which may serve to deal with the toxicity of this compound [
,
].
The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([intenz:2.4.1.-]) and related proteins into distinct sequence based families has been described []. This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.This domain is found in a diverse family of glycosyl transferases that transfer the sugar from UDP-glucose, UDP-N-acetyl-galactosamine, GDP-mannose or CDP-abequose, to a range of substrates including cellulose, dolichol phosphate and teichoic acids [
].
Porins are found in the outer membranes of Gram-negative bacteria,
mitochondria and chloroplasts, where they form ion-selective channels forsmall hydrophilic molecules (up to ~600 D) [
,
]. X-ray structure analysesof several bacterial porins [
,
,
] have revealed a 16-stranded anti-parallelβ-barrel structure enclosing the transmembrane pore, by contrast with
all other integral membrane proteins described to date, which are α-helical. Three subunits form a trimer; the 3-fold axis is approximatelyparallel to the barrel axes and is assumed to be perpendicular to the
membrane plane.From the range of porins now known, similarities have been observed between
porins from different species, and between porins of different specificitywithin the same species. But most porins cannot be related to each other on
the basis of sequence alone, and this is reflected in the lengths of theknown porin sequences, which range from 282-483 residues/monomer.This entry is specific for porins in the gammaproteobacteria.
Porins are found in the outer membranes of Gram-negative bacteria,
mitochondria and chloroplasts, where they form ion-selective channels forsmall hydrophilic molecules (up to ~600 D) [
,
]. X-ray structureanalyses of several bacterial porins [
,
,
] have revealed a large 16-strandedanti-parallel β-barrel structure enclosing the transmembrane pore, by
contrast with all other integral membrane proteins described to date,which are α-helical. Three subunits form a trimer; the 3-fold axis is
approximately parallel to the barrel axes and is assumed to beperpendicular to the membrane plane.
From the range of porins now known, similarities have been observed between
porins from different species, and between porins of different specificitywithin the same species. But most porins cannot be related to each other on
the basis of sequence alone, and this is reflected in the lengths of theknown porin sequences, which range from 282-483 residues/monomer.This entry represents porins from Gram-negative bacteria.
The Trp repressor (TrpR) binds to at least five operators in the Escherichia coli genome, repressing gene expression. The operators at which it binds vary considerably in DNA sequence and location within the promoter; when bound to the Trp operon it recognises the sequence 5'-ACTAGT-3' and acts to prevent the initiation of transcription. The TrpR controls the trpEDCBA (trpO) operon and the genes for trpR, aroH, mtr and aroL, which are involved in the biosynthesis and uptake of the amino acid tryptophan [
]. The repressor binds to the operators only in the presence of L-tryptophan, thereby controlling the intracellular level of its effector; the complex also regulates Trp repressor biosynthesis by binding to its own regulatory region. TrpR acts as a dimer that is composed of identical 6-helical subunits, where four of the helices form the core of the protein and intertwine with the corresponding helices from the other subunit.
The aquaporins (AQPs) are a family of integral membrane proteins composed of two subfamilies: the orthodox aquaporins, which transport only water, and the aquaglyceroporins, which transport glycerol, urea, or other small solutes [
]. AQP1 in pleural mesothelial cells participate in the formation of pleural fluid [], renal AQP2 is involved in levels of solutes [] and changes in AQP9 in the hippocampus are related to delayed neuronal death []. Aquaporins contain two tandem repeats, each containing three membrane-spanning domains and a pore-forming loop with the signature motif Asn-Pro-Ala (NPA).Aquaporin-11 (AQP11) and aquaporin-12 belong to a new aquaporin subfamily termed superaquaporins [
]. AQP11 is found in the endoplasmic reticulum and has been connected to policystic kidney disease through knock-out experiments []. It has also been shown that although the characteristic NPA motif may not be fully conserved in both tandem repeats, the molecule nevertheless preserves its water-transport function [].
TNF receptor-associated factor 4 (TRAF4) is an adapter protein and signal transducer that links members of the tumor necrosis factor receptor (TNFR) family to different signaling pathways. TRAF4 plays a role in the activation of NF-kappa-B and JNK, and in the regulation of cell survival and apoptosis. It regulates activation of NF-kappa-B in response to signaling through Toll-like receptors. TRAF4 modulates TRAF6 functions [
,
,
,
,
,
]. In mouse, it has been shown to be required for normal skeleton development, and for normal development of the respiratory tract []. TRAF4 contains a RING finger domain, seven zinc finger domains, and a TRAF domain.The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors [
,
].
This superfamily represents the N-terminal domain of HprK (HPr kinase/phosphorylase) and domains similar to it, such as the DRTGG domain.HprK is the sensor in a multicomponent phosphorelay system in control of carbon catabolic repression in bacteria [
]. It is unusual in that it recognises the tertiary structure of its target and is a member of a novel family unrelated to any previously described protein phosphorylating enzymes []. X-ray analysis of the full-length crystalline enzyme from Staphylococcus xylosus at a resolution of 1.95 A shows the enzyme to consist of two clearly separated domains that are assembled in a hexameric structure resembling a three-bladed propeller. The blades are formed by two N-terminal domains each, and the compact central hub assembles the C-terminal kinase domains [
]. The DRTGG domain can be found in phosphate acetyltransferases, which catalyse the reversible interconversion of acetyl-CoA and acetyl phosphate [
].
CoA-transferases are found in organisms from all kingdoms of life. They catalyse reversible transfer reactions of coenzyme A groups from CoA-thioesters to free acids. There are at least three families of CoA-transferases, which differ in sequence and reaction mechanism:Family I consists of CoA-transferases for 3-oxoacids (
,
), short-chain fatty acids (
,
) and glutaconate (
). Most use succinyl-CoA or acetyl-CoA as CoA donors.
Family II consists of the homodimeric alpha-subunits of citrate lyase and citramalate lyase (
,
). These enzymes catalyse the transfer of acyl carrier protein (ACP) with a covalently bound CoA derivative, but can accept free CoA thioesters as well.Family III consists of formyl-CoA:oxalate CoA-transferase [
], succinyl-CoA:(R)-benzylsuccinate CoA-transferase [], (E)-cinnamoyl-CoA:(R)-phenyllactate CoA-transferase [], succinyl-CoA:mesaconate CoA-transferase [] and butyrobetainyl-CoA:(R)-carnitine CoA-transferase []. These CoA-transferases occur in prokaryotes and eukaryotes, and catalyse CoA-transfer reactions in a highly substrate- and stereo-specific manner [].This entry represents family III CoA-transferases.
