This entry represents Type 3 secretion system stator proteins (also referred to HrpE-like proteins), which are the cytoplasmic components of bacterial type III secretion systems [
]. Type 3 secretion systems (T3SSs) are used by many different Gram-negative pathogens and symbionts to inject bacterial effector proteins into eukaryotic host cells and modulate the interaction with them. This entry includes Type 3 secretion system stator protein SCTL (also known as NolV) from Rhizobium, Type 3 secretion system stator protein SCTL (also known as Yop proteins translocation protein L) from Yersinia enterocolitica and SPI-2 type 3 secretion system stator protein SCTL2 (also known as Secretion system apparatus protein SsaK) from Salmonella typhimurium [,
,
]. SCTL and SCTL2 act as regulators of the YscN/SctN and SsaN/SctN2 ATPases activity, respectively. This entry excludes the related protein FliH of the bacterial flagellar apparatus (see ).
Protein of unknown function DUF1269, membrane associated
Type:
Family
Description:
There are currently no experimental data for members of this group or their homologues. However, these proteins are predicted to contain two or more transmembrane segments.
Growth arrest and DNA damage-inducible protein GADD45
Type:
Family
Description:
The growth arrest and DNA damage GADD45 proteins, which include GADD45A, GADD45B , and GADD45G, are implicated as stress sensors that modulate the response of mammalian cells to genotoxic/physiological stress, and modulate tumor formation [
,
,
]. GADD45 proteins interact with a number of other proteins implicated in stress responses, including PCNA, p21, Cdc2/CyclinB1, MEKK4, and p38 kinase. GADD45 stimulates DNA excision repair in vitro and inhibits the entry of cells into S phase during the cell cycle.
Photosystem II reaction centre protein H superfamily
Type:
Homologous_superfamily
Description:
Oxygenic photosynthesis uses two multi-subunit photosystems (I and II) located in the cell membranes of cyanobacteria and in the thylakoid membranes of chloroplasts in plants and algae. Photosystem II (PSII) has a P680 reaction centre containing chlorophyll 'a' that uses light energy to carry out the oxidation (splitting) of water molecules, and to produce ATP via a proton pump. Photosystem I (PSI) has a P700 reaction centre containing chlorophyll that takes the electron and associated hydrogen donated from PSII to reduce NADP+ to NADPH. Both ATP and NADPH are subsequently used in the light-independent reactions to convert carbon dioxide to glucose using the hydrogen atom extracted from water by PSII, releasing oxygen as a by-product.PSII is a multisubunit protein-pigment complex containing polypeptides both intrinsic and extrinsic to the photosynthetic membrane [
,
,
]. Within the core of the complex, the chlorophyll and beta-carotene pigments are mainly bound to the antenna proteins CP43 (PsbC) and CP47 (PsbB), which pass the excitation energy on to the reaction centre proteins D1 (Qb, PsbA) and D2 (Qa, PsbD) that bind all the redox-active cofactors involved in the energy conversion process. The PSII oxygen-evolving complex (OEC) oxidises water to provide protons for use by PSI, and consists of OEE1 (PsbO), OEE2 (PsbP) and OEE3 (PsbQ). The remaining subunits in PSII are of low molecular weight (less than 10kDa), and are involved in PSII assembly, stabilisation, dimerisation, and photo-protection []. This superfamily represents the low molecular weight phosphoprotein PsbH found in PSII. The phosphorylation site of PsbH is located in the N terminus, where reversible phosphorylation is light-dependent and redox-controlled. PsbH is necessary for the photoprotection of PSII, being required for: (1) the rapid degradation of photodamaged D1 core protein to prevent further oxidative damage to the PSII core, and (2) the insertion of newly synthesised D1 protein into the thylakoid membrane []. PsbH may also regulate the transfer of electrons from D2 (Qa) to D1 (Qb) in the reaction core.
Prepilin peptidase dependent protein C-like, C-terminal domain
Type:
Domain
Description:
This entry represents a domain found al proteins mainly found in Enterobacterales, including Prepilin peptidase-dependent protein C from Escherichia coli (PpdC). PpdC is predicted to be a bitopic inner membrane protein. This domain is found in association with
. There are two completely conserved C residues that may be functionally important.
Copper resistance protein CopA, second cupredoxin domain
Type:
Domain
Description:
CopA is a multicopper oxidase (MCO) related to laccase and L-ascorbate oxidase, both copper-containing enzymes [
,
]. CopA mutant causes a loss of function including copper tolerance and oxidase activity and copA transcription is inducible in the presence of copper [].Although MCOs have diverse functions, majority of them have three cupredoxin domain repeats that include one mononuclear and one trinuclear copper centre. The copper ions are bound in several sites: Type 1, Type 2, and/or Type 3. The ensemble of types 2 and 3 copper is called a trinuclear cluster. MCOs oxidize their substrate by accepting electrons at a mononuclear copper centre and transferring them to the active site trinuclear copper centre. The cupredoxin domain 2 of 3-domain MCOs has lost the ability to bind copper [
,
,
,
].
Conserved hypothetical protein CHP03858, luciferase-like monooxygenase, putative
Type:
Family
Description:
This entry represents a related group of proteins of unknown function within the luciferase-like monooxygenase (LLM) superfamily. As most proteins in this entry are from species incapable of synthesising coenzyme F420, they are likely to use FMN as a cofactor.
Conserved hypothetical protein CHP03879, regulatory domain, putative
Type:
Domain
Description:
This entry represents a domain shared by two different protein families of unknown function. These proteins are regularly encoded next to their corresponding putative partner family, a probable regulatory protein with homology to KaiC. By implication, therefore, proteins in this entry may also be involved in sensory transduction and/or regulation.
NHPM bacteriocin system ABC transporter, peptidase/ATP-binding protein
Type:
Family
Description:
This protein describes an multidomain ABC transporter subunit that is one of three protein families associated with some regularity with a distinctive family of putative bacteriocins. It includes a bacteriocin-processing peptidase domain at the N terminus. Model describes a conserved propeptide region for this bacteriocin family, unusual because it shows obvious homology a region of the enzyme nitrile hydratase up to the classic Gly-Gly cleavage motif. This family is therefore predicted to be a subunit of a bacteriocin processing and export system characteristic to this system that we designate NHPM, Nitrile Hydratase Propeptide Microcin.
NHPM bacteriocin system ABC transporter, ATP-binding protein
Type:
Family
Description:
Members of this protein family are ABC transporter ATP-binding subunits, part of a three-gene putative bacteriocin transport operon. The other subunits include another ATP-binding subunit (
), which has an N-terminal propeptide cleavage domain, and an HlyD homologue (
). In a number of genomes, a conserved propeptide sequence with a classic Gly-Gly motif
This family consists of secretion proteins like Yersinia YscK. The function of this protein is unknown but it belongs to an operon involved in the secretion of Yop proteins across bacterial membranes [
].
U3 small nucleolar RNA-associated protein 20, C-terminal
Type:
Domain
Description:
This domain is found towards the C-terminal the U3 small nucleolar RNA-associated protein 20 (UTP20) from yeast and its 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 [,
].
This family represents Tail assembly protein E' from Escherichia phage P2 and closely related proteins from Proteobacteria and tailed bacteriophages. GpE' essential for the lytic growth of P2 virus [
].
Hopanoid biosynthesis associated radical SAM protein HpnJ
Type:
Family
Description:
These proteins are members of the wider radical SAM superfamily of enzymes that enzymes utilise an iron-sulphur redox cluster and S-adenosylmethionine to carry out diverse radical mediated reactions [
]. The Acidithiobacillus ferrooxidans ATCC 23270 protein (AFE_0975) is encoded in the same locus as the genes for squalene-hopene cyclase (SHC, ) and other proteins associated with the biosynthesis of hopanoid natural products. Similarly, in Ralstonia eutropha (strain JMP134) (Alcaligenes eutrophus) (Reut_B4901) this protein is encoded adjacent to the genes for HpnAB, IspH and HpnH (
), although SHC itself is elsewhere in the genome. Notably, this protein (here named HpnJ) and three others form a conserved set (HpnIJKL) which occur in a subset of all genomes containing the SHC enzyme. This relationship was discerned using the method of partial phylogenetic profiling []. This group includes Zymomonas mobilis the organism where the initial hopanoid biosynthesis locus was described consisting of the genes HpnA-E and SHC (HpnF) []. Continuing past SHC are genes encoding a phosphorylase enzyme (ZMO0873, i.e. HpnG, ) and another radical SAM enzyme (ZMO0874), HpnH. Although discontinuous in Z. mobilis, we continue the gene symbol sequence with HpnIJKL. One of the well-described hopanoid intermediates is bacteriohopanetetrol. In the conversion from hopene several reactions must occur in the side chain for which a radical mechanism might be reasonable. These include the four (presumably anaerobic) hydroxylations and a methyl shift.
