Urease and other nickel metalloenzymes are synthesised as precursors devoid of the metalloenzyme active site. These precursors then undergo a complex post-translational maturation process that requires a number of accessory proteins.Members of this family are nickel-binding proteins required for urease metallocentre assembly [
]. They are believed to function as metallochaperones to deliver nickel to urease apoprotein [,
]. It has been shown by yeast two-hybrid analysis that UreE forms a dimeric complex with UreG in Helicobacter pylori []. The UreDFG-apoenzyme complex has also been shown to exist [,
] and is believed to be, with the addition of UreE, the assembly system for active urease []. The complexes, rather than the individual proteins, presumably bind to UreB via UreE/H recognition sites.The structure of Klebsiella aerogenes UreE reveals a unique two-domain architecture.The N-terminal domain is structurally related to a heat shock protein, while the C-terminal domain shows homology to the Atx1 copper metallochaperone [
,
]. Significantly, the metal-binding sites in UreE and Atx1 are distinct in location and types of residues despite the relationship between these proteins and the mechanism for UreE activation of urease is proposed to be different from the thiol ligand exchange mechanism used by the copper metallochaperones.The C-terminal domain of this protein is the metal-binding region, which can bind up to six Ni molecules per dimer. Most members of this group contain a histidine-rich C-terminal motif that is involved in, but not solely responsible for, binding nickel ions in K. aerogenes UreE [
]. However, internal ligands, not the histidine residues at the C terminus, are necessary for UreE to assist in urease activation in K. aerogenes [], even though the truncated protein lacking the His-rich region binds two nickel ions instead of six. In H. pylori and some other organisms, the terminal histidine-rich binding sites are absent, but the internal histidine sites are present, and the latter probably function as nickel donors. Deletion analysis shows that this domain alone is sufficient for metal-binding and activation of urease [].
Coenzyme A biosynthesis bifunctional protein CoaBC
Type:
Family
Description:
This entry represents a bifunctional enzyme CoaBC (gene name dfp) that catalyses the second and third steps (cysteine ligation, (
), and decarboxylation, (
)) in the biosynthesis of coenzyme A (CoA) from pantothenate in bacteria. This enzyme contains the FMN cofactor, but no FAD or pyruvoyl group. The amino-terminal region is responsible for the phosphopantothenoylcysteine decarboxylase activity [
].The protein product of the dfp gene in Escherichia coli was found to be able to restore a temperature-sensitive conditionally lethal mutation that resulted in a slow cessation of DNA synthesis [
]. The protein encoded by dfp was then found to affect both DNA and pantothenate metabolism []. Later, phosphopantothenate-cysteine ligase activity, which is involved in the biosynthesis of coenzyme A, was demonstrated in the same protein. Therefore this protein has been named bifunctional protein CoaBC [].
Cysteine-rich and transmembrane domain-containing protein WIH1-like
Type:
Family
Description:
This entry represents a group of cysteine-rich and transmembrane domain-containing proteins, including WIH1 (also known as CYSTEINE-RICH TRANSMEMBRANE MODULE 13), At3g57160 and CYSTEINE-RICH TRANSMEMBRANE MODULE (CYSTM) 1, 3-6 and 8 from Arabidopsis. WIH1 is required for the promotion of megasporogenesis, or promotion of germ cell formation from somatic precursor cells. It functions in a genetic pathway downstream of SPL/NZZ and WUS and together with TORNADO2 (TRN2) in promoting megasporogenesis [
]. WIH1 is also involved in resistance to abiotic stress []. CYSTMs , are ubiquitous non-secreted cysteine-rich proteins,which play an important role in resistance to abiotic stress []. CYSTM3 negatively regulates salt stress responses and Na+ homeostasis [,
].
COX14 plays an essential role in cytochrome oxidase assembly. The COX14 product is a low-molecular weight membrane protein of mitochondria, but it is not a subunit of cytochrome oxidase [
]. Orthology-prediction methods have identified the vertebrate C12orf62 orthologues to be orthologues of the yeast COX14 [].
TPTE, protein tyrosine phosphatase-like catalytic domain
Type:
Domain
Description:
Proteins containing this domain are a family of phosphoinositide phosphatases with substrates that include phosphatidylinositol-4,5-diphosphate and phosphatidylinositol-3,4,5-trisphosphate. This family is conserved in deuterostomes; VSP was first identified as a sperm flagellar plasma membrane protein in Ciona intestinalis [
]. Gene duplication events in primates resulted in the presence of paralogs, transmembrane phosphatase with tensin homology (TPTE) and TPTE2, that retain protein domain architecture but, in the case of TPTE, have lost catalytic activity. TPTE, also called cancer/testis antigen 44 (CT44), may play a role in the signal transduction pathways of the endocrine or spermatogenic function of the testis. TPTE2, also called TPTE and PTEN homologous inositol lipid phosphatase (TPIP), occurs in several differentially spliced forms; TPIP alpha displays phosphoinositide 3-phosphatase activity and is localized on the endoplasmic reticulum, while TPIP beta is cytosolic and lacks detectable phosphatase activity [
,
]. VSP/TPTE proteins contain an N-terminal voltage sensor consisting of four transmembrane segments, a protein tyrosine phosphatase (PTP)-like phosphoinositide phosphatase catalytic domain, followed by a regulatory C2 domain [].
Low density lipoprotein receptor-related protein 5/6
Type:
Family
Description:
LRP5/6 are transmembrane receptors that are involved in Wnt signal transduction [
]. Binding of the Wnts to LRP5/6 and their participating co-receptors, the frizzled (Fz) family of 7 transmembrane spanning proteins, results in a series of downstream intracelullar events, in particular the inhibition by subsequent phosphorylation of GSK-3beta []. LRP5/6 have been shown to play an role in bone homeostasis []. Mutations in the LRP5 gene cause vitreoretinopathy, exudative 4 (EVR4), a disorder of the retinal vasculature characterised by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina [
]. Mutations in the LRP6 gene cause coronary artery disease, autosomal dominant, 2 (ADCAD2), a common heart disease characterised by reduced or absent blood flow in one or more of the arteries that encircle and supply the heart [].
GspM is part of the inner membrane component of the type II secretion system (T2SS). It consists of a short cytosolic N-terminal domain, a transmembrane domain, and a C-terminal periplasmic domain. The precise function of this protein is unknown [
]. However, though in Vibrio cholerae, the EpsM protein interacts with the EpsL protein, and also forms homodimers [].The type II secretion system (T2SS) is one of several extracellular secretion systems in gram-negative bacteria. It delivers toxins and a range of hydrolytic enzymes including proteases, lipases and carbohydrate-active enzymes to the cell surface or extracellular space []. T2SS systems are composed of 11 to 15 different proteins, which are generally called GspA to GspO and GspS. The T2SS spans the two bacterial membranes and ensures secretion of folded proteins across the outer membrane pore formed by GspD. The inner membrane complex contains GspC, GspL, GspM, and GspF. The cytoplasmic domains of GspL and GspF interact with an ATPase, GspE. GspE is thought to energize the formation of a short pseudopilus by several pilin-like proteins, GspG to GspK []. GspD has been shown to interact with the inner membrane component GspC []. The T2SS pseudopilus is a periplasmic filament composed of the major pseudopilin, EpsG, and four minor pseudopilins, EpsH, EpsI, EpsJ and EpsK. Pseudopilus is assembled by the polymerization of GspG (also known as PulG) subunits. Pseudopilin proteins have a conserved N-terminal hydrophobic segment followed by a more variable C-terminal periplasmic and globular domain [
].
This entry represents the Sporulation inhibitor of replication (sirA) family of proteins from Bacillus sp. Induction of sporulation in rapidly growing cells inhibits replication; this is thought to be through the action of SirA protein and independent of phosphorylated Spo0A; however SirA protein synthesis is induced by Spo0A [
].
Ribosomal RNA-processing protein 8, N-terminal domain
Type:
Homologous_superfamily
Description:
Ribosomal RNA processing protein 8 (Rrp8) is a nucleolar Rossman-fold like methyltransferase. In yeast, it is involved in pre-rRNA cleavage at site A2 [
] and is responsible for a base methylation of the 25S rRNA []. In humans it is also known as nucleomethylin (NML), and it is important for mediating the assembly of the energy-dependent nucleolar silencing complex (eNoSC), which regulates rRNA transcription in response to glucose deprivation []. NML represses rDNA transcription by promoting H3K9 methylation and establishing heterochromatin across the rDNA [].This superfamily represents the N-terminal domain of the ribosomal RNA-processing protein 8 (RRP8).