CpdB is a bacterial periplasmic protein with an N-terminal metallophosphatase domain and a C-terminal 3'-nucleotidase domain. This entry represents the N-terminal metallophosphatase domain, which has 2',3'-cyclic phosphodiesterase activity, hydrolyzing the 2',3'-cyclic phosphates of adenosine, guanosine, cytosine and uridine to yield nucleoside and phosphate. CpdB also hydrolyzes the chromogenic substrates p-nitrophenyl phosphate (PNPP), bis(PNPP) and p-nitrophenyl phosphorylcholine (NPPC). CpdB is thought to play a scavenging role during RNA hydrolysis by converting the non-transportable nucleotides produced by RNaseI to nucleosides which can easily enter a cell for use as a carbon source [
,
]. This family also includes YfkN, a Bacillus subtilis nucleotide phosphoesterase with two copies of each of the metallophosphatase and 3'-nucleotidase domains []. The N-terminal metallophosphatase domain belongs to a large superfamily of distantly related metallophosphatases (MPPs) that includes: Mre11/SbcD-like exonucleases, Dbr1-like RNA lariat debranching enzymes, YfcE-like phosphodiesterases, purple acid phosphatases (PAPs), YbbF-like UDP-2,3-diacylglucosamine hydrolases, and acid sphingomyelinases (ASMases).
Nuclear receptor coactivator 1 (NCOA1, also known as SRC-1) belongs to the SRC/p160 nuclear receptor coactivator family, which contains proteins that are ligand-dependent transcription factors [
]. These receptors can function as molecular switches [].NCOA1 directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion [
]. It is involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs) []. It is also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors [,
,
]. It plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors []. It can be regulated by sumoylation and ubiquitination []. This entry represents the N-terminal basic helix-loop-helix (bHLH) domain of NCOA1.
The C-terminal domain (CTD) of RNA polymerase II (RNAPII) is an essential component of transcriptional regulation and RNA processing of protein-coding genes. CTD is implicated in the transcription and processing of RNAPII-mediated small nuclear RNAs (snRNAs), but the identity of the complex (or complexes) that associates with the CTD and mediates the processing of snRNAs has been elusive [
].An RNA polymerase II complex termed the Integrator, which contains at least 12 novel subunits and core RNAPII subunits has been identified. Two of the Integrator subunits share similarity with subunits of the cleavage and polyadenylation specificity factor (CPSF) complex. Integrator has been shown to be recruited to the U1 and U2 snRNA genes, and to mediate the snRNAs' 3' end processing. The Integrator complex is evolutionarily conserved in metazoans, and directly interacts with the C-terminal domain of the RNA polymerase II largest subunit [
].
Flavin-containing monooxygenases (FMOs) constitute a family of xenobiotic-
metabolising enzymes []. Using an NADPH cofactor and FAD prosthetic group,these microsomal proteins catalyse the oxygenation of nucleophilic nitrogen,sulphur, phosphorous and selenium atoms in a range of structurally diverse
compounds. Five mammalian forms of FMO are now known and have been designatedFMO1-FMO5 [
,
,
,
,
].FMO4 mRNA is present in low abundance in several foetal and adult tissues
and the corresponding gene thus appears to be expressed constitutively [].Sequence analysis reveals that FMO4 is 56% identical to FMO3; each is
encoded by a single gene []. The deduced amino acid sequence of human FM04 includes the putative FAD- (GxGxxG) and NADP
+pyrophosphate-binding (GxGxxA)
sites characteristic of mammalian FMOs, a 'FATGY' motif that has also beenobserved in a range of siderphore biosynthetic enzymes [
], and a C-terminalhydrophobic segment that is believed to anchor the monooxygenase to the
microsomal membrane [].
Colicins are plasmid-encoded polypeptide toxins produced by and active against Escherichia coli and closely related bacteria. Colicins are released into the environment to reduce competition from other bacterial strains. Colicins bind to outer membrane receptors, using them to translocate to the cytoplasm or cytoplasmic membrane, where they exert their cytotoxic effect, including depolarisation of the cytoplasmic membrane, DNase activity, RNase activity, or inhibition of murein synthesis. Channel-forming colicins (colicins A, B, E1, Ia, Ib, and N) are transmembrane proteins that depolarize the cytoplasmic membrane, leading to dissipation of cellular energy [
]. These colicins contain at least three domains: an N-terminal translocation domain responsible for movement across the outer membrane and periplasmic space; a central domain responsible for receptor recognition; and a C-terminal cytotoxic domain responsible for channel formation in the cytoplasmic membrane [].This entry represents the C-terminal cytotoxic domain, which has a globin-like fold with additional helices at either end.
This entry represents the C-terminal domain of DNA repair protein Rev1, an enzyme which allows DNA synthesis to proceed even in the presence of DNA damage. Rev1 belongs to the Y-family of TLS polymerases. Rev1 possess a limited catalytic activity but it has a second and more important function which involved the recruitment and coordination of other Y-family TLS polymerases and the regulatory subunit Rev7 of the B-family polymerase pol. This interaction is mediated by its C-terminal domain which therefore serves as a scaffold that allows access of the Y-family polymerases to their cognate DNA lesions and the subsequent exchange to pol, which then extends the distorted DNA primer terminus opposite the lesion [
,
]. This domain adopts a four-helix bundle that interacts with Rev7, Polkappa and Poleta. However, the Rev7-binding interface is distinct from the binding site of DNA polymerase eta or kappa [,
].
This entry represents Holliday junction resolvases (hjc gene) and related proteins, primarily from archaeal species [
]. The Holliday junction is an essential intermediate of homologous recombination. Holliday junctions are four-stranded DNA complexes that are formed during recombination and related DNA repair events. In the presence of divalent cations, these junctions exist predominantly as the stacked-X form inwhich the double-helical segments are coaxially stacked and twisted by 60 degrees in a right-handed direction across the junction cross-over. In this structure, the stacked arms resemble two adjacent double-helices, but are linked at the junction by two common strands that cross-over between the duplexes [
]. During homologous recombination, genetic information is physically exchanged between parental DNAs via crossing single strands of the same polarity within the four-way Holliday structure. This process is terminated by the endonucleolytic activity of resolvases, which convert the four-way DNA back to two double strands.