Cilia- and flagella-associated protein 61, N-terminal domain
Type:
Domain
Description:
This entry represents the N-terminal domain of proteins described as cilia- and flagella-associated protein. Proteins containing this domain includes FAP61 from Chlamydomonas reinhardtii. FAP61 is part of the calmodulin and spoke-associated complex (CSC) required for wild-type motility and for the stable assembly of a subset of radial spokes in motile cilia [
].
TrbE is encoded by the F-plasmid and is located between traN and traF. The product of trbE is a small, integral, inner membrane protein. Mutation of trbE by insertional mutagenesis suggests that TrbE is not essential for F transfer from Escherichia coli (strain K12) under standard mating conditions [
].
Lsb5 plays important roles in membrane-trafficking events through association with the actin regulators, the yeast Wiskott-Aldrich syndrome protein (WASP) homologue Las17 and the cortical protein Sla1, the yeast Arf3 (orthologous with mammalian Arf6), and ubiquitin. Lsb5 contains an N-terminal VHS (Vps27p/Hrs/STAM)-domain and a GAT (GGA and TOM1) domain. In contrast to GGA proteins, Lsb5 harbours a C-terminal NPF (Asn-Pro-Phe) motif, but does not have either a GAE (gamma-adaptin ear homology) domain or a clathrin-binding motif [
,
,
].This entry represents the GAT domain found in Lsb5.
This is a small highly conserved region of the C terminus of Fragile X-related proteins 1 and 2, FRX1, FRX2. The domain is immediately C-terminal to the core C- terminal region,
, and contains at least one block of RGG repeats that bind to G-quartet sequences in a wide variety of mRNAs [
].
Circadian clock protein kinase KaiC, N-terminal domain
Type:
Domain
Description:
KaiC is a circadian clock protein, most studied in cyanobacteria. KaiC, an autokinase, autophosphatase, and ATPase, is part of the core oscillator, composed of three proteins: KaiA, KaiB, and KaiC. The circadian oscillation is regulated via KaiC phosphorylation [,
,
,
,
,
,
]. This entry represents the N-terminal domain of KaiC and similar bacterial proteins.
Circadian clock protein kinase KaiC, C-terminal domain
Type:
Domain
Description:
KaiC is a circadian clock protein, most studied in cyanobacteria. KaiC, an autokinase, autophosphatase, and ATPase, is part of the core oscillator, composed of three proteins: KaiA, KaiB, and KaiC. The circadian oscillation is regulated via KaiC phosphorylation [
,
,
,
,
,
].This entry represents the C-terminal domain of KaiC and similar bacterial proteins.
Zinc finger FYVE domain-containing protein 21, C-terminal
Type:
Domain
Description:
Zinc finger FYVE domain-containing protein 21 (ZF21) regulates focal adhesions and cell migration binds by binding multiple factors that promote disassembly of focal adhesions (FAs) such as FAK, beta-tubulin, m-calpain, and SHP-2 [
].This is the C-terminal domain of ZF21. It has a PH-like fold and is required for the regulation of focal adhesions and in cell migration [
].
Protein kinases C (PKCs) constitute a family of Ser/Thr kinases. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain [
,
]. Novel PKCs (nPKCs) comprise delta, epsilon, eta, and theta isoforms, which have tandem C1 domains and a C2 domain that does not bind calcium []. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. PKC-delta plays a role in cell cycle regulation and programmed cell death in many cell types [
,
,
]. It slows down cell proliferation, inducing cell cycle arrest and enhancing cell differentiation. PKC-delta is also involved in the regulation of transcription as well as immune and inflammatory responses [,
]. It plays a central role in the genotoxic stress response that leads to DNA damaged-induced apoptosis [].
Protein kinases C (PKCs) constitute a family of Ser/Thr kinases. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain [
,
]. Novel PKCs (nPKCs) comprise delta, epsilon, eta, and theta isoforms, which have tandem C1 domains and a C2 domain that does not bind calcium []. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. PKC-epsilon has been shown to behave as an oncoprotein [
,
]. Its overexpression contributes to neoplastic transformation depending on the cell type. It contributes to oncogenesis by inducing disordered cell growth and inhibiting cell death. It also plays a role in tumour invasion and metastasis [,
]. PKC-epsilon has also been found to confer cardioprotection against ischemia and reperfusion-mediated damage [,
]. Other cellular functions include the regulation of gene expression, cell adhesion, and cell motility [].This entry also includes PKCs from invertebrates, such as Pkc98E from Drosophila, which exhibits sequence identity to PKC-epsilon [
].
Trp biosynthesis associated, conserved hypothetical membrane protein
Type:
Family
Description:
Members of this family are predicted transmembrane proteins with four membrane-spanning helices. Members are found in the Actinobacteria (Mycobacterium, Corynebacterium, Streptomyces), always associated with genes for tryptophan biosynthesis.
PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their N-terminal regulatory domain [
,
]. Atypical protein kinases C (aPKCs) have a PB1 and an atypical C1 domain, which only accepts phosphatidylserine [].In mammals there are two aPKC isoforms, zeta and iota/lambda (iota is the human orthologue and lambda the mouse orthologue) [
]. aPKCs are involved in many cellular functions including proliferation, migration, apoptosis, polarity maintenance and cytoskeletal regulation [,
]. They also play a critical role in the regulation of glucose metabolism and in the pathogenesis of type 2 diabetes [,
].PKC-zeta plays a critical role in activating the glucose transport response [
,
]. PKC-zeta also plays a central role in maintaining cell polarity in yeast and mammalian cells []. In addition, it affects actin remodeling in muscle cells [].
Classical Protein Kinase C alpha, catalytic domain
Type:
Domain
Description:
Protein kinases C (PKCs) constitute a family of Ser/Thr kinases. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain [
,
]. Conventional PKCs (cPKCs) have functional C1A and C1B domains, and a C2 domain. PKCs undergo three phosphorylations in order to take mature forms [,
]. In addition, cPKCs depend on calcium, DAG (1,2-diacylglycerol), and in most cases, phosphatidylserine for activation. There are three conventional PKC isoenzymes (alpha, beta, and gamma).PKC-alpha is expressed in many tissues and is associated with cell proliferation, apoptosis, and cell motility [
,
]. It plays a role in the signalling of the growth factors PDGF, VEGF, EGF, and FGF. Abnormal levels of PKC-alpha have been detected in many transformed cell lines and several human tumours [,
,
,
]. In addition, PKC-alpha is required for HER2 dependent breast cancer invasion [].
Protein kinases C (PKCs) constitute a family of Ser/Thr kinases. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain [
,
]. Conventional PKCs (cPKCs) have functional C1A and C1B domains, and a C2 domain. PKCs undergo three phosphorylations in order to take mature forms [,
]. In addition, cPKCs depend on calcium, DAG (1,2-diacylglycerol), and in most cases, phosphatidylserine for activation. There are three conventional PKC isoenzymes (alpha, beta, and gamma).The PKC beta isoforms (I and II), generated by alternative splicing of a single gene, are preferentially activated by hyperglycemia-induced DAG (1,2-diacylglycerol) in retinal tissues. This is implicated in diabetic microangiopathy such as ischemia, neovascularization, and abnormal vasodilator function [
,
,
,
]. PKC-beta is also being explored as a therapeutic target in cancer [,
]. It contributes to tumour formation and is involved in the tumour host mechanisms of inflammation and angiogenesis [].
Protein kinases C (PKCs) constitute a family of Ser/Thr kinases. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain [
,
]. Novel PKCs (nPKCs) comprise delta, epsilon, eta, and theta isoforms, which have tandem C1 domains and a C2 domain that does not bind calcium []. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. PKC-eta is predominantly expressed in squamous epithelia, where it plays a crucial role in the signaling of cell-type specific differentiation [
]. It is also expressed in pro-B cells and early-stage thymocytes, and acts as a key regulator in early B-cell development []. PKC-eta increases glioblastoma multiforme (GBM) proliferation and resistance to radiation, and is being developed as a therapeutic target for the management of GBM [].
Tetratricopeptide repeat protein 5, OB fold domain
Type:
Domain
Description:
This OB fold domain is located at the C terminus of tetratricopeptide repeat protein 5 (TTC5) and is required for effective p53 response [
]. TTC5 can activate the p53 pathway and inhibit AP-1 transcriptional activity [].