Stress-response A/B barrel domain-containing protein HS1/DABB1-like
Type:
Family
Description:
This entry represents a group of stress-response A/B barrel domain-containing proteins, including HS1 (also known as Protein HEAT STABLE 1 or Pop3 family protein At3g17210) and DABB1 from Arabidopsis thaliana [
,
]. Proteins in this family have two stress responsive dimeric A/B barrel domains (Dabb) whose function is not yet clear []. In general, stress-response A/B barrel domain-containing proteins in plants are involved in defense against fungal pathogens. This entry also includes Cannabis sativa olivetolic acid cyclase (OAC), which is an A/B barrel domain-containing protein structurally similar to HS1 and contains amino acid residues that are conserved in plant stress-responsive DABB proteins []. OAC functions in concert with OLS/TKS to form olivetolic acid, an alkylresorcinolic acid that forms the polyketide nucleus of the cannabinoids [].This entry also includes related proteins from bacteria and fungi.
AcrA-AcrB-AcrZ-TolC is a drug efflux protein complex with a broad substrate specificity. AcrZ binds to AcrB and is required for efflux of some, but not all substrates, suggesting it may influence the specificity of drug export [
].
Transcriptional activator protein LysR, PBP2 domain
Type:
Domain
Description:
LysR is the transcriptional activator of lysA, a diaminopimelate decarboxylase that catalyses the decarboxylation of diaminopimelate to produce lysine. The C-terminal substrate-binding domain of LysR shows significant homology to the type 2 periplasmic binding proteins (PBP2) [
]. The PBP2 are responsible for the uptake of a variety of substrates such as phosphate, sulfate, polysaccharides, lysine/arginine/ornithine, and histidine. The PBP2 bind their ligand in the cleft between these domains in a manner resembling a Venus flytrap. After binding their specific ligand with high affinity, they can interact with a cognate membrane transport complex comprised of two integral membrane domains and two cytoplasmically located ATPase domains. This interaction triggers the ligand translocation across the cytoplasmic membrane energized by ATP hydrolysis. Besides transport proteins, the PBP2 superfamily includes the substrate- binding domains from ionotropic glutamate receptors, LysR-like transcriptional regulators, and unorthodox sensor proteins involved in signal transduction [
,
,
].
Telomere repeats-binding bouquet formation protein 1
Type:
Family
Description:
Telomere repeats-binding bouquet formation protein 1 (TERB1) is a TRF1-binding protein that promotes chromosome movement and telomere rigidity in meiosis [
,
]. Disruption of the TRF1-TERB1 interaction has been shown to result in failure of spermatogenesis []. The structure of TERB1 has been revealed [].
WAP four-disulfide core domain protein 1 (WFDC1), also known as ps20, has been implicated in epithelial cell behaviour and angiogenesis [
]. It has been linked to prostate cancer [].
Glutamine amidotransferase domain containing protein ChyE-like
Type:
Family
Description:
This entry represents a subgroup of class 1 glutamine amidotransferase (GATase1). GATase activity catalyses the transfer of ammonia from the amide side chain of glutamine to an acceptor substrate. Glutamine amidotransferases (GATase) includes the triad family of amidotransferases which have a conserved Cys-His-Glu catalytic triad in the glutaminase active site. In this subgroup this triad is conserved.Proteins in this subgroup are mostly from archaea, bacteria, plants and fungi. This entry includes ChyE from Penicillium rubens, YLR126C from budding yeast, GGP1-5 from plants. ChyE converts 2-(2-aminopropanamido)benzoic acid and 2-(2-aminopropanamido)benzamidine into 2-(2-(2-carboxyacetamido)propanamido)benzoic acid and 3-((1-((2-carbamoylphenyl)amino)-1-oxopropan-2-yl)amino)-3-oxopropanoic acid, respectively []. In Arabidopsis, GGP1 hydrolyzes the gamma-glutamyl peptide bond of several glutathione (GSH) conjugates to produce Cys-Gly conjugates related to glucosinolates. The gamma-Glu-Cys-Gly-GSH conjugates are the sulfur-donating molecule in glucosinolate biosynthesis [,
]. The function of YLR126C is still not clear.
This entry represents a group of proteins from fungi. Ima1 couples centromeres to the nuclear envelope, thus contributing to their association with the microtubule organizing centre attachment site and to the positioning of the nucleus at the cell centre by microtubules [
,
].
This group represents protein phosphatase 1 regulatory subunits 12A/B/C (also known as MYPT1/MYPT2/Mbs85) from animals. They are key regulators of protein phosphatase 1C (PPP1C). They modulates Ca
2+-dependent phosphorylation of myosin light chain by myosin light chain kinase, which is essential for smooth muscle contraction [
,
]. MYPT2 have similar features as MYPT1, such as: a specific interaction with the catalytic subunit of type 1 phosphatase, delta isoform (PP1cdelta); interaction of MYPT2 with the small heart-specific MP subunit; interaction of the C-terminal region of MYPT2 with the active form of RhoA; phosphorylation by Rho-kinase at an inhibitory site, Thr646 and thiophosphorylation at Thr646 inhibited activity of the MYPT2-PP1cdelta complex []. Mbs85 has been shown to regulate myosin phosphatase activity [].
This entry represents glycogen-targeting PP1 (protein phosphatase 1) subunit GL (coded for by the PPP1R3B gene). It is primarily expressed in the liver where it promotes hepatic glycogen synthesis in response to insulin. It is also highly expressed in mammaian fetal lungs [
] and human (but not rodent) muscle [].
This entry represents protein phosphatase 1 regulatory subunit 3C
(PP1R3C), also known as PTG (protein targeting to glycogen). It acts as a glycogen-targeting subunits for PP1 (protein phosphatase 1) and regulates its activity. Overexpression of PTG causes large increases in glycogen storage in isolated hepatocytes or intact rat liver [].
The Gram-negative pathogen Escherichia coli causes several common bacterial illnesses in humans, including diarrhoea, neonatal meningitidis and urinary tract infections. Attachment to host tissues is essential for successful invasion, and requires interaction between a bacterial adhesive protein and its target receptor. This protein is usually
supported on a larger structure made up of heteropolymeric fibres []. Pyelonephritogenic E. coli specifically invade the uroepithelium by expressing between 100 and 300 pili on their cell surface. Pili are macromolecular structures that allow binding to a digalactoside receptor in the urinary tract.
P pili, or fimbriae, are ~68A in diameter and 1 micron in length, the bulk of which is a fibre composed of the main structural protein PapA [
]. At its tip, the pilus is terminated by a fibrillum consisting of repeating units of the PapE protein. This, in turn, is topped by the adhesins, PapF and PapG, both of which are needed for receptor binding. The tip fibrillum is anchored to the main PapA fibre by the PapK pilus-adaptor protein. PapH, an outer membrane protein, then anchors the entire rod in the bacterial envelope []. A cytoplasmic chaperone (PapD) assists in assembling the monomers of the macromolecule in the membrane.PapF, in addition to aiding in the virulence and binding of uropathogenic E. coli, also functions as an adapter protein that joins the distal end of the tip fibrillum to the main PapG adherence factor. By providing a complementary binding surface for PapE and PapG, pilus assembly is rapidly completed [].
Mitogen-activated protein kinase kinase kinase 12/13
Type:
Family
Description:
This entry represents mitogen-activated protein kinase kinase kinase, types 12/13 (MAP3K12 and MAP3K13), which form part of the mixed lineage kinase (MLK) family. MAP3K12 (also known as leucine-zipper protein kinase (ZPK), dual leucine zipper-bearing kinase (DLK) or MAPK-upstream kinase (MUK)) is a MAPKKK class protein kinase that induces JNK/SAPK activation. MAP3K12 is known to interact with MUK-binding inhibitory protein (MBIP). MBIP contains two tandem leucine-zipper-like motifs; MBIP interacts with one of the two leucine-zipper-like motifs of MAP3K12 and inhibits the activity of MAP3K12 to induce JNK/SAPK activation [
,
]. MAP3K12 is autophosphorylated on Ser/Thr in cytosol under basal conditions, and dephosphorylated when membrane-associated.MAP3K13 (also known as leucine zipper-bearing kinase LZK) activates the c-Jun-NH2 terminal kinase (JNK) pathway through activation of the MAP kinase kinase MAP2K7 [
]. MAP3K13 acts synergistically with peroxiredoxin-3 (PRDX3) to regulate the activation of NF-kappa-B in the cytosol. This activation is kinase-dependent and involves activating the IKK complex, the IKBKB-containing complex that phosphorylates inhibitors of NF-kappa-B [].
MAP3K12 (also known as leucine-zipper protein kinase (ZPK), dual leucine zipper-bearing kinase (DLK) or MAPK-upstream kinase (MUK)) is a MAPKKK class protein kinase that induces JNK/SAPK activation. MAP3K12 is known to interact with MUK-binding inhibitory protein (MBIP). MBIP contains two tandem leucine-zipper-like motifs; MBIP interacts with one of the two leucine-zipper-like motifs of MAP3K12 and inhibits the activity of MAP3K12 to induce JNK/SAPK activation [
,
]. MAP3K12 is autophosphorylated on Ser/Thr in cytosol under basal conditions, and dephosphorylated when membrane-associated.
