Nuclear speckle splicing regulatory protein 1, RS-like domain
Type:
Domain
Description:
This domain found at the C-terminal of Nuclear speckle splicing regulatory protein 1 (NRP1, also known as Nuclear speckle-related protein 70 and Coiled-coil domain-containing protein 55) from mammals and aves. This is the RS-like domain, that resembles the arginine/serine-rich (RS) domain in other SR proteins, interacts with two SR proteins and with target mRNA, being essential for NRP1 activity. NRP1 is a RNA-binding protein that mediates pre-mRNA alternative splicing regulation [
,
].
Arginine vasopressin-induced protein 1/transcriptional and immune response regulator
Type:
Domain
Description:
This entry includes arginine vasopressin-induced protein 1 (Avpi1) and C8orf4 protein. Avpi1 is thought to be involved in MAP kinase activation, epithelial sodium channel (ENaC) down-regulation and cell cycling [
]. C8orf4, also known as transcriptional and immune response regulator (TCIM) or thyroid cancer 1 (TC-1), plays important roles in many signalling pathways, such as Wnt/beta-catenin signalling pathway, and is involved in the development of many cancers []. C8orf4 also suppresses NOTCH2 signalling in liver cancer stem cells [
].
Zinc finger CCHC-type and RNA-binding motif-containing protein 1
Type:
Family
Description:
ZCRB1 is a novel multi-functional nuclear factor that may be involved in morphine dependence, cold/heat stress, and hepatocarcinoma. It is located in the nucleoplasm, but outside the nucleolus [
]. ZCRB1 is one of the components of U11/U12 snRNPs that bind to U12-type pre-mRNAs and form a di-snRNP complex, simultaneously recognizing the 5' splice site and branchpoint sequence [,
]. ZCRB1 is characterised by an RNA recognition motif (RRM), and a CCHC-type zinc finger motif. In addition, it contains core nucleocapsid motifs, and Lys- and Glu-rich domains.
Receptor-binding protein of phage tail base-plate Siphoviridae, head
Type:
Domain
Description:
This domain (caudo_bapla_RBP) can be found in a family of proteins expressed from ORF18 of the Lactococcus P2-like phage. This is one of three protein species, shoulders, neck, and head, that form the phage tail base-plate. In the overall structure this head domain exists as six trimers, and is necessary for specific recognition of the receptors at the host cell surface. Siphoviridae are the P2-like Caudovirales of Lactococcus [
].
Flagella basal body P-ring formation protein FlgA, C-terminal
Type:
Domain
Description:
This entry describes a conserved C-terminal region of the flagellar basal body P-ring formation protein FlgA. This sequence region contains a SAF domain.
Probable RNA polymerase II nuclear localization protein SLC7A6OS
Type:
Family
Description:
SLC7A6OS share protein sequence similarity with budding yeast Iwr1, which binds RNA pol II and regulates the transcription of specific genes. Danio rerio SLC7A6OS plays a role in defined areas of the developing central nervous system [
].
Ankyrin repeat and fibronectin type-III domain-containing protein 1
Type:
Family
Description:
Ankyrin repeat and fibronectin type-III domain-containing protein 1 (ANKFN1) is an uncharacterized protein containing two ANK repeats and a fibronectin type-III domain. Homologues are known from metazoa.
Large ribosomal RNA subunit accumulation protein YceD, bacteria
Type:
Family
Description:
YceD is believed to play a role in synthesis, processing and/or stability of 23S rRNA, as gene knockout in Escherichia coli leads to significant reduction of 23S rRNA [
].
Zinc finger ZZ-type and EF-hand domain-containing protein 1
Type:
Family
Description:
This group of proteins is found in animals and includes Zinc finger ZZ-type and EF-hand domain-containing protein 1 (ZZEF1). ZZEF1 is a histone H3 reader which may act as a transcriptional coactivator for KLF6 and KLF9 transcription factors [
].
5'-AMP-activated protein kinase alpha 1 catalytic subunit, 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. AMPKalpha1 is the predominant isoform expressed in bone; it plays a role in bone remodeling in response to hormonal regulation [
]. AMPK alpha1 impacts the regulation of fat metabolism []. It also mediates the vasoprotective effects of estrogen through phosphorylation of another in vivo substrate, RhoA [].