Protection of telomeres protein 1, ssDNA-binding domain
Type:
Domain
Description:
This entry represents the ssDNA-binding domain found in telomere protection protein 1 (Pot1). This domain is able to accommodate heterogeneous ssDNA ligands. Pot1 is responsible for binding to and protecting the 3' single-stranded DNA (ssDNA) overhang at most eukaryotic telomeres [
].
RMD5B is one of the vertebrate homologus of yeast Rmd5. The biological function of RMD5B remains unclear. RMD5B contains a Lissencephaly type-1-like homology motif (LisH), a C-terminal to LisH motif (CTLH) domain, and a degenerated RING finger that is characterised by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues compared with the classic C3H2C3-/C3HC4-type RING fingers [
].
RMD5A is one of the vertebrate homologus of yeast Rmd5. The biological function of RMD5A remains unclear. Like Rmd5/Gid2, RMD5A contains a Lissencephaly type-1-like homology motif (LisH), a C-terminal to LisH motif (CTLH) domain, and a degenerated RING finger that is characterised by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues compared with the classic C3H2C3-/C3HC4-type RING fingers [
].
Protein phosphatase 1 regulatory subunit 21, N-terminal
Type:
Domain
Description:
This entry represents a N-terminal 100 residues long domain found in Protein phosphatase 1 regulatory subunit 21, which contains a conserved KLRAQ motif. This domain is found in a family of coiled-coil domain-containing proteins that are conserved from nematodes to humans. These proteins also contain a C-terminal TTKRSYEDQ motif domain (
). Protein phosphatase 1 regulatory subunit 21 is likely a regulator of protein phosphatase 1 (PP1) activity [
]. It may play a role in the endosomal sorting process or in endosome maturation pathway [].
Protein phosphatase 1 regulatory subunit 21, C-terminal
Type:
Domain
Description:
This entry represents a C-terminal 500 residue region, which contains a conserved TTKRSYEDQ motif. It is found in a family of coiled-coil domain-containing proteins that are conserved from nematodes to humans, including protein phosphatase 1 regulatory subunit 21. These proteins also contain an N-terminal domain with a KLRAQ motif (). Protein phosphatase 1 regulatory subunit 21 is likely a regulator of protein phosphatase 1 (PP1) activity [
]. It may play a role in the endosomal sorting process or in endosome maturation pathway [].
Chloride intracellular channel protein 2, C-terminal domain
Type:
Domain
Description:
Chloride intracellular channel (CLIC) proteins are multifunctional and participate in a wide variety of signaling activities. CLIC proteins are able to convert from a water-soluble state to a membrane channel state [
]. Chloride intracellular channel protein 2 (CLIC-2) is found in in most tissues except the brain, and is highly expressed in the lung, spleen, skeletal muscle and myocardium. It inhibits cardiac ryanodine receptor Ca2+ release channels [,
,
]. It contains an intramolecular disulfide bond and exists as a monomer regardless of redox conditions [].This is the C-terminal helical domain.
Chloride intracellular channel protein 1, C-terminal domain
Type:
Domain
Description:
Intracellular chloride ion channel proteins (CLICs) has been shown to exist in both soluble and integral membrane forms. Chloride intracellular channel protein 1 (CLIC1) can insert into membranes and form chloride ion channels [
]. Membrane insertion seems to be redox-regulated and may occur only under oxydising conditions []. Channel activity has been shown to have a strong pH dependence []. The soluble form of CLIC1 is monomeric and structurally homologous to the glutathione S-transferase superfamily, with a redox-active site resembling glutaredoxin [].CLIC1 (also known as NCC27) is involved in regulation of the cell cycle [
].This entry represents the C-terminal, alpha helical domain of CLIC1 [
].
Isocitrate dehydrogenase/Hypothetical protein TT1725, C-terminal domain superfamily
Type:
Homologous_superfamily
Description:
This entry represents the C-terminal domain of Isocitrate dehydrogenase [NADP] from Rickettsia typhi and similar bacterial proteins. It is also found in the hypothetical protein TT1725 from Thermus thermophilus HB8. The sequence is conserved in three predicted prokaryotic proteins with unknown functions, including Deinococcus radiodurans, Stigmatella aurantiaca, and Mycobacterium leprae. The presence of positively-charged residues in the α1 helix suggests this region binds to a protein with a negatively charged region or to nucleic acids [].
Accessory protein NS7a, deltacoronavirus, avian coronavirus HKU16-like
Type:
Domain
Description:
This entry includes the accessory protein NS7a from White-eye coronavirus HKU16, Falcon coronavirus UAE-HKU27, Houbara coronavirus UAE-HKU28 and Pigeon coronavirus UAE-HKU29, within the Buldecovirus subgenus of deltacoronaviruses (deltaCoVs). NS7a proteins in this subfamily have yet to be characterised.In deltaCoVs, several avian species encode accessory protein NS7a, which is homologous to Porcine coronavirus (PDCoV) HKU15 accessory proteins NS7 and NS7a. PDCoV NS7a is a 100 amino-acid polypeptide identical to the C-terminal of NS7; it remains unclear whether their functions are redundant. The PDCoV NS7 protein is extensively distributed in the mitochondria and may be involved in various cellular processes such as cytoskeleton networks and cell communication, metabolism, and protein biosynthesis [
,
,
,
].
Ankyrin repeat and LEM domain-containing protein 1
Type:
Family
Description:
ANKLE1 is a LEM protein with a GIY-YIG-type endonuclease activity and unknown function [
,
,
]. Although most characterised LEM proteins are components of the inner nuclear membrane, ectopic Ankle1 shuttles between cytoplasm and nucleus. In mammals, ANKLE1 is predominantly expressed in hematopoietic tissues.
Non-structural protein 3c (NS3c), bat coronavirus HKU4-like
Type:
Family
Description:
This entry represents the accessory protein 4b, ORF4b (also called NS3c protein) of Tylonycteris bat coronavirus HKU4 and related bat coronaviruses including Tylonycteris pachypus bat coronavirus HKU4-related.ORF4b/NS3c plays a role in the inhibition of host innate immunity by inhibiting the interaction between host IkappaB kinase epsilon (IKBKE or IKKE) and mitochondrial antiviral-signalling protein (MAVS). In turn, this inhibition prevents the production of host interferon beta. Additionally, it may also interfere with host antiviral response within the nucleus. ORF4b/NS3c proteins in this subgroup are similar to the MERS-CoV ORF4b (also known as MERS-CoV 4b) which has been shown to interfere with the NF-kappaB-dependent innate immune response during infection, as well as antagonizing the early antiviral alpha/beta interferon (IFN-alpha/beta) response, which may significantly contribute to MERS-CoV pathogenesis [
,
,
,
].
Polycomb group RING finger protein 6 (PCGF6 or MBLR) is a transcriptional repressor [
]. It may activate KDM5D histone demethylase, which modulates the levels of histone H3K4Me3 []. PCGF6 is a component of the Polycomb group (PcG) multiprotein PRC1-like complex [], in which it regulates RNF2 ubiquitin ligase activity [], and the E2F6.com-1 complex []. PCGF6 contains a RING-type zinc finger.This entry represents the RING finger- and WD40-associated ubiquitin-like (RAWUL) domain of PCGF6.
Regulation of nuclear pre-mRNA domain-containing protein 1A/B
Type:
Domain
Description:
Regulation of nuclear pre-mRNA domain-containing protein 1A/B (also known as CREPT , cell-cycle alteration and expression-elevated protein in tumour) belong to a family of eukaryotic transcriptional regulators that promote the binding of RNA-polymerase to the CYCLIN D1, CCDN1, promoter and other genes involved in the cell-cycle [
]. It promotes the formation of a chromatin loop in the CYCLIN D1 gene, and is preferentially expressed in a range of different human tumours [].This entry represents the C-terminal coiled-coil domain which mediates the formation of homo and heterodimers [
].
Methylmalonic aciduria and homocystinuria type D protein
Type:
Family
Description:
This entry represents methylmalonic aciduria and homocystinuria type D protein (also known as cobalamin trafficking protein CblD) and homologues. These proteins are involved in cobalamin (vitamin B12) metabolism and trafficking [
,
,
,
] CblD plays a role in regulating the biosynthesis and the proportion of two coenzymes, methylcob(III)alamin (MeCbl) and 5'-deoxyadenosylcobalamin (AdoCbl) [,
,
]. It also promotes the oxidation of cob(II)alamin bound to MMACHC [].
Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus
Type:
Domain
Description:
This entry represents the N-terminal region of the SUD domain (SUD-N or Mac2) found in non-structural protein NSP3, the product of ORF1a in group 2 (beta) coronaviruses. It is found in human SARS-CoV and SARS-CoV-2 polyprotein 1a and 1ab, and in related coronavirus polyproteins [
].SUD consists of three globular domains separated by short linker peptide segments: SUD-N, SUD-M, and SUD-C [
]. Among these, SUD-N and SUD-M are macrodomains. The SUD-N domain is a related macrodomain which also binds G-quadruplexes []. While SUD-N is specific to the NSP3 of SARS and betacoronaviruses of the sarbecovirus subgenera (B lineage), SUD-M is present in most NSP3 proteins except the NSP3 from betacoronaviruses of the embecovirus subgenera (A lineage). SUD-M, despite its name, is not specific to SARS. SUD-C adopts a frataxin-like fold, has structural similarity to DNA-binding domains of DNA-modifying enzymes, binds single-stranded RNA, and regulates the RNA binding behavior of the SUD-M macrodomain. SARS-CoV Nsp3 contains a third macrodomain (the X-domain). The X-domain may function as a module binding poly(ADP-ribose); however, SUD-N and SUD-M do not bind ADP-ribose, as the triple glycine sequence involved in its binding is not conserved in these [].Nsp3c-N and Nsp3c-M each display a typical α/β/α Macro domain fold, in spite of the complete absence of sequence similarities. The central β-sheet with six β-strands in the order β1-β6-β5-β2-β4-β3 is flanked by two (or three) helices on either side. Only the last strand, β3, is antiparallel to the other strands. Currently, most known functions of Nsp3c-N/M are connected with RNA binding. All the residues important for binding ADP-ribose and for de-MARylation/de-PARylation activity are not conserved in Nsp3c-N/M; therefore Nsp3c-N/M cannot bind ADP-ribose. Both Nsp3c-N and Nsp3c-M domains bind unusual nucleic acid structures formed by consecutives guanosine nucleotides, where four strands of nucleic acid are forming a superhelix (so-called G-quadruplexes) [,
,
,
,
].
Potassium channel accessory subunit protein 4, MinK-related
Type:
Family
Description:
MinK-related peptides (MiRPs or KCNEs) are single-transmembrane proteins that associate with pore-forming ion-channel sub-units to form stable complexes with channel properties markedly distinct from those of the isolated pore-forming sub-units [
]. MPS-4 is expressed exclusively in the C. elegans nervous system and is essential for neuronal excitability [].
Predicted [NiFe]-hydrogenase-3-type complex Eha, membrane protein EhaG
Type:
Family
Description:
[NiFe] hydrogenases function in H2 metabolism in a variety of microorganisms, enabling them to use H2 as a source of reducing equivalent under aerobic and anaerobic conditions [NiFe]hydrogenases consist of two subunits, hydrogenase large and hydrogenase small. The large subunit contains the binuclear [NiFe] active site, while the small subunit binds at least one [4Fe-4S]cluster [
].Energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type) form a distinct group within the [NiFe] hydrogenase family [,
,
]. Members of this subgroup include:Hydrogenase 3 and 4 (Hyc and Hyf) from Escherichia coliCO-induced hydrogenase (Coo) from Rhodospirillum rubrumMbh hydrogenase from Pyrococcus furiosusEha and Ehb hydrogenases from Methanothermobacter speciesEch hydrogenase from Methanosarcina barkeriEnergy-converting [NiFe] hydrogenases are membrane-bound enzymes with a six-subunit core: the large and small hydrogenase subunits, plus two hydrophilic proteins and two integral membrane proteins. Their large and small subunits show little sequence similarity to other [NiFe]hydrogenases, except for key conserved residues coordinating the active site and [FeS] cluster. However, they show considerable sequence similarity to the six-subunit, energy-conserving NADH:quinone oxidoreductases (complex I), which are present in cytoplasmic membranes of many bacteria and in inner mitochondrial membranes. However, the reactions they catalyse differ significantly from complex I. Energy-converting [NiFe]hydrogenases function as ion pumps.Eha and Ehb hydrogenases contain extra subunits in addition to those shared by other energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type). Eha contains a 6[4Fe-4S] polyferredoxin, a 10[4F-4S]polyferredoxin, ten other predicted integral membrane proteins (EhaA
, EhaB
, EhaC
, EhaD
, EhaE
, EhaF
, EhaG
, EhaI
, EhaK
, EhaL
and
) and four hydrophilic subunits (EhaM, EhaR, EhS, EhT) [
,
]. The ten predicted integral membrane proteins are absent from Ech, Coo, Hyc and Hyf complexes, which may have simpler membrane components than Eha. Eha and Ehb catalyse the reduction of low-potential redox carriers (e.g. ferredoxins or polyferredoxins), which then might function as electron donors to oxidoreductases.Based on sequence similarity and genome context analysis, other organisms such as Methanopyrus kandleri, Methanocaldococcus jannaschii, and Methanothermobacter marburgensis also encode Eha-like [NiFe]-hydrogenase-3-type complexes and have very similar ehaoperon structure.
This entry represents small membrane proteins that are predicted to be the EhaG transmembrane subunits of multi-subunit membrane-bound [NiFe]-hydrogenase Eha complexes.
Predicted [NiFe]-hydrogenase-3-type complex Eha, membrane protein EhaD
Type:
Family
Description:
[NiFe] hydrogenases function in H2 metabolism in a variety of microorganisms, enabling them to use H2 as a source of reducing equivalent under aerobic and anaerobic conditions [NiFe]hydrogenases consist of two subunits, hydrogenase large and hydrogenase small. The large subunit contains the binuclear [NiFe] active site, while the small subunit binds at least one [4Fe-4S]cluster [
].Energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type) form a distinct group within the [NiFe] hydrogenase family [,
,
]. Members of this subgroup include:Hydrogenase 3 and 4 (Hyc and Hyf) from Escherichia coliCO-induced hydrogenase (Coo) from Rhodospirillum rubrumMbh hydrogenase from Pyrococcus furiosusEha and Ehb hydrogenases from Methanothermobacter speciesEch hydrogenase from Methanosarcina barkeriEnergy-converting [NiFe] hydrogenases are membrane-bound enzymes with a six-subunit core: the large and small hydrogenase subunits, plus two hydrophilic proteins and two integral membrane proteins. Their large and small subunits show little sequence similarity to other [NiFe]hydrogenases, except for key conserved residues coordinating the active site and [FeS] cluster. However, they show considerable sequence similarity to the six-subunit, energy-conserving NADH:quinone oxidoreductases (complex I), which are present in cytoplasmic membranes of many bacteria and in inner mitochondrial membranes. However, the reactions they catalyse differ significantly from complex I. Energy-converting [NiFe]hydrogenases function as ion pumps.Eha and Ehb hydrogenases contain extra subunits in addition to those shared by other energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type). Eha contains a 6[4Fe-4S] polyferredoxin, a 10[4F-4S]polyferredoxin, ten other predicted integral membrane proteins (EhaA
, EhaB
, EhaC
, EhaD
, EhaE
, EhaF
, EhaG
, EhaI
, EhaK
, EhaL
and
) and four hydrophilic subunits (EhaM, EhaR, EhS, EhT) [
,
]. The ten predicted integral membrane proteins are absent from Ech, Coo, Hyc and Hyf complexes, which may have simpler membrane components than Eha. Eha and Ehb catalyse the reduction of low-potential redox carriers (e.g. ferredoxins or polyferredoxins), which then might function as electron donors to oxidoreductases.
Based on sequence similarity and genome context analysis, other organisms such as Methanopyrus kandleri, Methanocaldococcus jannaschii, and Methanothermobacter marburgensis also encode Eha-like [NiFe]-hydrogenase-3-type complexes and have very similar ehaoperon structure.
This entry represents small membrane proteins that are predicted to be EhaD transmembrane subunits of multisubunit membrane-bound [NiFe]-hydrogenase Eha complexes.