Channel forming colicin, central receptor recognition domain superfamily
Type:
Homologous_superfamily
Description:
Colicins are plasmid-encoded polypeptide toxins produced by and active against Escherichia coli and closely related bacteria. Colicins are released into the environment to reduce competition from other bacterial strains. Colicins bind to outer membrane receptors, using them to translocate to the cytoplasm or cytoplasmic membrane, where they exert their cytotoxic effect, including depolarisation of the cytoplasmic membrane, DNase activity, RNase activity, or inhibition of murein synthesis. Channel-forming colicins (colicins A, B, E1, Ia, Ib, and N) are transmembrane proteins that depolarize the cytoplasmic membrane, leading to dissipation of cellular energy [
]. These colicins contain at least three domains: an N-terminal translocation domain responsible for movement across the outer membrane and periplasmic space; a central domain responsible for receptor recognition; and a C-terminal cytotoxic domain responsible for channel formation in the cytoplasmic membrane [,
].This entry represents the central receptor recognition domain, which has an α/β two-layer sandwich structure.
tRNA His molecules are unusual in having an extra 5' GMP residue (G(-1)) that, in eukaryotes, is added after transcription and RNase P cleavage. Incorporation of this G(-1) residue is a rare example of nucleotide addition occurring at an RNA 5' end in a normal phosphodiester linkage. In Saccharomyces cerevisiae, YGR024c (Thg1p) protein is responsible for this guanylyltransferase reaction [
]. It catalyses the guanylyltransferase step of G(-1) addition using a ppp-tRNA His substrate, and appears to catalyse the activation step using p-tRNA His and ATP. Thus, it catalyses phosphodiester bond formation at the 5' end of RNAs, formally in a 3'-5' direction []. Thg1 has also been shown to interact with the origin recognition complex and to be required for the G2/M phase transition [
], and to have polymerase activity []. The polymerase activity has been proposed to be the ancestral activity of this enzyme [].
Colicins are plasmid-encoded polypeptide toxins produced by and active against Escherichia coli and closely related bacteria. Colicins are released into the environment to reduce competition from other bacterial strains. Colicins bind to outer membrane receptors, using them to translocate to the cytoplasm or cytoplasmic membrane, where they exert their cytotoxic effect, including depolarisation of the cytoplasmic membrane, DNase activity, RNase activity, or inhibition of murein synthesis. Channel-forming colicins (colicins A, B, E1, Ia, Ib, and N) are transmembrane proteins that depolarize the cytoplasmic membrane, leading to dissipation of cellular energy [
]. These colicins contain at least three domains: an N-terminal translocation domain responsible for movement across the outer membrane and periplasmic space; a central domain responsible for receptor recognition; and a C-terminal cytotoxic domain responsible for channel formation in the cytoplasmic membrane [,
].This superfamily represents the N-terminal translocation domain, which consists of a long anti-parallel α-helical region.
Channel forming colicin, central receptor recognition
Type:
Domain
Description:
Colicins are plasmid-encoded polypeptide toxins produced by and active against Escherichia coli and closely related bacteria. Colicins are released into the environment to reduce competition from other bacterial strains. Colicins bind to outer membrane receptors, using them to translocate to the cytoplasm or cytoplasmic membrane, where they exert their cytotoxic effect, including depolarisation of the cytoplasmic membrane, DNase activity, RNase activity, or inhibition of murein synthesis. Channel-forming colicins (colicins A, B, E1, Ia, Ib, and N) are transmembrane proteins that depolarize the cytoplasmic membrane, leading to dissipation of cellular energy [
]. These colicins contain at least three domains: an N-terminal translocation domain responsible for movement across the outer membrane and periplasmic space; a central domain responsible for receptor recognition; and a C-terminal cytotoxic domain responsible for channel formation in the cytoplasmic membrane [
,
].This entry represents the central receptor recognition domain, which has an α/β two-layer sandwich structure.
(2R)-phospho-3-sulpholactate synthase, ComA superfamily
Type:
Homologous_superfamily
Description:
Methanogenic archaea produce methane via the anaerobic reduction of acetate or single carbon compounds [
]. Coenzyme M (CoM; 2-mercaptoethanesulphonic acid) serves as the terminal methyl carrier for this process. Previously thought to be unique to methanogenic archaea, CoM has also been found in methylotrophic bacteria.Biosynthesis of CoM begins with the Michael addition of sulphite to phosphoenolpyruvate, forming 2-phospho-3-sulpholactate (PSL). This reaction is catalyzed by members of this family, PSL synthase (ComA) [
]. Subsequently, PSL is dephosphorylated by phosphosulpholactate phosphatase (ComB) to form 3-sulpholactate [], which is then converted to 3-sulphopyruvate by L-sulpholactate dehydrogenase (ComC;
) [
]. Sulphopyruvate decarboxylase (ComDE; ) converts 3-sulphopyruvate to sulphoacetaldehyde [
]. Reductive thiolation of sulphoacetaldehyde is the final step.This entry also includes some proteins from plants and fungi, such as HEAT-STRESS-ASSOCIATED 32 from Arabidopsis [
]. The ComA structure has a TIM beta/α-barrel fold with a parallel β-sheet.
Alkylbase DNA glycosidases [
] are DNA repair enzymes that hydrolyse the deoxyribose N-glycosidic bond to excise various alkylated bases from a damaged DNA polymer. In Escherichia coli there are two alkylbase DNA glycosidases: one (gene tag) which is constitutively expressed and which is specific for the removal of 3-methyladenine (), and one (gene alkA) which is induced during adaptation to alkylation and which can remove a variety of alkylation products (
). Tag and alkA do not share any region of sequence similarity. In yeast there is an alkylbase DNA glycosidase (gene MAG1) [
,
], which can remove 3-methyladenine or 7-methyladenine and which is structurally related to alkA. MAG and alkA are both proteins of about 300 amino acid residues. While the C- and N-terminal ends appear to be unrelated, there is a central region of about 130 residues which is well conserved.
D-tagatose-bisphosphate aldolase, class II, non-catalytic subunit KbaZ
Type:
Family
Description:
Escherichia coli and other enteric bacteria contain two closely related D-tagatose 1,6-bisphosphate (TagBP)-specific aldolases involved in catabolism of galactitol (genes gatY gatZ) and of N-acetyl-galactosamine and D-galactosamine (genes kbaY, kbaZ, also called agaY, agaZ). The catalytic subunits GatY/KbaY alone are sufficient to show aldolase activity and contain most or all of the residues that have been identified as essential in substrate/product recognition and catalysis for class II aldolases [
,
]. However, these aldolases differ from other Class II aldolases (which are homodimeric enzymes) in that they require subunits GatZ/KbaZ for full activity and for good in vivo and in vitro stability. The Z subunits alone do not show any aldolase activity []. It should be noted that the previous suggestion of a tagatose 6P-kinase function for AgaZ [] and other members of this family have been debated [,
,
].This entry represents the KbaZ proteins.
D-tagatose-bisphosphate aldolase, class II, non-catalytic subunit GatZ
Type:
Family
Description:
Escherichia coli and other enteric bacteria contain two closely related D-tagatose 1,6-bisphosphate (TagBP)-specific aldolases involved in catabolism of galactitol (genes gatY gatZ) and of N-acetyl-galactosamine and D-galactosamine (genes kbaY, kbaZ, also called agaY, agaZ). The catalytic subunits GatY/KbaY alone are sufficient to show aldolase activity and contain most or all of the residues that have been identified as essential in substrate/product recognition and catalysis for class II aldolases [
,
]. However, these aldolases differ from other Class II aldolases (which are homodimeric enzymes) in that they require subunits GatZ/KbaZ for full activity and for good in vivo and in vitro stability. The Z subunits alone do not show any aldolase activity []. It should be noted that the previous suggestion of a tagatose 6P-kinase function for AgaZ [] and other members of this family have been debated [,
,
].This entry represents the GatZ proteins.