MAP3K13 (also known as leucine zipper-bearing kinase LZK) activates the c-Jun-NH2 terminal kinase (JNK) pathway through activation of the MAP kinase kinase MAP2K7 [
,
]. MAP3K13 acts synergistically with peroxiredoxin-3 (PRDX3) to regulate the activation of NF-kappa-B in the cytosol. This activation is kinase-dependent and involves activating the IKK complex, the IKBKB-containing complex that phosphorylates inhibitors of NF-kappa-B []. MAP3K13 forms dimers/oligomers through its dual leucine zipper-like motif, and that this is necessary for activation of the JNK/SAPK pathway [].
Protein phosphatase 1(PP-1) is a major protein serine/threonine phosphatase that regulates a vast array of cellular processes. PP-1 action is controlled through regulatory subunits that not only dictate substrate specificity and subcellular localisation, but often regulate PP-1 activity [
]. The myosin phosphatase targeting protein (MYPT) family consists of regulatory subunits MYPT1, MYPT2, MBS85, MYPT3 and TIMAP. MYPT family members share several conserved domains, including an RVxF motif for PP1c binding, and several ankyrin repeats that mediate protein-protein interactions [].This entry consists of protein phosphatase 1 regulatory subunits 16A (MYPT3) and 16B (TIMAP). MYPT3 and TIMAP contain a C-terminal CaaX box (a prenylation motif where 'a' indicates an aliphatic amino acid: CLLM in MYPT3 and CRIS in TIMAP), similar to that identified in the Rho family of small GTPases, which targets the proteins to the cell membrane [
]. MYPT3 binding to PP1c inhibits its catalytic activity towards LC20, contrary to other MYPT family members []. TIMAP (TGF-beta-inhibited membrane-associated protein) is primarily localised to the plasma membrane of endothelial cells [,
]. TIMAP-PP1c substrates identified include the non-integrin laminin receptor 1 (LAMR1), which is involved in regulation of cell motility and angiogenesis [], and ERM (ezrin-radixin-moesin) proteins, which crosslink actin filaments with plasma membranes [].
This entry represents the C-terminal domain of dynein regulatory complex protein 1 (DRC1, also known as CCDC164). DRC1 is a key component of the nexin-dynein regulatory complex (N-DRC), essential for N-DRC integrity. It is required for the assembly and regulation of specific classes of inner dynein arm motors. It may also function to restrict dynein-driven microtubule sliding, thus aiding in the generation of ciliary bending [
]. Mutations of DRC1 gene cause Ciliary dyskinesia, primary, 21 (CILD21), which is a disorder characterised by abnormalities of motile cilia [
].
Copper binding periplasmic protein CusF superfamily
Type:
Homologous_superfamily
Description:
This superfamily represents the periplasmic metallochaperone CusF, a non-essential component of the CusCFBA system that confers copper and silver resistance in E. coli. Although not essential, CusF is required for optimal function [
,
,
].This entry also matches PilY2 protein.
NLRC4 is a nucleotide binding/leucine-rich Repeat (NLR) protein and a inflammasome activator. It contains an N-terminal homotypic interaction domain, a central nucleotide binding domain, and a series of C-terminal LRRs. NLRC4 activates CASP1, the primary protease responsible for converting pro-IL-1beta to active, secreted IL-1beta. NLRC4 has been linked to autoinflammation diseases [
].
Myeloid differentiation primary response protein MyD88
Type:
Family
Description:
Myeloid differentiation primary response protein MyD88 is an intracellular adaptor protein that has an essential role in innate immune signalling. It is vital for the proper responses of interleukin-1 and interleukin-18 and nearly all toll-like receptors (except TLR3) in the activation of transcription factors NF-kappa B and AP-1 followed by the induction of pro-inflammatory genes [
]. MyD88 contains a TIR (Toll/Interleukin-1 receptor) domain and a death domain [
]. The TIR domain is important for the protein's interaction with receptors, while the death domain is involved in signal transduction. For example, MyD88 interacts with IL-1R-associated kinase (IRAK)-4 through its death domain, and in turn, IRAK-4 activates other members of the IRAK family, like IRAK-1 [].Defects in MYD88 are the cause of MYD88 deficiency [
], also known as as recurrent pyogenic bacterial infections due to MYD88 deficiency.
This entry represents domain 2 found in YycH and YycI proteins which share the same structural fold [
]. Both YycH and YycI are always found in pair on the chromosome, downstream of the essential histidine kinase YycG. Additionally, both proteins share a function in regulating the YycG kinase with which they appear to form a ternary complex. Lastly, the two proteins always contain an N-terminal transmembrane helix and are localized to the periplasmic space as shown by PhoA fusion studies.YycI and YycH proteins interact to control the activity of the YycG kinase. Both YycI and YycH proteins are localized outside the cytoplasm and attached to the membrane by an N-terminal transmembrane sequence. Bacterial two-hybrid data showed that the YycH, YycI, and the kinase YycG form a ternary complex. The data suggest that YycH and YycI control the activity of YycG in the periplasm and that this control is crucial in regulating important cellular processes [
,
].
F-actin-capping protein subunit alpha/beta, domain 2
Type:
Homologous_superfamily
Description:
The F-actin capping protein binds in a calcium-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike gelsolin and severin this protein does not sever actin filaments. The F-actin capping protein is a heterodimer composed of two unrelated subunits: alpha (
) and beta (
). Neither of the subunits shows sequence similarity to other filament-capping proteins [
].This entry represents the beta subunit (CAPZB) and alpha subunit (CAPZA) domain 2, whose sequence is well conserved in eukaryotic species [
]. In Drosophila, mutations of the alpha and beta subunits cause actin accumulation and subsequent retinal degeneration []. In humans, CAPZB is part of the WASH complex that controls the fission of endosomes [].
This entry represents a group of mammalian proteins. This entry includes the human C20orf144 protein, which is a Bcl-2-like protein preferentially expressed in the testis.
The function of the Zinc finger CCHC domain-containing protein 9 (ZCCHC9) is not clear. In humans, it suppresses the transcription activities of NF-kappa B and SRE, and may play roles in the Mitogen-Activated Protein Kinase (MAPK) signalling transduction pathway [
].
This entry is represented by the Tobacco rattle virus, 16 kDa protein and similar proteins from Tobravirus. This weak suppressor of RNA silencing [
] is not essential for the systemic spread of the plant virus []. However, it is required for the transient invasion of the meristem [].
Coenzyme F420 biosynthesis protein FbiB, C-terminal
Type:
Domain
Description:
Coenzyme F420 differs between the Archaea and the Actinobacteria, where the numbers of glutamate residues attached are 2 (Archaea) or 5 to 6 (Mycobacterium). The enzyme in the Archaea is homologous to the N-terminal domain of FbiB from Mycobacterium bovis, and is responsible for glutamate ligation. Therefore it seems likely that the C-terminal domain of FbiB is involved in additional glutamate ligation.
This domain is found at the C terminus of A-kinase anchor protein 2 (AKAP2). It includes the site where the regulatory subunits (RII) of protein kinase AII binds [
].Besides AKAP2, proteins containing this domain include mitotic interactor and substrate of PLK1 (Misp) [
] and uncharacterised protein LOC113230.
This entry includes EssD, which is a component of the type VII secretion system (Ess) and acts as a secretion factor for the Ess pathway in Staphylococcus aureus [
]. Proteins containing this domain are part of the DNA/RNA non-specific endonuclease family that contains the His-Me finger fold, which is thought to be suited for efficient, nonspecific DNA cleavage [].
CRISPR-associated protein Cas8a1/Csx13, Myxan subtype, N-terminal
Type:
Domain
Description:
Members of the Myxococcus xanthus subtype of the Cas8a1/Csx13 family are found among cas (CRISPR-Associated) genes close to CRISPR repeats in Leptospira interrogans (a spirochete), Myxococcus xanthus (a delta-proteobacterium), and Lyngbya sp. PCC 8106 (a cyanobacterium). They are found with other cas genes in Anabaena variabilis ATCC 29413. In Myxococcus xanthus Cas8a1 is also known as DevT (developmental protein T) where stimulates synthesis of a signal transduction protein required for fruiting body morphogenesis (formation of fruiting bodies within the rod-shaped cells under starvation conditions that differentiate into spherical spores) [
,
].This entry corresponds to the N-terminal domain of the proteins; the C-terminal domain is described by
. In Lyngbya sp., the protein is split into two tandem genes, and this entry corresponds to the upstream gene in these species.
This entry represents RNA binding protein fox-1 homologue 1-3 (RBFOX1-3) and its homologues predominantly found in vertebrates. Members of this family regulate alternative splicing events by binding to 5'-UGCAUGU-3' elements [
,
].