Mitochondrial intermembrane space import and assembly protein 40
Type:
Family
Description:
Mitochondrial intermembrane space import and assembly protein 40 (CHCHD4) is a chaperone and catalyses the formation of disulfide bonds in proteins within the mitochondrial intermembrane space (IMS) such as COX17 [
], COX19 [], MICU1 [] and GFER []. A precursor of one of these proteins in a reduced state is imported into the mitochondrion where it associates with CHCHD4 forming a transient intermolecular disulfide bridge. This leads to oxidation of the precursor, formation of an intramolecular disulfide bond and the folding in the IMS [].This entry also includes the uncharacterized protein F42H10.2 from
Caenorhabditis elegans.
Sporulation killing factor system integral membrane protein SkfF
Type:
Family
Description:
Spore formation by the bacterium Bacillus subtilis is a stress response triggered by nutrient limitation. Two operons are strongly induced at the start of sporulation; one of them is skf (for sporulation killing factor). skf produces a killing factor which, together with a signaling protein, act cooperatively to block sister cells from sporulating and cause them to lyse, providing a source of nutrients to support the sporulation process [
].The skf operon consists of skfA-H. SkfA induces the lysis of sibling cells that have not entered the sporulation pathway [
]. SkfF has multiple membrane-spanning domains and is encoded next to SkfE, a protein with ATP-binding cassette (ABC) homology, suggesting ABC transporter permease activity for this protein.
Twin-arginine translocation signal, Cys-rich four helix bundle protein
Type:
Family
Description:
Members of this family average about 150 amino acids in length, beginning with a twin-arginine translocation signal sequence, then a His-rich spacer region, followed by a ~105-residue region in which thirteen positions are nearly invariant Cys residues.
Four and a half LIM domains protein 1 (FHL1) play an essential role in skeletal muscle growth and differentiation, acts as a scaffolding protein in sarcomere assembly and is a regulator of skeletal muscle mass and energy metabolism [
]. It has been shown to bind to Myosin-binding protein C, regulating myosin filament formation and sarcomere assembly [
]. Mutations of the FHL1 gene cause skeletal and heart muscle myopathy [,
]. It contains an N-terminal zinc finger/half LIM domain, followed by 4 complete LIM domains.
Protein BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE
Type:
Family
Description:
Development of stomata in Arabidopsis thaliana begins with de novo asymmetric divisions in which a small cell, known as a meristemoid, and a larger daughter cell is formed. Stomatal protein BASL is a regulator of asymmetric cell division [,
]. It is required for the polar localization of POLAR [].
SXP/RAL-2 family protein Ani s 5-like, cation-binding domain
Type:
Domain
Description:
This domain is found in proteins from nematodes, including SXP/RAL-2 family protein Ani s 5 (ANIS5) from Anisakis simplex, and comprises two conserved motifs: SXP1 and SXP2 [
]. Although the function of this domain is not clear, structural information from ANIS5 revealed an alpha helical arrangement with a Calmodulin-like fold. Functional studies indicates that ANIS5 can bind magnesium and calcium, suggesting that this domain plays a role in cation binding []. These proteins are interesting targets to develop control strategies against the diseases caused by parasites.
HMG domain-containing protein 3, CxC4 like cysteine cluster
Type:
Domain
Description:
This entry represents a predicted Zinc chelating domain found in HMGXB3 (HMG-box containing 3), a protein involved in a range of cellular processes including cell migration and proliferation [
,
]. This domain is N-terminal to the KDZ transposase domain [].
Fanconi anemia core complex-associated protein 24, pseudonuclease domain
Type:
Domain
Description:
This entry represents the pseudonuclease domain (PND) from the FANCM protein [
]. This domain is part of the PD(D/E)XK superfamily but does not appear to have a full set of catalytic residues [].
Protein of unknown function DUF1780, putative endonuclease superfamily
Type:
Homologous_superfamily
Description:
This is a superfamily of uncharacterised proteins. The structure of a hypothetical protein from Pseudomonas aeruginosa has shown it to adopt an alpha/beta fold, placing it in the Endonuclease superfamily/clan of restriction endonucleases.
Chemotaxis protein CheA, P2 response regulator-binding domain superfamily
Type:
Homologous_superfamily
Description:
Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions []. Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk []. These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more []. Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) []. The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response [
,
].Signal transducing histidine kinases are the key elements in two-component signal transduction systems, which control complex processes such as the initiation of development in microorganisms [
,
]. Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation [], and CheA, which plays a central role in the chemotaxis system []. Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water []. The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily. HKs can be roughly divided into two classes: orthodox and hybrid kinases [
,
]. Most orthodox HKs, typified by the Escherichia coli EnvZ protein, function as periplasmic membrane receptors and have a signal peptide and transmembrane segment(s) that separate the protein into a periplasmic N-terminal sensing domain and a highly conserved cytoplasmic C-terminal kinase core. Members of this family, however, have an integral membrane sensor domain. Not all orthodox kinases are membrane bound, e.g., the nitrogen regulatory kinase NtrB (GlnL) is a soluble cytoplasmic HK []. Hybrid kinases contain multiple phosphodonor and phosphoacceptor sites and use multi-step phospho-relay schemes instead of promoting a single phosphoryl transfer. In addition to the sensor domain and kinase core, they contain a CheY-like receiver domain and a His-containing phosphotransfer (HPt) domain.The response regulators for CheA bind to the P2 domain, which is found between
and
as either one or two copies. Highly flexible linkers connect P2 to the rest of CheA and impart remarkable mobility to the P2 domain. This feature is thought to enhance the inter CheA dimer phosphotransfer reactions within the signalling complex, thereby amplifying the phosphorylation signal [
].