Acylphosphatase (
) is an enzyme of approximately 98 amino acid residues that specifically catalyses the hydrolysis of the carboxyl-phosphate bond of acylphosphates [
], its substrates including 1,3-diphosphoglycerate and carbamyl phosphate []. The enzyme has a mainly β-sheet structure with 2 short α-helical segments. It is distributed in a tissue-specific manner in a wide variety of species, although its physiological role is as yet unknown []: it may, however, play a part in the regulation of the glycolytic pathway and pyrimidine biosynthesis []. There are two known isozymes. One seems to be specific to muscular tissues, the other, called 'organ-common type', is found in many different tissues. A number of bacterial and archebacterial hypothetical proteins are highly similar to that enzyme and that probably possess the same activity. An acylphosphatase-like domain is also found in some prokaryotic hydrogenase maturation HypF carbamoyltransferases [
,
].
This entry refers to a domain found in uncharacterized subtilisin homologues, including the All0781 protein from the cyanobacterium Nostoc.This domain is part of a family of domains found in serine peptidases belonging to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin)) and S53 (sedolisin), both of which are members of clan SB [
,
,
,
].Peptidases S8 (or subtilases serine endo- and exo-peptidase clan) have an Asp/His/Ser catalytic triad similar to that found in trypsin-like proteases, but do not share their three-dimensional structure and are not homologous to trypsin. The stability of subtilases may be enhanced by calcium, some members have been shown to bind up to 4 ions via binding sites with different affinity. Some members of this clan contain disulfide bonds. These enzymes can be intra- and extracellular, some function at extreme temperatures and pH values [
,
,
,
].
This entry refers to a domain found in uncharacterized subtilisin homologues mainly from bacteria, including the Y4bN protein from Sinorhizobium fredii plasmid.This domain is part of a family of domains found in serine peptidases belonging to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin)) and S53 (sedolisin), both of which are members of clan SB [
,
,
,
].Peptidases S8 (or subtilases serine endo- and exo-peptidase clan) have an Asp/His/Ser catalytic triad similar to that found in trypsin-like proteases, but do not share their three-dimensional structure and are not homologous to trypsin. The stability of subtilases may be enhanced by calcium, some members have been shown to bind up to 4 ions via binding sites with different affinity. Some members of this clan contain disulfide bonds. These enzymes can be intra- and extracellular, some function at extreme temperatures and pH values [,
,
,
,
,
].
Ubiquinol oxidase is a multi-chain transmembrane protein located in the cell membrane and one of several aerobic bacterial terminal oxidases [
]. This complex couples oxidation of reduced quinones to the reduction of molecular oxygen to water, and the pumping of protons to form the proton gradient utilised for ATP production. aa3-type oxidases contain two haem A cofactors as well as copper atoms at the active site.Quinone oxidases feature four subunits in contrast to the 13 subunit bovine cytochrome c oxidase (CcO). Subunits I, II and III of ubiquinol oxidase are homologous to the corresponding subunits in bovine CcO [
,
]. Although not required for catalytic activity, subunit III appears to be involved in assembly of the multimer complex [].This entry represents a domain found in ubiquinol oxidase subunit III. While this signature predominantly matches the ubiquinol oxidase version of the domain, it also includes some cytochrome c oxidase homologues.
This entry represents the RNA recognition motif 1 (RRM1) of polypyrimidine tract-binding protein 1 (PTBP1). PTBP1 (also known as PTB) is involved in numerous post-transcriptional steps in gene expression in both the nucleus and cytoplasm. It can act as a negative regulator of alternative splicing and as an activator of translation driven by IRESs (internal ribosome entry segments) [
]. It contains four RNA recognition motifs (RRM). RRM1 and RRM2 are independent from each other and separated by flexible linkers. By contrast, there is an unusual and conserved interdomain interaction between RRM3 and RRM4. It is widely held that only RRMs 3 and 4 are involved in RNA binding and RRM2 mediates PTB homodimer formation. However, new evidence shows that the RRMs 1 and 2 also contribute substantially to RNA binding. Moreover, PTB may not always dimerize to repress splicing. It is a monomer in solution [,
].
NADH:ubiquinone oxidoreductase (complex I) (
) is a respiratory-chain enzyme that catalyses the transfer of two electrons from NADH to ubiquinone in a reaction that is associated with proton translocation across the membrane (NADH + ubiquinone = NAD+ + ubiquinol) [
]. Complex I is a major source of reactive oxygen species (ROS) that are predominantly formed by electron transfer from FMNH(2). Complex I is found in bacteria, cyanobacteria (as a NADH-plastoquinone oxidoreductase), archaea [], mitochondria, and in the hydrogenosome, a mitochondria-derived organelle. In general, the bacterial complex consists of 14 different subunits, while the mitochondrial complex contains homologues to these subunits in addition to approximately 31 additional proteins [
].This family represents an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain [
].
This is a hydrophilic cysteine-rich ligand-binding domain found in both TGF-beta receptor types (type I and II). In both types, this domain posses a 9 amino acid cysteine box, with the the consensus CCX{4-5}CN. The type I receptors also possess 7 extracellular residues preceding the cysteine box [
,
,
].The Transforming growth factor-beta superfamily of ligands include: bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), anti-mullerian hormone (AMH), activin, nodal and TGF-beta. Signalling begins with the binding of a TGF-beta superfamily ligand to a TGF-beta type II receptors. The type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators [
].The receptors for most of the members of this growth factor family are related. They are receptor-type kinases of Ser/Thr type, which have a single
transmembrane domain and a specific hydrophilic Cys-rich ligand-binding domain [,
,
].
4-hydroxybenzoate 3-monooxygenase is a flavoprotein that converts its substrate to 3,4-dihydroxybenzoate, which subsequently enters the beta-ketioadipate pathway of aromatic degradation, using molecular oxygen and NADPH as shown below [
].4-hydroxybenzoate + NADPH + O(2) = 3,4-dihydroxybenzoate + NADP(+) + H(2)O4-hydroxybenzoate is an intermediate in the degradation of lignin and other aromatic plant compounds, and this enzyme is found extensively in soil bacteria.This enzyme is a homodimer where each subunit is composed of three distinct domains: an N-terminal flavin-binding domain with a beta-α-β fold, a small substrate-binding domain composed of a single alpha helix and β-sheet, and a C-terminal helical domain [
]. The active site is found at the interface of all three domains. Catalysis occurs by a two-step reaction. In the first step, flavin is reduced by NADPH. Subsequently, the reduced flavin is oxygenated to a hydroperoxide which transfers the hydroxyl group to the substrate, forming 3,4-dihydroxybenzoate.