In mammals, there are three Fox-1 homologues, RBFOX1-3 (RNA binding protein Fox-1 homologue 1-3). RBFOX1 is predominantly expressed in neurons, skeletal muscle and heart [
]. RBFOX1 binds to the C terminus of ataxin-2 and forms an ataxin-2/A2BP1 complex involved in RNA processing []. RBFOX2 is expressed in ovary, whole embryo, and human embryonic cell lines in addition to neurons and muscle []. RBFOX2 activates splicing of neuron-specific exons []. RBFOX3 is a nuclear RNA-binding protein that regulates alternative splicing of the RBFOX2 pre-mRNA, producing a message encoding a dominant negative form of the RBFOX2 protein. Its message is detected exclusively in post-mitotic regions of embryonic brain []. RBFOX3 modulates brain and muscle-specific splicing of exon EIIIB of fibronectin, exon N1 of c-src, and calcitonin/CGRP []. This protein family includes these mammal proteins, its homologues, and related proteins predominantly found in animals, including Sex determination protein fox-1 from Caenorhabditis elegans. Fox-1 plays a role in the sex determination pathway and X chromosome dosage compensation, and together with sex-1 is involved in making the distinction between one and two X-chromosomes [
]. The Fox-1 family proteins are evolutionarily conserved regulators of tissue-specific alternative splicing in metazoans []. They bind specifically to an RNA element, UGCAUG []. Members in this family harbour one RNA recognition motif (RRM).
This represents a group of short repeats that occurs in a limited number of membrane proteins. It may divide further in short repeats of around 7-10 residues of the pattern G-#-X(2)-#(2)-X (#=hydrophobic) [
].
Protein PUTATIVE RECOMBINATION INITIATION DEFECT 1
Type:
Family
Description:
This entry represent a group of plant proteins, including AtPRD1 from Arabidopsis. AtPRD1 is required for meiotic double strand break formation [
]. AtPRD1 is homologous to MEI1 of humans and mice and contains a conserved N-terminal region that can interact with AtSPO11-1 and itself [].In flowering plants, gametophyte formation relies on meiosis. In meiosis I, the homologous chromosomes are separated into two daughter cells. In meiosis II, the sister chromosomes are then separated into newly formed daughter cells. During prophase I, several events occurs: sister chromatid cohesion, homologous chromosome synapsis, recombination, crossover formation and chromosome segregation. Homologous recombination is initiated from the formation of DNA double-strand breaks (DSBs). The formation of DSBs is catalyzed by Spo11 and its homologues. So far, six Arabidopsis proteins, AtSPO11-1, AtSPO11-2, AtPRD1, AtPRD2, AtPRD3 and AtDFO, have been shown to be involved in DSB formation [
].
Protein RESISTANCE TO PHYTOPHTHORA 1, chloroplastic
Type:
Family
Description:
This entry represents a group of plant proteins, including RPH1 from Arabidopsis. RPH1 is a chloroplast protein that plays a role in immune reactions in response to pathogen Phytophthora brassicae [
].
The replicase polyproteins of the Nidoviruses such as, porcine arterivirus PRRSV, equine arterivirus EAV, human coronavirus 229E, and severe acute respiratory syndrome coronavirus (SARS-CoV), are predicted to be cleaved into 14 non-structural proteins (nsps) by the nsp4 main proteinase
and three accessory proteinases residing in nsp1-alpha, nsp1-beta and nsp2 [
,
,
].This entry represents the two nsp1 proteins that together act in a papain-like way to separate off the rest of the various functional domains of the polyprotein. Once inside the host cell, this nsp1 interferes with the regulation of interferon, thereby enabling the virus to replicate [
,
].
Zinc finger Ran-binding domain-containing protein 2
Type:
Family
Description:
ZRANB2 is a splice factor required for alternative splicing of TRA2B/SFRS10 transcripts. It may interfere with constitutive 5'-splice site selection [
].
Shp is a cell-surface protein which forms part of a complex responsible for haem uptake in Streptococcus pyogenes. During haem uptake Shp transfers a bound haem to HtsA, the lipoprotein component of an ABC transporter. This entry represents the haem-binding domain of Shp. It contains an immunoglobulin-like β-sandwich fold and has a unique haem-iron coordination, with the axial ligands being two methionine residues from the same Shp molecule []. Surrounding the haem pocket, there is a negative surface which may serve as a docking interface for haem transfer.
TRAF3-interacting protein 1, N-terminal domain superfamily
Type:
Homologous_superfamily
Description:
TRAF3-interacting protein 1 (TRAF3IP1) recruits TRAF3 (tumour necrosis factor receptor-associated factor 3) and DISC1 (Disrupted-In-Schizophrenia 1) to the microtubules and is conserved from worms to humans [
]. The N-terminal region is the microtubule binding domain and is well-conserved; the C-terminal 100 residues, also well-conserved, constitute the coiled-coil region which binds to TRAF3. The central region of the protein is rich in lysine and glutamic acid and carries KKE motifs which may also be necessary for tubulin-binding, but this region is the least well-conserved []. In humans, it plays an inhibitory role on IL13 signaling by binding to IL13RA1. It is involved in suppression of IL13-induced STAT6 phosphorylation, transcriptional activity and DNA-binding [,
].This superfamily represents the N-terminal domain of TRAF3-interacting protein 1.
Bridge-like lipid transfer protein family member 3A/B
Type:
Family
Description:
This family consists of bridge-like lipid transfer protein family member 3a/B (also known as UHRF1-binding protein 1 and 1-like proteins. These are tube-forming lipid transport proteins which mediate the transfer of lipids between membranes at organelle contact sites [
], and they are required for retrograde traffic of vesicle clusters in the early endocytic pathway to the Golgi complex [,
].
This entry represents the C-terminal domain of ER membrane protein complex subunit 1.ER membrane protein complex subunit 1 is a component of the ER membrane protein complex (EMC, composed of EMC1, EMC2, EMC3, EMC4, EMC5 and EMC6). In Saccharomyces cerevisiae, the EMC seems to be required for efficient folding of proteins in the endoplasmic reticulum (ER) [
].
Breast cancer type 1 susceptibility protein (BRCA1)
Type:
Family
Description:
Breast cancer is a common malignancy, affecting 1 in 8 women. A major contributary factor in disease development lies in a positive family history, a correlation that is striking for early-onset breast cancer. Mutations in the DNA-damage repair protein BRCA1 [
,
] are believed to be responsible for 45% of inherited breast cancer and more than 80% of inherited breast and ovarian cancer.The BRCA1 protein is a E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage [
,
]. It contains an N-terminal zinc-finger domain. It also contains a BRCT C-terminal domain, an approximately 100 amino acid tandem repeat, which appears to act as a phospho-protein binding domain [].
This presumed domain is always found to the N-terminal side of the NUDIX hydrolase domain
. This domain appears to be specific to mRNA decapping protein 2 (DCP2)
and its close homologues. This region has been termed Box A [
].
RecQ mediated genome instability protein 1, N-terminal
Type:
Domain
Description:
This entry represents the N-terminal domain of RMI1 (RecQ-mediated genome instability protein 1) and similar proteins [
]. This domain carries an oligo-nucleotide-binding domain or OB-fold, and forms a stable complex with Bloom syndrome protein BLM and DNA topoisomerase 3-alpha [].
Vesicle tethering protein Uso1/P115-like , head domain
Type:
Domain
Description:
This domain identifies a group of proteins, which are described as: General vesicular transport factor, Transcytosis associated protein (TAP) or Vesicle docking protein, this myosin-shaped molecule consists of an N-terminal globular head region, a coiled-coil tail which mediates dimerisation, and a short C-terminal acidic region [
]. p115 tethers COP1 vesicles to the Golgi by binding the coiled coil proteins giantin (on the vesicles) and GM130 (on the Golgi), via its C-terminal acidic region. It is required for intercisternal transport in the Golgi stack. This domain is found in the head region. The head region is highly conserved, but its function is unknown. It does not seem to be essential for vesicle tethering []. The N-terminal part of the head region contains context-detected Armadillo/beta-catenin-like repeats.
Probable cytosolic iron-sulfur protein assembly protein, CIAO1/Cia1
Type:
Family
Description:
Proteins in this entry are probable cytosolic iron-sulfur (FeS) protein assembly proteins from eucaryotes, including Cia1 from Saccharomyces cerevisiae and CIAO1 from humans. Iron-sulfur [Fe-S] clusters are ubiquitous and evolutionary ancient prosthetic groups that are required to sustain fundamental life processes []. They can be used as part of catalytic centres for chemical sensing, stabilise protein structure and determine protein function []. In Saccharomyces cerevisiae, Cia1 is a component of cytosolic iron-sulfur cluster assembly (CIA) system (consists of Nar1, Nbp35 and Cia1). It is involved in a late step of Fe/S cluster incorporation into target proteins [
]. In humans, it is also a component of the human CIA system. Moreover, it binds to IOP1 and forms the MMXD complex (MMS19, XPD, MIP18 and ANT2), which is involved in chromosome segregation [
,
].