Stage III sporulation protein AA, AAA+ ATPase domain
Type:
Domain
Description:
This entry represents the AAA+ ATPase domain found in Sporulation stage III protein AA from Bacillus subtilis.The AAA+ superfamily of ATPases is found in all kingdoms of living organisms where they participate in diverse cellular processes including membrane fusion, proteolysis and DNA replication. Although the terms AAA+ and AAA are often used loosely and interchangeably, the classical AAA family members are distinguished by their possession of the SRH region in the AAA module. Many AAA+ proteins are involved in similar processes to those of AAA proteins (facilitation of protein folding and unfolding, assembly or disassembly of proteins complexes, protein transport and degradation), but others function in replication, recombination, repair and transcription. For a review see [
]. The proteins in this superfamily are characterised by the structural conservation of a central ATPase domain of about 250 amino acids called the AAA+ module. Typically, the AAA+ domain can be divided into two structural subdomains, an N-terminal P-loop NTPase α-β-α subdomain that is connected to a smaller C-terminal all-α subdomain. The α-β-α subdomain adopts a Rossman fold and contains several motifs involved in ATP binding and hydrolysis, including classical motifs Walker A and Walker B [
,
]. The all-α subdomain [], is much less conserved across AAA+ proteins.
60S ribosome subunit biogenesis protein NIP7, pre-PUA domain
Type:
Domain
Description:
Human 60S ribosome subunit biogenesis protein NIP7 homologue (also known as KD93) is essential in the accurate processing of pre-rRNA [
]. The overall fold of KD93 consists of two interlinked α/β domains. The C-terminal domain resembles the PUA domain of some RNA modification enzymes, especially that of archaeosine tRNA-ribosyltransferase (ArcTGT), suggesting a possible molecular function related to RNA binding [].This entry represents the N-terminal, pre-PUA domain of NIP7 and homologues, some uncharacterised proteins from the UPF0113 family and similar sequences predominantly found in eukaryota.
SPRY domain-containing SOCS box protein 3, SPRY domain
Type:
Domain
Description:
The SPRY domain-containing SOCS box protein family (SPSB1-4, also known as SSB-1 to -4) is composed of a central SPRY protein-interaction domain and a C-terminal SOCS box. All four SPSB proteins interact with c-Met, the hepatocyte growth factor receptor [
]. This entry represents the the SPRY domain of SPSB3.
M protein trans-acting positive regulator (MGA), PRD domain
Type:
Domain
Description:
Mga is a DNA-binding protein that activates the expression of several important virulence genes in group A streptococcus in response to changing environmental conditions [
]. This region corresponds to the PRD like region.
Type II secretion system protein GspE, N-terminal superfamily
Type:
Homologous_superfamily
Description:
This domain superfamily is found at the N terminus of members of the general secretory system II protein E. Proteins in this subfamily are typically involved in Type IV pilus biogenesis (e.g.
), though some are involved in other processes; for instance aggregation in Myxococcus xanthus (e.g.
) [
]. Its structure contains an extra C-terminal helix that packs against a shorter N-terminal helix.
Probable ABC transporter arginine-binding protein ArtJ, PBP2 domain
Type:
Domain
Description:
This entry represents the periplasmic binding domain type 2 (PBP2) found in the arginine-binding proteins from Chlamydiae trachomatis (CT-ArtJ) and pneumoniae (CPn-ArtJ) and closely related proteins. CT- and CPn-ArtJ are shown to have different immunogenic properties despite a high sequence similarity. The ArtJ proteins display the PBP2 fold organized in two α-β domains with arginine-binding region at their interface [
].
Limiting CO2-inducible protein B/C, beta carbonyic anhydrase domain
Type:
Domain
Description:
Limiting CO2-inducible B protein (LCIB)-LCIC complex plays an important role in the microalgal CO2-concentrating mechanisms (CCMs). LCIB and homologues (LCIB1-4 and LCIC) structurally resemble beta carbonyic anhydrases (b-CAs) with striking similarities in overall fold, zinc-binding motif, and especially putative active site architecture [
].