Predicted [NiFe]-hydrogenase-3-type complex Eha, membrane protein EhaL
Type:
Family
Description:
[NiFe] hydrogenases function in H2 metabolism in a variety of microorganisms, enabling them to use H2 as a source of reducing equivalent under aerobic and anaerobic conditions [NiFe]hydrogenases consist of two subunits, hydrogenase large and hydrogenase small. The large subunit contains the binuclear [NiFe] active site, while the small subunit binds at least one [4Fe-4S]cluster [
].Energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type) form a distinct group within the [NiFe] hydrogenase family [,
,
]. Members of this subgroup include:Hydrogenase 3 and 4 (Hyc and Hyf) from Escherichia coliCO-induced hydrogenase (Coo) from Rhodospirillum rubrumMbh hydrogenase from Pyrococcus furiosusEha and Ehb hydrogenases from Methanothermobacter speciesEch hydrogenase from Methanosarcina barkeriEnergy-converting [NiFe] hydrogenases are membrane-bound enzymes with a six-subunit core: the large and small hydrogenase subunits, plus two hydrophilic proteins and two integral membrane proteins. Their large and small subunits show little sequence similarity to other [NiFe]hydrogenases, except for key conserved residues coordinating the active site and [FeS] cluster. However, they show considerable sequence similarity to the six-subunit, energy-conserving NADH:quinone oxidoreductases (complex I), which are present in cytoplasmic membranes of many bacteria and in inner mitochondrial membranes. However, the reactions they catalyse differ significantly from complex I. Energy-converting [NiFe]hydrogenases function as ion pumps.Eha and Ehb hydrogenases contain extra subunits in addition to those shared by other energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type). Eha contains a 6[4Fe-4S] polyferredoxin, a 10[4F-4S]polyferredoxin, ten other predicted integral membrane proteins (EhaA
, EhaB
, EhaC
, EhaD
, EhaE
, EhaF
, EhaG
, EhaI
, EhaK
, EhaL
and
) and four hydrophilic subunits (EhaM, EhaR, EhS, EhT) [
,
]. The ten predicted integral membrane proteins are absent from Ech, Coo, Hyc and Hyf complexes, which may have simpler membrane components than Eha. Eha and Ehb catalyse the reduction of low-potential redox carriers (e.g. ferredoxins or polyferredoxins), which then might function as electron donors to oxidoreductases.Based on sequence similarity and genome context analysis, other organisms such as Methanopyrus kandleri, Methanocaldococcus jannaschii, and Methanothermobacter marburgensis also encode Eha-like [NiFe]-hydrogenase-3-type complexes and have very similar ehaoperon structure.
This entry represents small membrane proteins that are predicted to be the EhaL transmembrane subunits of multisubunit membrane-bound [NiFe]-hydrogenase Eha complexes.
Predicted [NiFe]-hydrogenase-3-type complex Eha, membrane protein EhaC
Type:
Family
Description:
[NiFe] hydrogenases function in H2 metabolism in a variety of microorganisms, enabling them to use H2 as a source of reducing equivalent under aerobic and anaerobic conditions [NiFe]hydrogenases consist of two subunits, hydrogenase large and hydrogenase small. The large subunit contains the binuclear [NiFe] active site, while the small subunit binds at least one [4Fe-4S]cluster [
].Energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type) form a distinct group within the [NiFe] hydrogenase family [,
,
]. Members of this subgroup include:Hydrogenase 3 and 4 (Hyc and Hyf) from Escherichia coliCO-induced hydrogenase (Coo) from Rhodospirillum rubrumMbh hydrogenase from Pyrococcus furiosusEha and Ehb hydrogenases from Methanothermobacter speciesEch hydrogenase from Methanosarcina barkeriEnergy-converting [NiFe] hydrogenases are membrane-bound enzymes with a six-subunit core: the large and small hydrogenase subunits, plus two hydrophilic proteins and two integral membrane proteins. Their large and small subunits show little sequence similarity to other [NiFe]hydrogenases, except for key conserved residues coordinating the active site and [FeS] cluster. However, they show considerable sequence similarity to the six-subunit, energy-conserving NADH:quinone oxidoreductases (complex I), which are present in cytoplasmic membranes of many bacteria and in inner mitochondrial membranes. However, the reactions they catalyse differ significantly from complex I. Energy-converting [NiFe]hydrogenases function as ion pumps.Eha and Ehb hydrogenases contain extra subunits in addition to those shared by other energy-converting [NiFe] hydrogenases (or [NiFe]-hydrogenase-3-type). Eha contains a 6[4Fe-4S] polyferredoxin, a 10[4F-4S]polyferredoxin, ten other predicted integral membrane proteins (EhaA
, EhaB
, EhaC
, EhaD
, EhaE
, EhaF
, EhaG
, EhaI
, EhaK
, EhaL
and
) and four hydrophilic subunits (EhaM, EhaR, EhS, EhT) [
,
]. The ten predicted integral membrane proteins are absent from Ech, Coo, Hyc and Hyf complexes, which may have simpler membrane components than Eha. Eha and Ehb catalyse the reduction of low-potential redox carriers (e.g. ferredoxins or polyferredoxins), which then might function as electron donors to oxidoreductases.Based on sequence similarity and genome context analysis, other organisms such as Methanopyrus kandleri, Methanocaldococcus jannaschii, and Methanothermobacter marburgensis also encode Eha-like [NiFe]-hydrogenase-3-type complexes and have very similar ehaoperon structure.
This entry represents small membrane proteins that are predicted to be EhaC transmembrane subunits of multisubunit membrane-bound [NiFe]-hydrogenase Eha complexes.
Glucose-6-phosphate dehydrogenase assembly protein OpcA, C-terminal domain
Type:
Domain
Description:
OpcA protein may play a role in the functional assembly of glucose-6-phosphate dehydrogenase [
]. The opcA gene is found immediately downstream of zwf, the glucose-6-phosphate dehydrogenase (G6PDH) gene, in a number of species, including Mycobacterium tuberculosis, Streptomyces coelicolor, Nostoc punctiforme (strain ATCC 29133/PCC 73102), and Synechococcus sp. (strain PCC 7942). In the latter, disruption of opcA was shown to block assembly of G6PDH into active oligomeric forms.
This entry represents the C-terminal domain.
Glucose-6-phosphate dehydrogenase assembly protein OpcA, N-terminal domain
Type:
Domain
Description:
OpcA protein may play a role in the functional assembly of glucose-6-phosphate dehydrogenase [
]. The opcA gene is found immediately downstream of zwf, the glucose-6-phosphate dehydrogenase (G6PDH) gene, in a number of species, including Mycobacterium tuberculosis, Streptomyces coelicolor, Nostoc punctiforme (strain ATCC 29133/PCC 73102), and Synechococcus sp. (strain PCC 7942). In the latter, disruption of opcA was shown to block assembly of G6PDH into active oligomeric forms.This entry represents the N-terminal Rossmann-like domain.
This entry represents an N-terminal region of the FapA protein and its homologues. This region is found in multiple copies in some proteins such as . Members of this family include FapA (flagellar assembly protein A,
) from Vibrio vulnificus. The synthesis of flagella allows bacteria to respond to chemotaxis by facilitating motility. Studies examining the role of FapA show that the loss or delocalization of FapA results in a complete failure of the flagellar biosynthesis and motility in response to glucose mediated chemotaxis. The polar localization of FapA is required for flagellar synthesis, and dephosphorylated EIIAGlc (Glucose-permease IIA component) inhibited the polar localization of FapA through direct interaction [
].
Flagellar Assembly Protein A, beta solenoid domain
Type:
Repeat
Description:
This entry represents the C-terminal β-solenoid domain of FapA (flagellar assembly protein A,
) from Vibrio vulnificus and its homologues. The synthesis of flagella allows bacteria to respond to chemotaxis by facilitating motility. Studies examining the role of FapA show that the loss or delocalization of FapA results in a complete failure of the flagellar biosynthesis and motility in response to glucose mediated chemotaxis. The polar localization of FapA is required for flagellar synthesis, and dephosphorylated EIIAGlc (Glucose-permease IIA component) inhibited the polar localization of FapA through direct interaction [
. This entry shows similarity to
, suggesting a similar functional role.
RNA transcription, translation and transport factor protein
Type:
Family
Description:
This entry represents RNA transcription, translation and transport factor protein (RTRAF, also known as hCLE/C14orf166) from eukaryotes. It is part of the DDX1-HSPC117-FAM98B complex that shuttles between the nucleus and the cytoplasm transporting RNAs [
]. It is also a component of the tRNA-splicing ligase complex and is required for tRNA ligation []. Human RTRAF works as a positive modulator of the RNA polymerase II activity []. It also interacts with influenza virus polymerase subunit PA and plays an important role in influenza virus replication [].
Ral GTPase-activating protein subunit alpha/beta, N-terminal domain
Type:
Domain
Description:
This putative domain is found at the N-terminal of the Ral GTPase-activating protein alpha and beta subunits and similar proteins found in animals and some fungal species. The function of this region is not known.
The stage IV sporulation protein A (
) is an ATPase that has a role at an early stage in the morphogenesis of the spore coat and is required for proper coat localisation to the forespore [
,
,
]. A comparative genome analysis of all sequenced genomes of Firmicutes shows that the proteins are strictly conserved among the sub-set of endospore-forming species. This protein contains an ATPase domain at the N-terminal, a structural middle domain and a C-terminal domain that is key for targeting SpoIVA to the outer forespore membrane [].This entry represents the ATPase domain located at the N-terminal of SpoIVA [
,
]. It contains a conserved 'sensor' threonine residue that is involved in coordinating a Mg 2 ion [].