Clp protease proteolytic subunit /Translocation-enhancing protein TepA
Type:
Family
Description:
This entry includes peptidases from the MEROPS peptidase family S14, including ClpP endopeptidase and translocation-enhancing protein TepA.ClpP is an ATP-dependent protease that cleaves a number of proteins, such as casein and albumin [
]. It exists as a heterodimer of ATP-binding regulatory A and catalytic P subunits, both of which are required for effective levels of protease activity in the presence ofATP [
], although the P subunit alone does possess some catalytic activity. Proteases highly similar to ClpP have been found to be encoded in the genome of bacteria, metazoa, some viruses and in the chloroplast of plants. A number of the proteins in this family are classified as non-peptidase homologues as they have been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for catalytic activity. Translocation-enhancing protein TepA displays sequence similarity to ClpP. It is required for efficient translocation of pre-proteins across the membrane [
].
Nuclear pore localisation protein Npl4, ubiquitin-like domain
Type:
Domain
Description:
Npl4, along with Ufd1, forms the heterodimer adaptor complex UN, which is involved in the recruitment of p97, an AAA ATPase, for tasks involving the ubiquitin pathway.Npl4 has a N-terminal ubiquitin-like domain which has within its structure a β-grasp fold with a helical insert [
]. This entry represents the ubiquitin-like domain.
Ribosomal protein L25/Gln-tRNA synthetase, anti-codon-binding domain superfamily
Type:
Homologous_superfamily
Description:
The bacterial ribosomal protein L25 is bound to 5S rRNA along with L5 and L18, forming a separate domain of the ribosome [
]. The solution structure of protein L25 uncomplexed with RNA shows two significantly disordered loops and a closed β-barrel domain with a complex topology that has significant structural similarities to the N-terminal domain of the Thermus thermophilus ribosomal protein TL5, to the general stress protein CTC, and to the C-terminal anticodon-binding domain of Escherichia coli glutaminyl-tRNA synthetase (GlnRS) [,
]. GlnRS contains a duplication consisting of two L25-like β-barrels domains with the swapping of N-terminal strands.
NADH dehydrogenase ubiquinone Fe-S protein 4 mitochondrial-like
Type:
Family
Description:
This entry includes NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUS4), an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), initially identified in Neurospora crassa as a 21kDa protein [,
]. It is believed that members of this family are not involved in catalysis. This entry also includes uncharacterised bacterial sequences.
Nuclear speckle splicing regulatory protein 1, N-terminal
Type:
Domain
Description:
This domain is found at the N-terminal of Nuclear speckle splicing regulatory protein 1 (NRP1, also known as Nuclear speckle-related protein 70 and Coiled-coil domain-containing protein 55) and contains a coiled-coil domain that plays a critical role in NRP1 alternative splicing activity and self-oligomerization. NRP1 is a RNA-binding protein that mediates pre-mRNA alternative splicing regulation [
,
].
Nuclear pore complex protein NUP96, C-terminal domain
Type:
Domain
Description:
This entry represents the Nuclear pore complex protein Nup96 from animals its homologues from yeast and plants.Nuclear pore complexes (NPCs) facilitate all nucleocytoplasmic transport in eukaryotic cells, playing essential roles in cellular homeostasis. The NPC is a modular structure composed of multiple copies of ~30 proteins (nucleoporins, Nups) arranged into distinct subcomplexes [
,
]. A number of these peptides are synthesised as precursors and undergo self-catalyzed cleavage. The largest NPC sub-complex is the heptameric Y-shaped mammalian Nup107-Nup160 complex (called Nup84 complex in budding yeast), an essential scaffolding component of the NPC [,
,
]. Nup98 and Nup96 are encoded by the same gene that produces a 190 kDa polyprotein with autoproteolytic activity which generates the N-terminal NUP98 and C-terminal NUP96 proteins, part of the Nup107-Nup160 subcomplex [
,
]. The yeast homologue Nup145 undergoes the similar proteolytic event to produce Nup145N and Nup145C, which are part of the Nup84 complex. The function of the heptamer is to coat the curvature of the nuclear pore complex between the inner and outer nuclear membranes. Nup96, which is predicted to be an alpha helical solenoid, complexes with Sec13 in the middle of the heptamer. The interaction between Nup96 and Sec13 is the point of curvature in the heptameric complex [,
].
DNA recombination and repair protein RecA, C-terminal
Type:
Homologous_superfamily
Description:
The recA gene product is a multifunctional enzyme that plays a role in homologous recombination, DNA repair and induction of the SOS response [
]. In homologous recombination, the protein functions as a DNA-dependent ATPase, promoting synapsis, heteroduplex formation and strand exchange between homologous DNAs []. RecA also acts as a protease cofactor that promotes autodigestion of the lexA product and phage repressors. The proteolytic inactivation of the lexA repressor by an activated form of recA may cause a derepression of the 20 or so genes involved in the SOS response, which regulates DNA repair, induced mutagenesis, delayed cell division and prophage induction in response to DNA damage []. RecA is a protein of about 350 amino-acid residues. Its sequence is very well conserved [
,
,
] among eubacterial species. It is also found in the chloroplast of plants []. RecA-like proteins are found in archaea and diverse eukaryotic organisms, like fission yeast, mouse or human. In the filamentvisualised by X-ray crystallography, β-strand 3, the loop C-terminal to β-strand 2, and α-helix D of the core domain form one surface that packs against α-helix A and β-strand 0 (the N-terminal domain) of an adjacent monomer during polymerisation [
]. The core ATP-binding site domain is well conserved, with 14 invariant residues. It contains the nucleotide binding loop between β-strand 1 and α-helix C. The Escherichia coli sequence GPESSGKT matches the consensus sequence of amino acids (G/A)XXXXGK(T/S) for the Walker A box (alsoreferred to as the P-loop) found in a number of nucleoside triphosphate (NTP)-binding proteins. Another
nucleotide binding motif, the Walker B box is found at β-strand 4 in the RecA structure. The Walker Bbox is characterised by four hydrophobic amino acids followed by an acidic residue (usually aspartate). Nucleotide specificity and additional ATP binding interactions are contributed by the amino acid residues at β-strand 2 and the loop C-terminal to that
strand, all of which are greater than 90% conserved among bacterial RecA proteins.This superfamily represents the C-terminal domain, which forms an alpha/beta two layer sandwich [
].
U3 small nucleolar RNA-associated protein 13, C-terminal
Type:
Domain
Description:
A large ribonuclear protein complex is required for the processing of the small-ribosomal-subunit rRNA - the small-subunit (SSU) processome [,
]. This preribosomal complex contains the U3 snoRNA and at least 40 proteins, which have the following properties: They are nucleolar.They are able to coimmunoprecipitate with the U3 snoRNA and Mpp10 (a protein specific to the SSU processome). They are required for 18S rRNA biogenesis.There appears to be a linkage between polymerase I transcription and the formation of the SSU processome; as some, but not all, of the SSU processome components are required for pre-rRNA transcription initiation. These SSU processome components have been termed t-Utps. They form a pre-complex with pre-18S rRNA in the absence of snoRNA U3 and other SSU processome components. It has been proposed that the t-Utp complex proteins are both rDNA and rRNA binding proteins that are involved in the initiation of pre18S rRNA transcription. Initially binding to rDNA then associating with the 5' end of the nascent pre18S rRNA. The t-Utpcomplex forms the nucleus around which the rest of the SSU processome components, including snoRNA U3, assemble [
]. From electron microscopy the SSU processome may correspond to the terminal knobs visualized at the 5' ends of nascent 18S rRNA. Utp13 is a nucleolar protein and component of the small subunit (SSU) processome containing the U3 snoRNA that is involved in processing of pre-18S rRNA [
]. Upt13 is also a component of the Pwp2 complex that forms part of a stable particle subunit independent of the U3 small nucleolar ribonucleoprotein that is essential for the initial assembly steps of the 90S pre-ribosome [
]. Components of the Pwp2 complex are:Utp1 (Pwp2), Utp6, Utp12 (Dip2), Utp13, Utp18, and Utp21. The relationship between the Pwp2 complex and the t-Utps complex [
] that also associates with the 5' end of nascent pre-18S rRNA is unclear. This is the C-terminal helical domain of yeast Utp13 and its orthologue from human, Transducin beta-like protein 3, whose function is not clear. This domain is also found in protein TORMOZ EMBRYO DEFECTIVE from plants, which is an essential protein involved in the regulation of cell division planes during embryogenesis and defines cell patterning [
].