Formylglycinamide ribonucleotide amidotransferase (FGAR-AT), also known as phosphoribosylformylglycinamidine synthase, PurL and formylglycinamidine ribonucleotide (FGAM) synthase, catalyzes the ATP-dependent conversion of formylglycinamide ribonucleotide (FGAR) and glutamine to formylglycinamidine ribonucleotide (FGAM), ADP, Pi, and glutamate in the fourth step of the purine biosynthetic pathway [
].Two types of phosphoribosylformylglycinamidine synthases (PurLs) have been detected. The first consists of a single polypeptide chain of about 1300 amino acids and is found in eukaryotes and Gram-negative bacteria. This type is designated large PurL. The second type consists of about 800 amino acids and is found in Gram-positive bacteria and archaebacteria. This type is designated small PurL. In this case PurL is part of the the FGAM synthase complex that is composed of three subunits and requires two additional proteins, PurQ, a glutaminase, and PurS, of unknown function [
].This entry represents the small PurL, also known as phosphoribosylformylglycinamidine synthase II, or FGAM synthase II.
CD4 is a glycoprotein found on the surface of T cells. It is a co-receptor that assists the T cell receptor (TCR) in communicating with an antigen-presenting cell (APC). The structure of a soluble fragment of CD4 has been determined to 2.3 A and reveals that the molecule has two intimately-associated immunoglobulin-like domains connected by a continuous beta strand. Residues implicated in HIV recognition reside in domain D1. Domain D2 is distinguished by a variation in the β-strand topologies of antibody domains that results in a truncated β-barrel with a non-standard intra-sheet disulphide bond [
,
]. The binding sites for monoclonal antibodies, class II major histocompatibility complex molecules, and HIV gp120 can be mapped on the molecular surface. Ligation of CD4 by MHC-II on blood monocytes mediates macrophage differentiation and it also increases the susceptibility of blood-derived monocytes to HIV binding and subsequent infection [].
This entry represents the SH2 domain of SOCS3.Cytokine signaling mediated by the JAK-STAT pathway plays essential roles in differentiation, maturation, proliferation and apoptosis of a various types of cells. Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of the JAK-STAT signaling pathway. SOCS1 and SOCS3 are potent inhibitors of JAKs and can play pivotal roles in inflammation, as well as in the development and progression of cancers [
]. All SOCS share a central SH2 domain and a C-terminal SOCS box, but only SOCS1 and SOCS3 possess a kinase inhibitory region immediately upstream of the central SH2 [].SOCS3 interacts with gp130, a common cytokine receptor for interleukin (IL)-6, leukemia inhibitory factor (LIF) and other members of the IL-6 family of cytokines. SOCS3 has been reported also to interact with the leptin receptor, erythropoietin receptor, insulin receptor, IL-12beta receptor and granulocyte-colony stimulating factor receptor [
].
In prokaryotes, for example Enterococcus faecalis (Streptococcus faecalis), the conjugative transfer of certain plasmids is controlled by peptide pheromones [
]. Plasmid free recipient cells secret plasmid specific oligopeptides, termed sex pheromones. They induce bacterial clumping and specifically activate the conjugative transfer of the corresponding plasmid. Once recipient cells acquire the plasmid they start to produce a pheromone inhibitor to block the activity of the pheromone and to prevent plasmid containing cells from clumping; they also become donor cells able to transfer the plasmid to plasmid free recipient cells. Examples of such plasmid-pheromone systems are bacteriocin plasmid pPD1 [], haemolysin/bacteriocin plasmid, pAD1 [], tetracycline-resistance plasmid,pCF10 [
], and the haemolysin/bacteriocin plasmid, pOB1 [].TraB in combination with another factor contributes to pheromone shutdown in cells that have acquired a plasmid. Based on its homology with TIKI proteins, TraB may act as a protease to inactivate the mating pheromone [
].
The Trp repressor (TrpR) binds to at least five operators in the Escherichia coli genome, repressing gene expression. The operators at which it binds vary considerably in DNA sequence and location within the promoter; when bound to the Trp operon it recognises the sequence 5'-ACTAGT-3' and acts to prevent the initiation of transcription. The TrpR controls the trpEDCBA (trpO) operon and the genes for trpR, aroH, mtr and aroL, which are involved in the biosynthesis and uptake of the amino acid tryptophan [
]. The repressor binds to the operators only in the presence of L-tryptophan, thereby controlling the intracellular level of its effector; the complex also regulates Trp repressor biosynthesis by binding to its own regulatory region. TrpR acts as a dimer that is composed of identical 6-helical subunits, where four of the helices form the core of the protein and intertwine with the corresponding helices from the other subunit.
This family consists of several Bacteriophage lambda Kil protein like sequences. A cessation of division, followed by one or two fairly synchronous cell divisions in Escherichia coli is due to two genetically separable events: a temporary block of cell division and, at the same time, a block to the initiation of new rounds of DNA replication. The cell division block is a result of the transient expression of the lambda kil gene [
].The lambda kil gene has been shown to be responsible for premature lysis on the addition of chloramphenicol between 15 and 20 min after thermal induction of a lambda prophage [
]. Induction of a lambda prophage causes the death of the host cell even in the absence of phage replication and lytic functions due to expression of functions from the lambda p(L) operon. The kil gene causes cell death and filamentation [].
This entry contains of several mammalian and one bird sequence from Gallus gallus (Chicken) and represents the C-terminal region of repulsive guidance molecule (RGM), although in some sequences it represents the full protein. RGM is a GPI-linked axon guidance molecule of the retinotectal system, and controls cell motility, adhesion, immune cell regulation and systemic iron metabolism [
,
]. RGM is repulsive for a subset of axons, those from the temporal half of the retina. Temporal retinal axons invade the anterior optic tectum in a superficial layer, and encounter RGM expressed in a gradient with increasing concentration along the anterior-posterior axis. Temporal axons are able to receive posterior-dependent information by sensing gradients or concentrations of guidance cues. Thus, RGM is likely to provide positional information for temporal axons invading the optic tectum in the stratum opticum [
]. This domain is responsible for neogenin (NEO1) binding [,
].
This entry consists of several phage terminase large subunit proteins, including GpA (also known as TerL) from Bacteriophage lambda and from Enterobacteria phage P21, as well as related sequences from several bacterial species. The DNA packaging enzyme of Bacteriophage lambda, terminase, is a heteromultimer composed of a small subunit, gpNu1 involved in DNA recognition, and a large subunit, gpA involved in late stages of packaging, products of the Nu1 and A genes, respectively. Terminase is involved in the site-specific binding and cutting of the DNA in the initial stages of packaging. This large subunit is an ATPase required for viral DNA translocation into empty capsids and also acts as an endonuclease that cuts the viral genome from the concetamer to initiate and to end the packaging reaction [
,
,
].This entry represents the C-terminal domain, which shows DNA maturation (nuclease/helicase) catalytic activity [
,
,
].