The stage IV sporulation protein A (
) is an ATPase that has a role at an early stage in the morphogenesis of the spore coat and is required for proper coat localisation to the forespore [
,
,
]. A comparative genome analysis of all sequenced genomes of Firmicutes shows that the proteins are strictly conserved among the sub-set of endospore-forming species. This protein contains an ATPase domain at the N-terminal, a structural middle domain and a C-terminal domain that is key for targeting SpoIVA to the outer forespore membrane [].This is the structural middle domain of Stage IV sporulation protein A (SpoIVA) which follows the ATPase domain and the predicted secondary structure suggests that it is composed of two symmetrical units containing α-helices and β-strands [
].
RING finger and transmembrane domain-containing protein 1/2
Type:
Family
Description:
This family represents RING finger and transmembrane domain-containing protein RNFT1 and RNTF2. RNFT1 is an E3 ubiquitin-protein ligase that acts in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, a mechanism that protects cells from ER stress-induced apoptosis. Misfolded proteins that have been accumulated in the ER are targeted for ubiquitination and selectively transported to the cytosol for degradation by a ubiquitin-proteasome system [
]. The function of RNTF2 is not clear.
Six Tra proteins encoded by the F plasmid and required by F(+) cells to elaborate F pili. The six proteins are TraH, TraF, TraW, TraU, TrbI, and TrbB. Except for TrbI, these proteins were all identified as hallmarks of F-like type IV secretion systems (TFSSs), with no homologues among TFSS genes of P-type or I-type systems. With the exception of TrbI, which is an inner membrane protein, the remaining proteins are or are predicted to be periplasmic. TrbI consists of one membrane-spanning segment near its N terminus and an 88-residue, hydrophilic domain that extends into the periplasm []. It has been proposed that the TraH interaction group is to control F-pilus extension and retraction during conjugation [,
,
].
CD-NTase-associated protein 12/Pycsar effector protein, TIR domain
Type:
Domain
Description:
This entry represents a TIR domain found in prokaryotic nucleotide-binding proteins, including CD-NTase-associated protein 12 (CAP12) and Pycsar effector proteins (
). Members of this entry are part of anti phage resistance systems that provide immunity against bacteriophage. CAP12 is part of the CBASS (cyclic oligonucleotide-based antiphage signaling system) and binds c-di-GMP and 3'-3'-cGAMP, cyclic nucleotides synthesized by the CD-NTase protein in response to infection that serve as specific second messenger signals to activate a diverse range of effectors, leading to bacterial cell death and thus abortive phage infection [
,
]. Pycsar effector proteins are part of the Pycsar (pyrimidine cyclase system for anti phage resistance) and are activated by cyclic nucleotides produced by the pyrimidine cyclase (PycC) in response to infection. The TIR effector domain oligomerizes and functions as NADase that deplete the cell of NAD+.
Uncharacterised protein family UPF0029, Impact, conserved site
Type:
Conserved_site
Description:
This entry contains the protein Impact, which is a translational regulator that ensures constant high levels of translation under amino acid starvation. It acts by interacting with Gcn1/Gcn1L1, thereby preventing activation of Gcn2 protein kinases (EIF2AK1 to 4) and subsequent down-regulation of protein synthesis. It is evolutionary conserved from eukaryotes to archaea [
]. This signature pattern matches a conserved region.
Ankyrin repeat and BTB/POZ domain-containing protein 1-like
Type:
Family
Description:
This entry represents a group of ankyrin repeat-containing proteins, including ABTB1 from humans, Btb3 from fission yeasts, YIL001W from budding yeasts and At2g04740 from Arabidopsis. ABTB1 is an anti-proliferative factor that may act as a mediator of the phosphatase and tensin homologue (PTEN) growth-suppressive signaling pathway [
].
Non-structural protein NSP3, nucleic acid-binding domain, betacoronavirus
Type:
Domain
Description:
This entry represents the nucleic acid binding domain (NAB/NAR), of approximately 100 residues in length, found in the multidomain nonstructural protein NSP3 from betacoronavirus, and described as NSP3e domain. NSP3 is part of Orf1a polyproteins in SARS-CoV [
]. It is an essential component of the replication/transcription complex [].The global domain of the NAB represents a new fold, with a parallel four-strand β-sheet holding two α-helices of three and four turns that are oriented antiparallel to the β-strands. A group of residues form a positively charged patch on the protein surface as the binding site responsible for binding affinity for nucleic acids. When binding to ssRNA, the NAB prefers sequences with repeats of three consecutive Gs, such as (GGGA)5 and (GGGA)2. A positively charged surface patch (Lys75, Lys76, Lys99, and Arg106) is involved in RNA binding [
,
,
].
tRNA U-34 5-methylaminomethyl-2-thiouridine biosynthesis protein MnmC, C-terminal
Type:
Domain
Description:
In Escherichia coli, the protein previously designated YfcK is now identified as the bifunctional enzyme MnmC. It acts, following the action of the heterotetramer of GidA and MnmE, in the modification of U-34 of certain tRNA to 5-methylaminomethyl-2-thiouridine (mnm5s2U). In other bacteria, the corresponding proteins are usually but always found as a single polypeptide chain, but occasionally as the product of tandem genes. This entry represents the C-terminal region of the multifunctional protein.
DOCK1, also called Dock180, is a class A DOCK and an atypical guanine nucleotide exchange factor (GEF). DOCK1 interacts with the scaffold protein Elmo and the resulting complex functions upstream of Rac in many biological events including phagocytosis of apoptotic cells, cell migration and invasion [
,
,
,
]. Class A DOCKs contain a C2 domain and additionally, an SH3 domain at the N-terminal region and a PxxP motif at the C-terminal; they are specific GEFs for Rac.This entry represents the C2 domain of DOCK1 [
]. This domain has been shown to bind phosphatidylinositol-3, 4, 5-triphosphate (PtdIns(3,4,5)P3).
Phosphonate degradation operon associated HDIG domain protein
Type:
Family
Description:
This protein is found adjacent to other genes implicated in the catabolism of phosphonates and contain a series of five invariant histidines, the domain in general has only four.
High-affinity branched-chain amino acid transport ATP-binding protein
Type:
Family
Description:
This entry represents a group of ABC-type high-affinity branched-chain amino acid transport ATP-binding proteins, including LivF from E. coli [
] and BraG from Pseudomonas aeruginosa [].
Vitelline membrane outer layer protein I (VMO-I) is one of the proteins found in the outer layer of the vitelline membrane of eggs. VMO-I, lysozyme, and VMO-II are bound tightly to ovomucin fibrils of the egg yolk membrane. The structure of VMO-I [
] consists of three β-sheets forming Greek key motifs, which are related by an internal pseudo three-fold symmetry. It is a member of the β-prism-fold family and the structure of VOM-I has strong similarity to the structure of the delta-endotoxin, as well as a carbohydrate-binding site in the top region of the common fold []. VMO-I has been shown to synthesize N-acetylchito-oligosaccharides from N-acetylglucosamine.
Non-structural protein NSP15, N-terminal domain superfamily, coronavirus
Type:
Homologous_superfamily
Description:
The unique coronavirus transcription/replication machinery comprised of multiple virus-encoded non structural proteins (NSP) plays a vital role during initial and intermediate phases of the viral life cycle. NSP15 forms a hexamer made of dimers of trimers which is suggested to be a functional unit, responsible for the endoribonuclease activity. The NSP15 monomer consists of three domains: N-terminal, middle and C-terminal [
,
]. The catalytic function of NSP15 resides in the C-terminal NendoU domain. The active site carries six key residues conserved among SARS-CoV-2, SARS-CoV and MERS-CoV, suggesting that its activity is important for sustained replication in the host [,
].This superfamily represents the N-terminal oligomerization domain of NSP15, which is an uridine-specific endonuclease []. This domain stabilises the hexamer and is critical for its formation []. Structurally, this domain consists of 2 small α-helices and 3 β-strands.
Cytochrome c nitrate reductase biogenesis protein NrfE
Type:
Family
Description:
Members of this protein family closely resemble the CcmF protein of the CcmABCDEFGH system, or system I, for c-type cytochrome biogenesis (
). Members are found, as a rule, next to closely related paralogues of CcmG and CcmH and always located near other genes associated with the cytochrome c nitrite reductase enzyme complex. As a rule, members are found in species that also encode bona fide members of the CcmF, CcmG, and CcmH families.
SARM1 (sterile alpha and TIR motif-containing protein 1) is a TIR (Toll-interleukin 1 receptor) adaptor that downregulates Toll-like receptor signalling [
,
,
]. It plays a role in innate immunity []. It is also an essential mediator of axon degeneration know as Wallerian degeneration [,
]. A specific motif in its TIR domain is responsible for NAD+ loss and injury-induced SARM1 activation [,
].