Protein N-terminal glutamine amidohydrolase, alpha beta roll
Type:
Domain
Description:
This entry represents a structural domain found in the N-terminal glutamine amidohydrolase (Nt
Q-amidase) family of proteins. These proteins contain a region of approximately 200 residues carrying several distinctive motifs including a WDYHV motif and one of three cysteines. Protein N-terminal glutamine amidohydrolase is responsible for degradation of N-terminal glutamine [
].
U3 small nucleolar RNA-associated protein 10, N-terminal
Type:
Domain
Description:
This entry represents the N-terminal domain of Utp10, which is a HEAT-repeat containing protein involved in nucleolar processing of pre-18S ribosomal RNA [
]. Utp10 is also involved in 40S ribosome maturation []. Proteins containing this domain also include HEATR1 from humans. HEATR1 is required for optimal pre-ribosomal RNA transcription by RNA polymerase I [].
U3 small nucleolar RNA-associated protein 15, C-terminal
Type:
Domain
Description:
This entry represents the C-terminal domain of the U3 small nucleolar RNA-associated protein 15 (UTP15). This protein is involved in nucleolar processing of pre-18S ribosomal RNA, and is required for optimal pre-ribosomal RNA transcription by RNA polymerase I together with a subset of U3 proteins required for transcription (t-UTPs). UTP15 is a component of the ribosomal small subunit (SSU) processome, which is a large ribonucleoprotein (RNP) required for processing of precursors to the small subunit RNA, the 18S, of the ribosome [,
]. This domain is found C-terminal to the WD40 repeat (). UTP15 associates with U3 snoRNA, which is ubiquitous in eukaryotes and is required for nucleolar processing of pre-18S ribosomal RNA [
].
Large ribosomal RNA subunit accumulation protein YceD
Type:
Family
Description:
This family includes the large ribosomal RNA subunit accumulation protein YceD. Gene knockout in
Escherichia colileads to significant reduction of 23S rRNA. These proteins are nearly universally conserved in bacteria and plants. In
Nicotiana benthamianaleaves the protein is localized in chloroplasts [
].
Protein phosphatase 4 core regulatory subunit R2 (PPP4R2), also known as Psy4 in budding yeast, is the regulatory subunit of the histone H2A phosphatase complex. The histone H2A phosphatase complex dephosphorylates H2AS128ph (gamma-H2A) that has been displaced from sites of DNA lesions in the double-stranded DNA break repair process. Dephosphorylation of Psy4 is necessary for efficient recovery from the DNA damage checkpoint [
].
Molybdenum cofactor biosynthesis protein A-like, twitch domain
Type:
Domain
Description:
This entry represents the iron-sulfur cluster-binding twitch domain of GTP 3',8-cyclase, which is also known as molybdenum cofactor biosynthesis protein A (MoaA) in bacteria and archaea, molybdenum cofactor biosynthesis protein 1 (MOCS1) in most eukaryotes, and molybdenum cofactor biosynthesis enzyme CNX2 in plants [
]. They belong to a family of enzymes involved in the synthesis of metallo-cofactors (). Each subunit of the MoaA dimer is comprised of an N-terminal SAM domain (
) that contains the [4Fe-4S] cluster typical for this family of enzymes, as well as an additional [4Fe-4S]cluster in the C-terminal domain that is unique to MoaA proteins, involved in substrate binding [
]. The unique Fe site of the C-terminal [4Fe-4S]cluster is thought to be involved in the binding and activation of 5'-GTP [
].Mutations in the human MoCF biosynthesis proteins MOCS1, MOCS2 or GEPH cause MoCF Deficiency type A (MOCOD), causing the loss of activity of MoCF-containing enzymes, resulting in neurological abnormalities and death [
].The majority of molybdenum-containing enzymes utilise a molybdenum cofactor (MoCF or Moco) consisting of a Mo atom coordinated via a cis-dithiolene moiety to molybdopterin (MPT). MoCF is ubiquitous in nature, and the pathway for MoCF biosynthesis is conserved in all three domains of life. MoCF-containing enzymes function as oxidoreductases in carbon, nitrogen, and sulphur metabolism [
,
]. In Escherichia coli, biosynthesis of MoCF is a three stage process. It begins with the MoaA and MoaC conversion of GTP to the meta-stable pterin intermediate precursor Z. The second stage involves MPT synthase (MoaD and MoaE), which converts precursor Z to MPT; MoeB is involved in the recycling of MPT synthase. The final step in MoCF synthesis is the attachment of mononuclear Mo to MPT, a process that requires MoeA and which is enhanced by MogA in an Mg2 ATP-dependent manner [
]. MoCF is the active co-factor in eukaryotic and some prokaryotic molybdo-enzymes, but the majority of bacterial enzymes requiring MoCF, need a modification of MTP for it to be active; MobA is involved in the attachment of a nucleotide monophosphate to MPT resulting in the MGD co-factor, the active co-factor for most prokaryotic molybdo-enzymes. Bacterial two-hybrid studies have revealed the close interactions between MoeA, MogA, and MobA in the synthesis of MoCF []. Moreover the close functional association of MoeA and MogA in the synthesis of MoCF is supported by fact that the known eukaryotic homologues to MoeA and MogA exist as fusion proteins: CNX1 () of Arabidopsis thaliana (Mouse-ear cress), mammalian Gephryin (e.g.
) and Drosophila melanogaster (Fruit fly) Cinnamon (
) [
].
Vacuolar ATPase assembly integral membrane protein Vma21
Type:
Family
Description:
The vacuolar ATPase assembly integral membrane protein Vma21 is required for the assembly of the integral membrane sector (V0 component) of the vacuolar ATPase (V-ATPase) in the endoplasmic reticulum [
].
U3 small nucleolar RNA-associated protein 20, N-terminal
Type:
Domain
Description:
This entry represents a domain found towards the N-terminal of eukaryotic proteins including U3 small nucleolar RNA-associated protein 20 from yeast and the human homologue, also known as DRIM (Down-Regulated In Metastasis) (
). DRIM is differentially expressed in metastatic and non-metastatic human breast carcinoma cells [
]. Proteins of this entry are involved in processing of non-coding RNA as components of the small-subunit (SSU) processome; SSU processome is involved in the biogenesis of the 18S rRNA [
,
]. UTP20 is a huge α-solenoid that functions as a scaffold [,
].
DNA recombination and repair protein Rad51-like, C-terminal
Type:
Domain
Description:
This domain is found at the C terminus of DNA repair and recombination protein Rad51, and eukaryotic and archaeal Rad51-like proteins. It is critical for DNA binding [
]. Rad51 is a homologue of the bacterial RecA protein. Rad51 and RecA share a core ATPase domain.Unlike eubacteria, several archaeal species have two recA/RAD51-like genes, called RadA and RadB. Among eukaryotes, yeast contain four RAD51-like genes (RAD51, DMC1, RAD55/rhp55, and RAD57/rhp57). In vertebrate animals and plants, there are different RAD51-like genes: RAD51, RAD51B, RAD51C, RAD51D, DMC1, XRCC2, and XRCC3 [
].
ATPase family AAA domain-containing protein 3, N-terminal
Type:
Domain
Description:
This is the conserved N-terminal domain of ATPase family AAA domain-containing protein 3 (ATAD3) which is involved in dimerisation [
] and interacts with the inner surface of the outer mitochondrial membrane []. This domain is found associated with the AAA ATPase domain . ATAD3 is essential for mitochondrial network organisation, mitochondrial metabolism and cell growth at organism and cellular level. It may also play an important role in mitochondrial protein synthesis.
Regulator of chromosome condensation 1/beta-lactamase-inhibitor protein II
Type:
Homologous_superfamily
Description:
The beta-lactamase-inhibitor protein II (BLIP-II) is a secreted protein produced by the soil bacteria Streptomyces exfoliates SMF19. BLIP-II acts as a potent inhibitor of beta-lactamases such as TEM-1, which is the most widespread resistance enzyme to penicillin antibiotics. BLIP-II binds competitively to TEM-1, but no direct contacts are made with TEM-1 active site residues. BLIP-II shows no sequence similarity with BLIP, even though both bind to and inhibit TEM-1. However, BLIP-II does share significant sequence identity with the regulator of chromosome condensation (RCC1) family of proteins. These two families are clearly related, both having a seven-bladed β-propeller structure, although they differ in the number of strands per blade, BLIP-II having three antiparallel β-strands per blade, while RCC1 has four-stranded blades []. RCC1 is a eukaryotic nuclear protein that acts as a guanine nucleotide exchange factor for Ran, a member of the Ras GTPase family. RCC1 mediates a Ran-GTP gradient necessary for the regulation of spindle formation and nuclear assembly during mitosis, as well as for the transport of macromolecules across the nuclear membrane during interphase.