This entry consists of several phage terminase large subunit proteins, including GpA (also known as TerL) from Bacteriophage lambda and from Enterobacteria phage P21, as well as related sequences from several bacterial species. The DNA packaging enzyme of Bacteriophage lambda, terminase, is a heteromultimer composed of a small subunit, gpNu1 involved in DNA recognition, and a large subunit, gpA involved in late stages of packaging, products of the Nu1 and A genes, respectively. Terminase is involved in the site-specific binding and cutting of the DNA in the initial stages of packaging. This large subunit is an ATPase required for viral DNA translocation into empty capsids and also acts as an endonuclease that cuts the viral genome from the concetamer to initiate and to end the packaging reaction [,
,
].This entry represents the N-terminal domain, which shows DNA translocase (packaging) and ATPase activities [
,
,
].
Phosphoinositide-specific phospholipase C (PI-PLC), also known as 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase, plays a role in the inositol phospholipid signaling by hydrolysing phosphatidylinositol-4,5-bisphosphate to produce the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These cause the increase of intracellular calcium concentration and the activation of protein kinase C (PKC), respectively.The PLC family in murine or human species is comprised of multiple subtypes. On the basis of their structure, they have been divided into five classes, beta (beta-1, 2, 3 and 4), gamma (gamma-1 and 2), delta (delta-1, 3 and 4), epsilon, zeta, and eta types [
,
].The PLC-eta gene is transcribed to several splicing variants. This entry represents PLC-eta-1, which may have an important role in the brain [
,
].PLC-eta-1 contains a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs (represented by this entry), a PLC catalytic core, and a single C2 domain.
O-Glycosyl hydrolases (
) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families [
,
]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.This entry represents the glycogen debranching enzyme GlgX found in Escherichia coli, as well as its equivalogs in other prokaryotic species. This enzyme encodes an isoamylase-type debranching enzyme with high specificity for hydrolysis of chains consisting of three or four glucose residues, and is classed as family 13 of glycosyl hydrolases []. GlgX is not required for glycogen biosynthesis, but instead acts as a debranching enzyme for glycogen catabolism. This entry distinguishes GlgX from pullanases and other related proteins that also operate on alpha-1,6-glycosidic linkages [].
This entry represents NH(3)-dependent NAD(+) synthetases from prokaryotes.NAD+ is involved electron transport and redox reactions and in DNA ligation and protein ADP-ribosylation. In yeast and most other organisms, NAD is generated through the de novo pathway and the salvage pathway. In the de novo pathway, quinolinic acid is converted to nicotinic acid mononucleotide (NaMN). In the salvage pathway, NaMN is generated by recycling of nicotinamide. Both pathways converge on NaMN, which is then converted into deamido-NAD+. Subsequently, deamido-NAD+ is converted to NAD+ by NAD+ synthetase [
].NAD+ synthetase has been extensively studied in bacteria. It is encoded by nadE gene in E. coli and by outB gene in B. subtilis [
]. These prokaryotic enzymes are ammonia-dependent (containing an ammonia-utilising domain) []. However, some prokaryotic NAD(+) synthetases, such as that from Mycobacterium tuberculosis, contain a nitrilase-related domain, are glutamine-dependent, and are not included in this entry [].
TCF-19, also termed transcription factor SC1, was identified as a putative trans-activating factor with expression beginning at the late G1-S boundary in dividing cells [
]. It also functions as a novel islet factor necessary for proliferation and survival in the INS-1 beta cell line. It plays an important role in susceptibility to both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM); it has been suggested that it may positively impact beta cell mass under conditions of beta cell stress and increased insulin demand [].TCF-19 contains an N-terminal fork head association domain (FHA), a proline rich region, and a C-terminal plant homeodomain (PHD) finger. The FHA domain may serve as a nuclear signaling domain or as a phosphoprotein binding domain. The proline rich region is a common characteristic of trans-activating factors. The PHD finger may allow TCF-19 to interact with chromatin via methylated histone H3 [
].
Glial cell line-derived neurotrophic factor (GDNF) and its related factors
neurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNFfamily of neurotrophic factors. They form a sub-group in the transforming
growth factor-beta (TGF-beta) superfamily. These factors are involved inthe promotion of neurone survival, exerting their effects through specific
receptors.The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked,
cell surface receptors []. Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-3 has been cloned from mammalian tissue []. It represents the least conserved member of the GFR family in terms of amino acid sequence, and is activated by artemin [].Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation,
triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and
phospholipase C gamma (PLC gamma) dependent pathways [].
This entry represents a sirtuin-like domain domain found in FAM118A and FAM118B from vertebrates and bacterial NAD(+) hydrolase ThsA. ThsA is a component of bacterial antiphage defense system Thoeris and has robust NAD+ cleavage activity. It consists of a N-terminal NAD-binding domain (denoted as sirtuin-like or Macro) and C-terminal SLOG-like domain (
). In some instances, such as in B. amyloliquefaciens, ThsA has an N-terminal transmembrane domain [2]. In ThsA, this domain binds and cleaves NAD+, required for antiphage activity [,
].FAM118A has been identified as a gene expressed in glioblastoma stem cells, but not expressed in neural stem cells [
]. Its function is unkown.Cajal bodies are specialized compartments in the nucleus that are involved in the biogenesis of small nuclear ribonucleoproteins (snRNPs). FAM118B is a component of Cajal bodies that plays an important role in Cajal body formation, snRNP biogenesis and cell viability [
].
Isoprenoids are a large class of compounds, with more than 20,000 structures currently known, which are found in all living organisms. Some play essential physiological roles, such as sterols that stabilise cell membranes or carotenoids involved in photosynthesis, while the function of many others is not well understood. In all eukaryotes and some prokaryotes, isoprenoids are synthesised by the mevalonate pathway, while most prokaryotes use a mevalonate-independent pathway [
,
].This entry represents acetoacetyl-CoA synthase (
), catalysing the first step of the mevalonate pathway of isoprenoid biosynthesis via isopentenyl diphosphate.
ATP + acetoacetate + CoA = AMP + diphosphate + acetoacetyl-CoA A Sinorhizobium protein in this entry is also required for growth on polyhydroxybutyrate, a commonly used carbon storage molecule in bacteria [
]. This entry also includes malonamoyl-CoA synthetase which in Penicillium is involved in the biosynthesis of the tetracycline-like viridicatumtoxin [].