Max dimerization protein 1, basic Helix-Loop-Helix-zipper domain
Type:
Domain
Description:
MXD1, also known as MAD, binds Max to form a repressive transcription factor. It antagonizes MYC transcriptional activity by competing for MAX [
]. It has also been shown to regulate rRNA synthesis [].This entry represents the basic Helix-Loop-Helix-zipper (bHLHzip) domain of MXD1. The N-terminal basic region of this domain mediates high-affinity DNA-binding to specific hexanucleotide sequences [
].
RNA polymerase II nuclear localization protein Iwr1
Type:
Family
Description:
Budding yeast Iwr1 binds to Pol II and directs its nuclear import [
]. It also plays an important role in preinitiation complex formation by all three nuclear RNA polymerases [].
Conserved hypothetical protein CHP03437, C-terminal, Solibacter usitatus
Type:
Domain
Description:
This entry describes a protein domain found in roughly 90 proteins from Solibacter usitatus (strain Ellin6076), nearly always as the C-terminal domain of a much larger protein. Few homologues to this domain are detected outside of S. usitatus, a member of the Acidobacteria.
SecE subunit of protein translocation complex, bacterial-like
Type:
Family
Description:
Secretion across the inner membrane in some Gram-negative bacteria occurs via the preprotein translocase pathway. Proteins are produced in the cytoplasm as precursors, and require a chaperone subunit to direct them to the translocase component [
]. From there, the mature proteins are either targeted to the outer membrane, or remain as periplasmic proteins. The translocase protein subunits are encoded on the bacterial chromosome.The translocase itself comprises 7 proteins, including a chaperone protein (SecB), an ATPase (SecA), an integral membrane complex (SecCY, SecE and SecG), and two additional membrane proteins that promote the release of the mature peptide into the periplasm (SecD and SecF) [
]. The chaperone protein SecB [] is a highly acidic homotetrameric protein that exists as a "dimer of dimers"in the bacterial cytoplasm. SecB maintains preproteins in an unfolded state after translation, and targets these to the peripheral membrane protein ATPase SecA for secretion [
]. SecE, part of the main SecYEG translocase complex, is ~106 residues in length, and spans the inner membrane of the Gram-negative bacterial envelope. Together with SecY and SecG, SecE forms a multimeric channel through which preproteins are translocated, using both proton motive forces and ATP-driven secretion. The latter is mediated by SecA. The structure of the Escherichia coli SecYEG assembly revealed a sandwich of two membranes interacting through the extensive cytoplasmic domains []. Each membrane is composed of dimers of SecYEG. The monomeric complex contains 15 transmembrane helices.
Outer membrane exchange protein TraA, N-terminal domain
Type:
Domain
Description:
In Myxococcus xanthus, the TraA (MXAN_6895) and TraB (MXAN_6898) proteins (encoded within the traAB operon) serve as a bacterial transfer system required for contact-dependent exchange of outer membrane proteins. They are required in both donor and recipient cells. This entry represents the N-terminal domain of TraA. This domain is suggested to be similar to the PA14 domain (
); the processed PA14 domain may serve as a receptor for ligand binding [
].
Hopanoid biosynthesis associated radical SAM protein HpnH
Type:
Family
Description:
Proteins in this entry are members of the radical SAM superfamily of enzymes that utilise an iron-sulphur redox cluster and S-adenosylmethionine to carry out diverse radical mediated reactions [
]. This group of proteins are frequently encoded in the same locus as squalene-hopene cyclase (SHC, ) and other proteins associated with the biosynthesis of hopanoid natural products. The linkage between SHC and this radical SAM enzyme is strong; one is nearly always observed in the same genome where the other is found. A hopanoid biosynthesis locus was described in Zymomonas mobilis consisting of the genes for HpnA-E and SHC (HpnF) [
]. Continuing past SHC are the genes for a phosphorylase enzyme (ZMO0873, i.e. HpnG, ) and this radical SAM enzyme (ZMO0874) which we name here HpnH. Granted, in Z. mobilis, HpnH is in a convergent orientation with respect to HpnA-G, but one gene beyond HpnH and running in the same convergent direction is IspH (ZM0875, 4-hydroxy-3-methylbut-2-enyl diphosphate reductase), an essential enzyme of IPP biosynthesis and therefore essential for the biosynthesis of hopanoids. One of the well-described hopanoid intermediates is bacteriohopanetetrol. In the conversion from hopene several reactions must occur in the side chain for which a radical mechanism might be reasonable. These include the four (presumably anaerobic) hydroxylations and a methyl shift.
Cysteine-rich Golgi apparatus protein 1 repeat, eukaryote
Type:
Repeat
Description:
This entry is found in Golgi apparatus protein 1 (GLG1,
) and related proteins in the metazoa. GLG1 is located in Golgi cisterns of various cell types, can bind fibroblast growth factor and E-selectin. Sixteen cysteine-rich GLG1 repeats form the core of the protein and are located in the lumen. The C-terminal part of GLG1 is composed of a transmembrane region and a short cytoplasmic tail. The Cys-rich GLG1 repeat is a ~60 amino acid module that contains 4 Cys residues, which can form intrachain disulphide bridges [
]. Homologues of the vertebrate GLG1/Golgi sialoglycoprotein MG-160 (Mg160)/E-selectin ligand 1 (ESL1)/cysteine-rich fibroblast growth factor receptor 1 (CFR1)/latent transforming growth factor-beta complex protein 1 (LTCP-1) have been found in insects and the nematode Caenorhabditis elegans [].
cAMP-dependent protein kinase regulatory subunit, dimerization-anchoring domain
Type:
Domain
Description:
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].In the absence of cAMP, Protein Kinase A (PKA) exists as an equimolar tetramer of regulatory (R) and catalytic (C) subunits [
]. In addition to its role as an inhibitor of the C subunit, the R subunit anchors the holoenzyme to specific intracellular locations and prevents the C subunit from entering the nucleus. All R subunits have a conserved domain structure consisting of the N-terminal dimerization domain, inhibitory region, cAMP-binding domain A and cAMP-binding domain B. R subunits interact with C subunits primarily through the inhibitory site. The cAMP-binding domains show extensive sequence similarity and bind cAMP cooperatively.Two types of regulatory (R) subunits exist - types I and II - which differ in molecular weight, sequence, autophosphorylation capability, cellular location and tissue distribution. Types I and II were further sub-divided into alpha and beta subtypes, based mainly on sequence similarity. This entry represents the dimerization-anchoring domain of types I-alpha, I-beta, II-alpha and II-beta regulatory subunits of PKA proteins.The dimerization-anchoring domain is located within the first 45 residues of each regulatory subunit, and forms a high affinity binding site for A-kinase-anchoring proteins (AKAPs) [
].
Putative ABC transporter periplasmic binding protein PhnD-like
Type:
Family
Description:
This entry represent a group of putative ABC transporter periplasmic binding proteins that belong to a larger family that includes phosphate, phosphite, and phosphonate transporters. It includes Prochlorococcus PhnD1, which binds strongly to inorganic phosphite and has very weak affinities to methylphosphonate (MPn) and phosphate [
].
Type III secretion system apparatus protein YscQ/HrcQ/SpaO
Type:
Family
Description:
Proteins in this entry are encoded within type III secretion operons and are involved in many different functions. For example, YscQ in Yersinia is essential for YOPs secretion [
], while SpaO in Shigella is involved in the Surface Presentation of Antigens apparatus found on the virulence plasmid [], and HrcQ is involved in the Harpin secretory system in organisms like Pseudomonas syringae [].
2-oxoglutarate and iron-dependent oxygenase domain-containing protein 3
Type:
Family
Description:
2-Oxoglutarate and iron-dependent oxygenase domain-containing protein 3 (OGFOD3) is an uncharacterized protein predominantly found in animals and SAR supergroup organisms. It is a type II transmembrane protein with a short N-terminal cytoplasmic section and the bulk of the protein in the lumen. It contains a Fe(2+) and 2-oxoglutarate (2OG)-dependent dioxygenase domain and is assumed to be an enzyme that catalyses the oxidation of an organic substrate using a dioxygen molecule.
The function of LY6G6C is not clear [
]. It is a GPI-anchored cell surface protein, highly expressed at the leading edges of cells, on filopodia, which are normally involved in cell adhesion and migration []. Homologues are found only in mammals.