Organic solute transporter subunit alpha/Transmembrane protein 184
Type:
Family
Description:
This entry includes Organic solute transporter subunit alpha (OSTalpha, also known as SLC51A) and Transmembrane protein 184 (TMEM184). Ost-alpha protein is a 7-transmembrane (TM) domain containing protein that forms a transporter complex with Ost-beta protein, which is a single-TM domain polypeptide. This heterodimerisation is required for the delivery of the complex to the plasma membrane. The OSTalpha-OSTbeta complex serves as a multispecific transporter that may participate in cellular uptake of bile acids, some endogenous and exogenous steroids, and eicosanoids. It functions via a facilitated diffusion mechanism. Interestingly, this transporter also transports dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PREGS), which are major excitatory neurosteroids. This suggests a possible function for OSTalpha-OSTbeta complex in the brain [
]. In plants this complex may transport brassinosteroid-like compounds and act as regulators of cell death [].Human TMEM184C is a possible tumour suppressor which may play a role in cell growth [
]. This entry also includes Arabidopsis protein LAZ1, which is required for programmed cell death (PCD) associated with hypersensitive response (HR) [].
Putative zinc- or iron-chelating domain containing protein
Type:
Family
Description:
This family of proteins contains 8 conserved cysteines. It has in the past been annotated as being one of the complex of proteins of the flagellar Fli complex. However this was due to a mis-annotation of the original Salmonella LT2 Genbank entry of 'fliB'. With all its conserved cysteines it is possibly a domain that chelates iron or zinc ions [
,
].
Guanine nucleotide binding protein (G-protein), alpha subunit
Type:
Family
Description:
Guanine nucleotide binding proteins (G proteins) are membrane-associated, heterotrimeric proteins composed of three subunits: alpha (
), beta (
) and gamma (
) [
]. G proteins and their receptors (GPCRs) form one of the most prevalent signalling systems in mammalian cells, regulating systems as diverse as sensory perception, cell growth and hormonal regulation []. At the cell surface, the binding of ligands such as hormones and neurotransmitters to a GPCR activates the receptor by causing a conformational change, which in turn activates the bound G protein on the intracellular-side of the membrane. The activated receptor promotes the exchange of bound GDP for GTP on the G protein alpha subunit. GTP binding changes the conformation of switch regions within the alpha subunit, which allows the bound trimeric G protein (inactive) to be released from the receptor, and to dissociate into active alpha subunit (GTP-bound) and beta/gamma dimer. The alpha subunit and the beta/gamma dimer go on to activate distinct downstream effectors, such as adenylyl cyclase, phosphodiesterases, phospholipase C, and ion channels. These effectors in turn regulate the intracellular concentrations of secondary messengers, such as cAMP, diacylglycerol, sodium or calcium cations, which ultimately lead to a physiological response, usually via the downstream regulation of gene transcription. The cycle is completed by the hydrolysis of alpha subunit-bound GTP to GDP, resulting in the re-association of the alpha and beta/gamma subunits and their binding to the receptor, which terminates the signal []. The length of the G protein signal is controlled by the duration of the GTP-bound alpha subunit, which can be regulated by RGS (regulator of G protein signalling) proteins or by covalent modifications [].G protein alpha subunits are 350-400 amino acids in length and have
molecular weights in the range 40-45kDa. Seventeen distinct types ofalpha subunit have been identified in mammals. These fall into 4 main
groups on the basis of both sequence similarity and function: alpha-S (),
alpha-Q (), alpha-I (
)and alpha-12(
) [
].The specific combination of subunits in heterotrimeric G proteins affects not only which receptor it can bind to, but also which downstream target is affected, providing the means to target specific physiological processes in response to specific external stimuli [,
]. G proteins carry lipid modifications on one or more of their subunits to target them to the plasma membrane and to contribute to protein interactions.This family consists of the G protein alpha subunit, which acts as a weak GTPase. G protein classes are defined based on the sequence and function of their alpha subunits, which in mammals fall into four main categories: G alpha-S (
), G alpha-Q (
), G alpha-I (
) and G alpha-12 (
); there are also fungal (
) and plant classes (
) of alpha subunits.
Many alpha subunits are substrates for ADP-ribosylation by cholera or pertussis toxins. They are often N-terminally acylated, usually with myristate and/or palmitoylate, and these fatty acid modifications are probably important for membrane association and high-affinity interactions with other proteins. The alpha subunit consists of two domains: a GTP-binding domain and a helical insertion domain (
). The GTP-binding domain is homologous to Ras-like small GTPases, and includes switch regions I and II, which change conformation during activation. The switch regions are loops of α-helices with conformations sensitive to guanine nucleotides. The helical insertion domain is inserted into the GTP-binding domain before switch region I and is unique to heterotrimeric G proteins. This helical insertion domain functions to sequester the guanine nucleotide at the interface with the GTP-binding domain and must be displaced to enable nucleotide dissociation.
Domain 2 of the ribosomal protein S5 has a left-handed β-α-β fold that is found in numerous RNA/DNA-binding proteins, as well as in kinases from the GHMP kinase family. Proteins containing this β-α-β fold domain include: Translational machinery components (ribosomal proteins S5 and S9, and domain IV of elongation factors EF-G and eEF-2) [
].Ribonuclease P protein (RNase P) [
].DNA modification proteins (DNA mismatch repair proteins MutL and PMS2, DNA gyrase B, DNA topoisomerase II, IV-B and VI-B) [
].GHMP kinases that transfer a phosphoryl group from ATP to an acceptor (galactokinase (
), homoserine kinase (
), and mevalonate kinase (
)) [
,
].Caenorhabditis elegans early switch protein Xol-1 (a divergent member of the GHMP kinase family that has lost the ATP-binding site) [
].
Solute-binding protein family 3/N-terminal domain of MltF
Type:
Domain
Description:
Bacterial high affinity transport systems are involved in active transport of solutes across the cytoplasmic membrane. Most of the bacterial ABC (ATP-binding cassette) importers are composed of one or two transmembrane permease proteins, one or two nucleotide-binding proteins and a highly specific periplasmic solute-binding protein. In Gram-negative bacteria the solute-binding proteins are dissolved in the periplasm, while in archaea and Gram-positive bacteria, their solute-binding proteins are membrane-anchored lipoproteins [
,
]. On the basis of sequence similarities, the vast majority of these solute-binding proteins can be grouped [
] into eight families or clusters, which generally correlate with the nature of the solute bound.This entry represents a domain found in the solute-binding protein family 3 members from Gram-positive bacteria, Gram-negative bacteria and archaea. This domain can also be found in the N-terminal of the membrane-bound lytic murein transglycosylase F (MltF) protein. MltF is a murein-degrading enzyme that degrades murein glycan strands and insoluble, high-molecular weight murein sacculi, with the concomitant formation of a 1,6-anhydromuramoyl product [
].Familiy 3 members include:Histidine-binding protein (gene hisJ) of Escherichia coli and related bacteria. An homologous lipoprotein exists in Neisseria gonorrhoeae. Lysine/arginine/ornithine-binding proteins (LAO) (gene argT) of Escherichia coli and related bacteria are involved in the same transport system than hisJ. Both solute-binding proteins interact with a common membrane-bound receptor hisP of the binding protein dependent transport system HisQMP. Glutamine-binding proteins (gene glnH) of Escherichia coli and Bacillus stearothermophilus.Glutamate-binding protein (gene gluB) of Corynebacterium glutamicum. Arginine-binding proteins artI and artJ of Escherichia coli. Nopaline-binding protein (gene nocT) from Agrobacterium tumefaciens. Octopine-binding protein (gene occT) from Agrobacterium tumefaciens. Major cell-binding factor (CBF1) (gene: peb1A) from Campylobacter jejuni. Bacteroides nodosus protein aabA. Cyclohexadienyl/arogenate dehydratase of Pseudomonas aeruginosa, a periplasmic enzyme which forms an alternative pathway for phenylalanine biosynthesis. Escherichia coli L-cystine-binding protein TcyJ, previously known as protein fliY.Vibrio harveyi protein patH. Bacillus subtilis Probable ABC transporter extracellular-binding protein yckB. Bacillus subtilis L-cystine-binding protein TcyA, also known as yckK.
Cyclase-associated protein CAP/septum formation inhibitor MinC, C-terminal
Type:
Homologous_superfamily
Description:
Cyclase-associated proteins (CAPs) are highly conserved monomeric actin-binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways [
,
,
,
]. Only yeast CAPs are involved in adenylate cyclase activation. The C-terminal domain of CAP proteins is responsible for G-actin-binding that regulates actin remodelling in response to cellular signals and is required for normal cellular morphology, cell division, growth and locomotion in eukaryotes.In Escherichia coli, three Min proteins (MinC, MinD and MinE) negatively regulate FtsZ assembly at the cell poles in order to ensure the Z-ring only assembles at cell midpoint. MinC inhibits formation of the Z-ring by preventing FtsZ assembly. MinD binds to MinC near the cell poles, sequestering MinC away from the cell midpoint so the Z-ring can form there. MinC is an oligomer, probably a dimer, that consists of two domains: the N-terminal domain is responsible for FtsZ inhibition, while the C-terminal domain is responsible for binding to MinD and to a component of the division septum [
,
].This entry represents a structural domain found at the C-terminal of CAP proteins as well as MinC. This domain has a superhelical structure, where the superhelix turns are made of either two (CAP) or three (MinC) β-strands each.