This domain superfamily is found in several bacterial cytotoxic necrotizing factor proteins as well as related dermonecrotic toxin (DNT) from Bordetella species [
].Cytotoxic necrotizing factor 1 (CNF1) is a toxin whose structure from Escherichia coli revealed a 4-layer alpha/beta/beta/alpha structure containing mixed β-sheets [
]. CNF1 is expressed in strains of E. coli causing uropathogenic and neonatal meningitis. CNF1 alters host cell actin cytoskeleton and promotes bacterial invasion of the blood-brain barrier endothelial cells []. CNF1 belongs to a unique group of large cytotoxins that cause constitutive activation of Rho guanosine triphosphatases (GTPases), which are key regulators of the actin cytoskeleton [].Bordetella dermonecrotic toxin (DNT) stimulates the assembly of actin stress fibres and focal adhesions by deamidating or polyaminating Gln63 of the small GTPase Rho. DNT is an A-B toxin composed of an N-terminal receptor-binding (B) domain and a C-terminal enzymatically active (A) domain [
].
This conserved region is found in four-carbon acid sugar kinases from a range of Proteobacteria as well as the Gram-positive Oceanobacillus iheyensis. These four-carbon acid sugar kinases are composed of two domains: an N-terminal domain and a C-terminal domain connected by a variable linker sequence. The N-terminal domain exhibits an α/β-fold composed of an eight-stranded parallel β-sheet. The C-terminal domain also exhibits an α/β-fold composed of a seven-stranded mixed β-sheet. The acid sugar is bound by the N-terminal domain, while nucleotide by the C-terminal domain [
].Proteins containing this domain include D-threonate kinase from Salmonella typhimurium (DtnK), 3-oxo-tetronate kinase from Methylobacterium radiotolerans, 3-oxo-isoapionate kinase from Paraburkholderia graminis and D-erythronate kinase from Heliobacterium modesticaldum. DtnK catalyzes the ATP-dependent phosphorylation of D-threonate to D-threonate 4-phosphate and is also able to phosphorylate 4-hydroxy-L-threonine, which may serve to deal with the toxicity of this compound [
,
].
This entry represents the subunit 10 (also known as CI-42kD) of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I). It is an accessory subunit that is believed not to be involved in catalysis [
]. NADH:ubiquinone oxidoreductase (complex I) (
) is a respiratory-chain enzyme that catalyses the transfer of two electrons from NADH to ubiquinone in a reaction that is associated with proton translocation across the membrane (NADH + ubiquinone = NAD+ + ubiquinol) [
]. Complex I is a major source of reactive oxygen species (ROS) that are predominantly formed by electron transfer from FMNH(2). Complex I is found in bacteria, cyanobacteria (as a NADH-plastoquinone oxidoreductase), archaea [], mitochondria, and in the hydrogenosome, a mitochondria-derived organelle. In general, the bacterial complex consists of 14 different subunits, while the mitochondrial complex contains homologues to these subunits in addition to approximately 31 additional proteins [].
In metazoans, Plk4 kinases control daughter centriole assembly. Plk4 homologues have an N-terminal kinase domain, a C-terminal polo box, and a central domain termed the 'cryptic polo box' (CPB) that has been shown to dimerize, to be sufficient for centriole localization and to be required for Plk4 to promote centriole assembly. Probable serine/threonine-protein kinase zyg-1 (
) (ZYG-1) is a Plk4 homlogue found in C. elegans. Crystal structure for the CPB of C. elegans ZYG-1, reveals that it forms a Z-shaped dimer containing an intermolecular β-sheet with an extended basic surface patch. Electrostatic interactions between the basic patch on the ZYG-1 CPB dimer and the SPD-2 acidic region dock ZYG-1 onto centrioles to promote new centriole assembly. ZYG-1 CPB contains two tandem polo boxes (PB1 and PB2), each containing a six-stranded β-sheet with an α-helix packed against one side [
]. This entry represents PB1.
In metazoans, Plk4 kinases control daughter centriole assembly. Plk4 homologs have an N-terminal kinase domain, a C-terminal polo box, and a central domain termed the 'cryptic polo box' (CPB) that has been shown to dimerize, to be sufficient for centriole localization and to be required for Plk4 to promote centriole assembly. Probable serine/threonine-protein kinase zyg-1 (
) (ZYG-1) is a Plk4 homlog found in C. elegans. Crystal structure for the CPB of C. elegans ZYG-1, reveals that it forms a Z-shaped dimer containing an intermolecular β-sheet with an extended basic surface patch. Electrostatic interactions between the basic patch on the ZYG-1 CPB dimer and the SPD-2 acidic region dock ZYG-1 onto centrioles to promote new centriole assembly. ZYG-1 CPB contains two tandem polo boxes (PB1 and PB2), each containing a six-stranded β-sheet with an α-helix packed against one side [
]. This entry represents PB2.
Bacteriophages recognize and bind to their hosts with the help of receptor-binding proteins (RBPs) that emanate from the phage particle in the form of fibres or tailspikes. RBPs of podovirus G7C tailspikes gp63.1 and gp66 are essential for infection of its natural host bacterium E. coli 4s. Gp63.1 and gp66 form a stable complex, in which the N-terminal part of gp66 serves as an attachment site for gp63.1 and anchors the gp63.1-gp66 complex to the G7C tail. The two N-terminal domains show 70% sequence identity to the N-terminal region of the CBA120 phage tailspike 1 (orf210, TSP1) [
]. The N-terminal domain of TSP1 is the virion head binding domain that interfaces with the phage baseplate. The N-terminal domain can be further divided into two subdomains, each beginning with a α-helix followed by an anti-parallel β-sandwich. Subdomain two folds similarly to the chitin binding domain of Chitinase from Bacillus circulans [].
Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7) or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac1 [
], and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion [,
,
,
].PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs [
,
].This entry represents the SH3 domain of beta-PIX.
Hex1 is the major component of the Woronin body in filamentous fungi [
,
] and it has an essential function in conidia production and secondary metabolism in A. flavus. Hex1 may also play an important role in the invasion of A. flavus to the host. The Woronin body is a dense vesicle and plays a vital role in filamentous fungi cell integrity. When cell damage occurs, Woronin bodies seal the septal pore to prevent further cytoplasmic bleeding. Hex1 protein self-assembles to form the solid core of the Woronin body vesicle. The Hex1 sequence and structure are similar to eukaryotic initiation factor 5A (eIF5A), suggesting they share a common ancestor during evolution []. All members of the EF superfamily to which Hex1 belongs, contain an S1 domain, which has been shown to bind RNA or single-stranded DNA and often interacts with the ribosome [].
This entry represents the C terminus of the SH2 domain found in Spt6. Spt6 is an essential transcription elongation factor and histone chaperone that binds the C-terminal repeat domain (CTD) of RNA polymerase II []. Spt6 contains a tandem SH2 domain with a novel structure and CTD-binding mode. The tandem SH2 domain binds to a serine 2-phosphorylated CTD peptide in vitro, whereas its N-terminal SH2 subdomain does not. CTD binding requires a positively charged crevice in the C-terminal SH2 subdomain, which lacks the canonical phospho-binding pocket of SH2 domains. The tandem SH2 domain is apparently required for transcription elongation in vivo as its deletion in cells is lethal in the presence of 6-azauracil. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites [].