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases [
]. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [,
]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. All DOCKs contain two homology domains: the DHR-1 (Dock homology region-1), also called CZH1 (CED-5, Dock180, and MBC-zizimin homology 1), and DHR-2 (also called CZH2 or Docker). DOCK5 is an atypical guanine nucleotide exchange factor (GEF) that lacks the conventional Dbl homology (DH) domain. It functions upstream of Rac1 to regulate osteoclast function [
]. Along with DOCK1, DOCK5 mediates CRK/CRKL regulation of epithelial and endothelial cell spreading and migration on collagen IV [].This entry represents the DHR-2 domain of DOCK5, which contains the catalytic GEF activity for Rac and/or Cdc42. Class A DOCKs, like DOCK5, are specific GEFs for Rac.
Type VI secretion system, FHA domain-containing protein
Type:
Family
Description:
Members of this protein family are FHA (forkhead-associated) domain-containing proteins that are part of type VI secretion loci in a considerable number of bacteria, most of which are known pathogens. Species include Pseudomonas aeruginosa PAO1, Aeromonas hydrophila, Yersinia pestis, Burkholderia mallei, etc.
Effector protein HopAB, E3 ubiquitin ligase domain
Type:
Domain
Description:
HopAB family members are type III effector proteins that are secreted by the plant pathogen Pseudomonas syringae into the host plant to inhibit its immune system and facilitate the spread of the pathogen [
]. AvrPtoB, also called HopAB3, is the best studied member of the family. It suppresses host basal defenses by interfering with PAMP (pathogen-associated molecular signature)-triggered immunity (PTI) through binding and inhibiting BAK1, a kinase which serves to activate defense signaling []. It also recognizes the kinase Pto to activate effector-triggered immunity (ETI) [].AvrPtoB contains an N-terminal region that contains two kinase-interacting domains (KID) and a C-terminal E3 ligase domain. The first KID recognizes the PTI-associated kinase Bti9 as well as Pto, and is referred to as the Pto-binding domain (PID). The second KID interacts with BAK1 and FLS2, which are leucine-rich repeat-containing receptor-like kinases, and is called the BAK1-interacting domain (BID) [
,
]
. The family member HopPmaL is shorter and lacks the C-terminal E3 ligase domain [].The E3 ubiquitin ligase domain found in the bacterial protein AvrPtoB inhibits immunity-associated programmed cell death (PCD) when translocated into plant cells, probably by recruiting E2 enzymes and transferring ubiquitin molecules to cellular proteins involved in regulation of PCD and targeting them for degradation. The structure reveals a globular fold centred on a four-stranded β-sheet that packs against two helices on one face and has three very extended loops connecting the elements of secondary structure, with remarkable homology to the RING-finger and U-box families of proteins involved in ubiquitin ligase complexes in eukaryotes [
].
ABC transporter, urea permease protein UrtB, bacterial-type
Type:
Family
Description:
This entry consists of ABC transporter permease proteins associated with urea transport and metabolism. They are encoded in a conserved five-gene transport operon typically found adjacent to urease genes. It was shown in Cyanobacteria that disruption leads to the loss of high-affinity urea transport activity [
].
The function of these proteins is unknown but they are almost always encoded in operons for the SUF system of iron-sulphur cluster biosynthesis. In a few species the SUF system is present elsewhere on the chromosome. This group shares this property of association with the SUF system with a related group,
. These groups of proteins both share a domain of unknown function which covers the whole protein in
but only the C-terminal portion of proteins in this entry, which have an additional unique uncharacterised N-terminal domain. As these proteins are encoded immediately downstream of the cysteine desulphurase gene sufS in many contexts, they have been deignated SufT. Homologous proteins not covered by this entry or
are found in operons associated with phenylacetic acid (or other ring-hydroxylating) degradation pathways.
5'-AMP-activated protein kinase catalytic subunit alpha-2, C-terminal
Type:
Domain
Description:
AMPK, a serine/threonine protein kinase (STK), catalyzes the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. It acts as a sensor for the energy status of the cell and is activated by cellular stresses that lead to ATP depletion such as hypoxia, heat shock, and glucose deprivation, among others. AMPK is a heterotrimer of three subunits: alpha, beta, and gamma [
]. The alpha subunit is the catalytic subunit and it contains an N-terminal kinase domain, a putative autoinhibitory domain (AID) and a C-terminal region required for beta subunit binding. The beta scaffolding subunit mediates AMPK assembly by bridging alpha and gamma subunits. The C-terminal domain of the AMPK alpha 1 subunit interacts with the C-terminal region of the beta subunit to form a tight alpha-beta complex that is associated with the gamma subunit. The AMPK alpha subunit auto-inhibitory region interacts with the kinase domain; this inhibition is negated by the interaction with the AMPK gamma subunit [].AMPK has been implicated in a number of diseases related to energy metabolism including type 2 diabetes, obesity and cancer [
,
]. AMPK is activated by rising AMP concentrations coupled with falling ATP concentrations. Activation of AMPK is also dependent on the phosphorylation of alpha subunit by upstream kinases such as LKB1 [].Vertebrates contain two isoforms of the alpha subunit, alpha1 and alpha2, which are encoded by different genes, PRKAA1 and PRKAA2, respectively, and show varying expression patterns. AMPKalpha2 shows cytoplasmic and nuclear localization, whereas AMPKalpha1 is localized only in the cytoplasm [
,
].
ASB17 (ankyrin repeat and SOCS box protein 17) is expressed in testis and may play essential roles in testis development and spermatogenesis [
,
]. Homologues contain an ankyrin repeat and a SOCS box domain, and are found only in metazoa.
SH3 domain and tetratricopeptide repeat-containing protein SH3TC1/SH3TC2
Type:
Family
Description:
This entry includes SH3TC1 and SH3TC2. SH3TC2 is an effector of Rab11 in Schwann cells [
]. Mutations of the SH3TC2 gene cause Charcot-Marie-Tooth disease 4C (CMT4C), a recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterised by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms []. The function of SH3TC1 is not clear.
This entry represent the C-terminal domain of GspI, which is a pseudopilin component of the type II secretion system (T2SS). It contains the prepilin signal sequences [
]. In Pseudomonas aeruginosa GspI homologue, known as XcpV, has been suggested to be the central component and initiator of pseudopilus formation [
].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 [
].
Transcriptional regulatory protein PcoR, heavy metal response
Type:
Family
Description:
Proteins in this entry contain a response regulator receiver domain and an associated transcriptional regulatory region. This group is separated phylogenetically from related proteins with similar architecture and contains a number of proteins associated with heavy metal resistance efflux systems for copper, silver, cadmium, and/or zinc. Most members are encoded by genes adjacent to genes which code for a member of the heavy metal sensor histidine kinase family (
), its partner in the two-component response regulator system.
Baseplate structural protein Gp9 C-terminal domain superfamily
Type:
Homologous_superfamily
Description:
The Bacteriophage T4 is a double-stranded, structurally complex virus that infects Escherichia coli. Gene product 9 (Gp9) connects the long tail fibres to the baseplate, and triggers baseplate reorganisation and tail contraction after virus attachment to the host cell. The Gp9 protein forms a homotrimer, with each monomer having three domains: the N-terminal α-helical domain forms a triple coiled coil, the middle domain is a mixed, seven-stranded beta sandwich with a unique fold, and the C-terminal domain is a eight-stranded β-sandwich with similarity to jellyroll viral capsid protein structures [
]. The flexible loops that occur between domains may enable the conformational changes necessary during infection. This superfamily represents the Gp9 C-terminal domain.
Baseplate structural protein Gp9/Gp10 middle domain superfamily
Type:
Homologous_superfamily
Description:
This superfamily represents the middle domain found in baseplate structural protein Gp9 and Gp10 of bacteriophage T4.The Bacteriophage T4 is a double-stranded, structurally complex virus that infects Escherichia coli. Gene product 9 (Gp9) connects the long tail fibres to the baseplate, and triggers baseplate reorganisation and tail contraction after virus attachment to the host cell. The Gp9 protein forms a homotrimer, with each monomer having three domains: the N-terminal α-helical domain forms a triple coiled coil, the middle domain is a mixed, seven-stranded beta sandwich with a unique fold, and the C-terminal domain is a eight-stranded β-sandwich with similarity to jellyroll viral capsid protein structures [
]. The flexible loops that occur between domains may enable the conformational changes necessary during infection. Together with gp11, gp10 initiates the assembly of wedges that then go on to associate with a hub to form the viral baseplate [].
Surface glycan-binding protein B, xyloglucan binding domain
Type:
Domain
Description:
This is the C-terminal domain found in the surface glycan-binding protein-B (SGBP-B) from Bacteroides ovatus. SGBP-B is a cell-surface-localized, xyloglucan-specific binding protein. The C-terminal domain mediates xyloglucan binding. The domain displays similarity to the C-terminal β-sandwich domain of many GH13 enzymes [
].