DNA mismatch repair protein MutS, connector domain
Type:
Domain
Description:
Mismatch repair contributes to the overall fidelity of DNA replication and is essential for combating the adverse effects of damage to the genome. It involves the correction of mismatched base pairs that have been missed by the proofreading element of the DNA polymerase complex. The post-replicative Mismatch Repair System (MMRS) of Escherichia coli involves MutS (Mutator S), MutL and MutH proteins, and acts to correct point mutations or small insertion/deletion loops produced during DNA replication [
]. MutS and MutL are involved in preventing recombination between partially homologous DNA sequences. The assembly of MMRS is initiated by MutS, which recognises and binds to mispaired nucleotides and allows further action of MutL and MutH to eliminate a portion of newly synthesized DNA strand containing the mispaired base []. MutS can also collaborate with methyltransferases in the repair of O(6)-methylguanine damage, which would otherwise pair with thymine during replication to create an O(6)mG:T mismatch []. MutS exists as a dimer, where the two monomers have different conformations and form a heterodimer at the structural level []. Only one monomer recognises the mismatch specifically and has ADP bound. Non-specific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. Mismatch binding induces ATP uptake and a conformational change in the MutS protein, resulting in a clamp that translocates on DNA. MutS is a modular protein with a complex structure [
], and is composed of:N-terminal mismatch-recognition domain, which is similar in structure to tRNA endonuclease.Connector domain, which is similar in structure to Holliday junction resolvase ruvC.Core domain, which is composed of two separate subdomains that join together to form a helical bundle; from within the core domain, two helices act as levers that extend towards (but do not touch) the DNA.Clamp domain, which is inserted between the two subdomains of the core domain at the top of the lever helices; the clamp domain has a β-sheet structure.ATPase domain (connected to the core domain), which has a classical Walker A motif.HTH (helix-turn-helix) domain, which is involved in dimer contacts.The MutS family of proteins is named after the Salmonella typhimurium MutS protein involved in mismatch repair. Homologues of MutS have been found in many species including eukaryotes (MSH 1, 2, 3, 4, 5, and 6 proteins), archaea and bacteria, and together these proteins have been grouped into the MutS family. Although many of these proteins have similar activities to the E. coli MutS, there is significant diversity of function among the MutS family members. Human MSH has been implicated in non-polyposis colorectal carcinoma (HNPCC) and is a mismatch binding protein [
].This diversity is even seen within species, where many species encode multiple MutS homologues with distinct functions []. Inter-species homologues may have arisen through frequent ancient horizontal gene transfer of MutS (and MutL) from bacteria to archaea and eukaryotes via endosymbiotic ancestors of mitochondria and chloroplasts []. This entry represents the connector domain (domain 2) found in proteins of the MutS family. The structure of the MutS connector domain consists of a parallel β-sheet surrounded by four alpha helices, which is similar to the structure of the Holliday junction resolvase ruvC.
This entry includes TssB1, which is a sheath protein of the bacterial type VI secretion system (T6SS) [
]. The type VI secretion system (T6SS) is a supra-molecular bacterial complex that resembles phage tails. It is a toxin delivery systems which fires toxins into target cells upon contraction of its TssBC sheath [
]. Thirteen essential core proteins are conserved in all T6SSs: the membrane associated complex TssJ-TssL-TssM, the baseplate proteins TssE, TssF, TssG, and TssK, the bacteriophage-related puncturing complex composed of the tube (Hcp), the tip/puncturing device VgrG, and the contractile sheath structure (TssB and TssC). Finally, the starfish-shaped dodecameric protein, TssA, limits contractile sheath polymerization at its distal part when TagA captures TssA [].
A number of bacterial proteins, some of which are involved in a general secretion pathway (GSP) for the export of proteins (also called the type II pathway) [
], have been found to be evolutionary related. These are proteins of about 400 amino acids that are highly hydrophobic and which are thought to be integral protein of the inner membrane. Proteins with this domain form a platform for the type II secretion machinery, as well as the type IV pili and the archaeal flagellae [].
Molybdopterin-guanine dinucleotide biosynthesis protein B (MobB) domain
Type:
Domain
Description:
The MobB domain is similar to that of the urease accessory protein UreG and the hydrogenase accessory protein HypB, both GTP hydrolases involved in loading nickel into the metallocentres of their respective target enzymes. It is involved in the final step of molybdenum-cofactor biosynthesis. While its precise function has not been identified it is thought to be involved in the transfer of a guanine dinucleotide moiety to molybdopterin, as it shows GTP-binding and weak GTPase activity [
]. The MobB protein () from Escherichia coli, which is comprised of this domain, is a homodimer [
]. Each molecule is composed of two distinct regions - an outer region comprised of 6 β-strands and three alpha helices, and an inner region comprised of a two-strand beta hairpin followed by an alpha helix. These regions require interaction with the second monomer to allow proper folding to occur. The two monomers are intertwined and form an extensive 16-stranded β-sheet. While the active site could not be positively identified, the presence of highly conserved residues suggests the substrate binding site occurs in the central solvent channel.The majority of molybdenum-containing enzymes utilise a molybdenum cofactor (MoCF or Moco) consisting of a Mo atom coordinated via a cis-dithiolene moiety to molybdopterin (MPT). MoCF is ubiquitous in nature, and the pathway for MoCF biosynthesis is conserved in all three domains of life. MoCF-containing enzymes function as oxidoreductases in carbon, nitrogen, and sulphur metabolism [
,
]. In Escherichia coli, biosynthesis of MoCF is a three stage process. It begins with the MoaA and MoaC conversion of GTP to the meta-stable pterin intermediate precursor Z. The second stage involves MPT synthase (MoaD and MoaE), which converts precursor Z to MPT; MoeB is involved in the recycling of MPT synthase. The final step in MoCF synthesis is the attachment of mononuclear Mo to MPT, a process that requires MoeA and which is enhanced by MogA in an Mg2 ATP-dependent manner [
]. MoCF is the active co-factor in eukaryotic and some prokaryotic molybdo-enzymes, but the majority of bacterial enzymes requiring MoCF, need a modification of MTP for it to be active; MobA is involved in the attachment of a nucleotide monophosphate to MPT resulting in the MGD co-factor, the active co-factor for most prokaryotic molybdo-enzymes. Bacterial two-hybrid studies have revealed the close interactions between MoeA, MogA, and MobA in the synthesis of MoCF [
]. Moreover the close functional association of MoeA and MogA in the synthesis of MoCF is supported by fact that the known eukaryotic homologues to MoeA and MogA exist as fusion proteins: CNX1 () of Arabidopsis thaliana (Mouse-ear cress), mammalian Gephryin (e.g.
) and Drosophila melanogaster (Fruit fly) Cinnamon (
) [
].
This entry represents TraV, a component of a conjugative type IV secretion system. TraV is an outer membrane lipoprotein that is believed to interact with the secretin TraK [
,
,
]. This protein contains three conserved cysteines in the N-terminal half.
Ribosomal protein L4, eukaryotic and archaeal type
Type:
Family
Description:
Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites [
,
]. About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to - the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits. Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome [
,
].This family includes ribosomal L4 from eukaryotes and archaea. L4 from yeast has been shown to bind rRNA [].
Type-IV secretion system protein TraC/Conjugative transfer ATPase
Type:
Family
Description:
This family of TraC-related proteins is conserved in Proteobacteria. TraC is a cytoplasmic, peripheral membrane protein and is one of the proteins encoded by the F transfer region of the conjugative plasmid that is required for the assembly of F pilin into the mature F pilus structure. F pili are filamentous appendages that help establish the physical contact between donor and recipient cells involved in the conjugation process [
]. This family also includes predicted ATPases associated with DNA conjugal transfer. These are found both in plasmids and in bacterial chromosomal regions that appear to derive from integrative elements such as conjugative transposons.
Type IV conjugative transfer system protein TraF-like
Type:
Family
Description:
This entry contains TraF-like proteins that are related to the F-type conjugation system pilus assembly proteins TraF (
)and TrbB (
) both of which exhibit a thioredoxin fold [
]. The proteins in this entry have the same length and architecture as TraF, but lack the CXXC-motif found in TrbB that is believed to be responsible for the disulphide isomerase activity.