This entry represents the SH2 domain found in Spt6.Spt6 is an essential transcription elongation factor and histone chaperone that binds the C-terminal repeat domain (CTD) of RNA polymerase II [
]. Spt6 contains a tandem SH2 domain with a novel structure and CTD-binding mode. The tandem SH2 domain binds to a serine 2-phosphorylated CTD peptide in vitro, whereas its N-terminal SH2 subdomain does not. CTD binding requires a positively charged crevice in the C-terminal SH2 subdomain, which lacks the canonical phospho-binding pocket of SH2 domains. The tandem SH2 domain is apparently required for transcription elongation in vivo as its deletion in cells is lethal in the presence of 6-azauracil. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites [].
This entry represents the N terminus of the SH2 domain found in Spt6. Spt6 is an essential transcription elongation factor and histone chaperone that binds the C-terminal repeat domain (CTD) of RNA polymerase II [
]. Spt6 contains a tandem SH2 domain with a novel structure and CTD-binding mode. The tandem SH2 domain binds to a serine 2-phosphorylated CTD peptide in vitro, whereas its N-terminal SH2 subdomain does not. CTD binding requires a positively charged crevice in the C-terminal SH2 subdomain, which lacks the canonical phospho-binding pocket of SH2 domains. The tandem SH2 domain is apparently required for transcription elongation in vivo as its deletion in cells is lethal in the presence of 6-azauracil. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites [].
This entry represents the PH domain of guanine nucleotide exchange factor DBS. The DBS PH domain participates in binding to both the Cdc42 and RhoA GTPases [
]. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner [].DBS, also called MCF2L or OST, functions as a Rho GTPase guanine nucleotide exchange factor (RhoGEF), facilitating the exchange of GDP and GTP. It was originally isolated from a cDNA screen for sequences that cause malignant growth. It plays roles in regulating clathrin-mediated endocytosis and cell migration through its activation of Rac1 and Cdc42 [
,
]. Depending on cell type, DBS can also activate RhoA and RhoG [,
]. DBS contains a Sec14-like domain [], spectrin-like repeats, a RhoGEF or Dbl homology (DH) domain, a Pleckstrin homology (PH) domain [], and an SH3 domain.
This entry describes purine nucleotide phosphorylases (PNPs). Some proteins in this entry have been shown to act on inosine and guanosine, though their physiological substrates and role in vivo are not known [,
]. Closely related clades act on inosine and guanosine (PNPH, ), and xanthosine, inosine and guanosine (XAPA,
) neither of these will act on adenosine. A more distantly related clade (MTAP,
) acts on methylthioadenosine.
The structure of the Cellulomonas enzyme (
) has been determined [
]. This enzyme is a homotrimer where the subunits appear to bind cooperatively and trimerisation occurs through both hydrogen bonding and hydrophobic interactions. The core of each subunit, like other trimeric PNPs, consists of a nine-stranded beta sheet, though the surrounding helices are less well conserved. The postions and geometric arrangments of the three active sites of each trimer are also conserved with other trimeric PNPs.
Cytochrome bc1 complex (ubiquinol:ferricytochrome c oxidoreductase) is
found in mitochondria, photosynthetic bacteria and other prokaryotes. It is minimally composed of three subunits: cytochrome b, carrying a low- and a high-potential haem group; cytochrome c1 (cyt c1); and a high-potential Rieske iron-sulphur protein. The general function of the complex is electron transfer between two mobile redox carriers, ubiquinol and
cytochrome c; the electron transfer is coupled with proton translocation across the membrane, thus generating proton-motive force in the form of an
electrochemical potential that can drive ATP synthesis. In its structure andfunctions, the cytochrome bc1 complex bears extensive analogy to the
cytochrome b6f complex of chloroplasts and cyanobacteria; cyt c1 plays ananalogous role to cytochrome f, in spite of their different structures [
].This entry represents the transmembrane anchor of the cytochrome c1 subunit from the cytochrome bc1 complex. This region contains a single transmembrane helix.
Glucose-6-phosphate dehydrogenase (
) (G6PDH) is a ubiquitous protein, present in bacteria and all eukaryotic cell types [
]. The enzyme catalyses the the first step in the pentose pathway, i.e. the conversion of glucose-6-phosphate to gluconolactone 6-phosphate in the presence of NADP, producing NADPH. The ubiquitous expression of the enzyme gives it a major role in the production of NADPH for the many NADPH-mediated reductive processes in all cells, and is critical for NADPH homeostasis and redox regulation []. Deficiency of G6PDH is a common genetic abnormality affecting millions of people worldwide. Many sequence variants, most caused by single point mutations, are known, exhibiting a wide variety of phenotypes with the distinctive one being chronic and drug- or food-induced hemolytic anemia, attributed to the inability to produce NADPH and withstand harmful oxidants in erythrocyte cells [,
].This entry represents the C-terminal domain of glucose-6-phosphate dehydrogenase.
This entry represents the fused enzyme II B and C components of the trehalose-specific PTS sugar transporter system [
]. Trehalose is converted to trehalose-6-phosphate in the process of translocation into the cell. These transporters lack their own IIA domains and instead use the glucose IIA protein (IIAglc or Crr) []. The exceptions to this rule are Staphylococci and Streptococci which contain their own A domain as a C-terminal fusion. This family is closely related to the sucrose transporting PTS IIBC enzymes described by the IIB component and the IIC component (), respectively. In Escherichia coli, Bacillus subtilis and Pseudomonas fluorescens the presence of this gene is associated with the presence of trehalase which degrades T6P to glucose and glucose-6-P. Trehalose may also be transported (in Salmonella) via the mannose PTS or galactose permease systems [
], or (in Sinorhizobium, Thermococcus and Sulfolobus, for instance) by ABC transporters [,
,
].
Orexins (also known as hypocretins) are neuropeptides that are specifically localised to the hypothalamus. They are thought to interact with autonomic, neurendocrine and neuroregulatory systems, and play an important role in the regulation of feeding behaviour [
,
]. When applied to hypothalamic neurones, these peptides are neuroexcitatory, which action is probably mediated by their binding to a new family of G-protein-coupled receptors (orexin receptors 1 and 2), which were previously orphan [].To date, two orexins have been characterised (orexin-A and -B), both encoded by a single mRNA transcript (prepro-orexin or hypocretin neuropeptide precursor, whose product is represented in this entry): orexin-A is a 33-residue peptide with two intramolecular disulphide bonds in the N-terminal region; and orexin-B is a linear 28-residue peptide. These peptides have 46% identity at the amino acid sequence level, and show some similarity to the glucagon/vasoactive intestinal polypeptide/secretin peptide family.