M protein trans-acting positive regulator (MGA) HTH domain
Type:
Domain
Description:
Mga is a DNA-binding protein that activates the expression of several important virulence genes in group A streptococcus in response to changing environmental conditions. It appears to contain two DNA-binding domains that are required for direct activation of the Mga virulence regulon in vivo [
]. This entry represents the Mga DNA binding domain, which also appears to be found in other regulatory proteins.
Protein N-terminal glutamine amidohydrolase, alpha beta roll superfamily
Type:
Homologous_superfamily
Description:
This entry represents a structural domain superfamily 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 [
].
SAM and SH3 domain-containing protein 1, SH3 domain
Type:
Domain
Description:
SASH1 is a potential tumour suppressor in breast and colon cancer. Its decreased expression is associated with aggressive tumour growth, metastasis, and poor prognosis [
,
]. It is widely expressed in normal tissues (except lymphocytes and dendritic cells) and is localized in the nucleus and the cytoplasm []. SASH1 interacts with the oncoprotein cortactin and is important in cell migration and adhesion. It is a member of the SLY family of proteins, which are adaptor proteins containing a central conserved region with a bipartite nuclear localization signal (NLS) as well as SAM (sterile alpha motif) and SH3 domains [].This entry represents the SH3 domain of SASH1.
SAM and SH3 domain-containing protein 3, SH3 domain
Type:
Domain
Description:
SASH3, also called SLY/SLY1 (SH3-domain containing protein expressed in lymphocytes), is expressed exclusively in lymhocytes and is essential in the full activation of adaptive immunity [
]. It is involved in the signaling of T cell receptors []. It was the first described member of the SLY family of proteins, which are adaptor proteins containing a central conserved region with a bipartite nuclear localization signal (NLS) as well as SAM (sterile alpha motif) and SH3 domains [].This entry represents the SH3 domain of SASH3.
Cas scaffolding protein family member 4, SH3 domain
Type:
Domain
Description:
CASS4, also called HEPL (HEF1-EFS-p130Cas-like), is a member of the CAS family. It localizes to focal adhesions and plays a role in regulating FAK activity, focal adhesion integrity, and cell spreading [
]. CAS (Crk-associated substrate) family members are adaptor proteins that contain a highly conserved N-terminal SH3 domain, an adjacent unstructured domain (substrate domain) containing multiple tyrosine phosphorylation sites that enable binding by SH2-domain containing proteins, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. Most of these domains mediate protein-protein interactions. Through these interactions, they assemble larger signaling complexes that are essential for cell proliferation, survival, migration, and other processes [
]. The CAS family consists of four members: BCAR1, HEF1, EFS, and CASS4 [].
SH3 domain-containing kinase-binding protein 1, first SH3 domain
Type:
Domain
Description:
CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1), CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins [
,
,
]. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others []. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This entry represents the first SH3 domain (SH3A) of CIN85; SH3A binds to internal proline-rich motifs within the proline-rich region. This intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. SH3A has also been shown to bind ubiquitin and to an atypical PXXXPR motif at the C terminus of Cbl and the cytoplasmic end of the cell adhesion protein CD2 [
].
SH3 domain-containing kinase-binding protein 1, second SH3 domain
Type:
Domain
Description:
CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1), CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins [
,
,
]. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others []. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This entry represents the second SH3 domain (SH3B) of CIN85. SH3B has been shown to bind Cbl proline-rich peptides and ubiquitin [
].
SH3 domain-containing kinase-binding protein 1, third SH3 domain
Type:
Domain
Description:
CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1), CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins [
,
,
]. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others []. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This entry represents the third SH3 domain (SH3C) of CIN85. SH3C has been shown to bind ubiquitin [
].
Tubulin epsilon and delta complex protein 1 domain
Type:
Domain
Description:
This entry represents a domain found in TEDC1 (Tubulin epsilon and delta complex protein 1). TEDC is a complex required for centriole maintenance and it is a component of several ciliary structures. It acts as a positive regulator of hedgehog signalling, which play key roles in embryonic development and in cancers []. Additionally, this protein may play a role in counteracting perturbation of actin filaments, such as after treatment with the actin depolymerising microbial metabolite Chivosazole F [].
Bifunctional polymyxin resistance protein ArnA-like, extended (e) SDRs
Type:
Domain
Description:
This entry represents the decarboxylase domain of ArnA. This domain can also be found in plant UDP-D-apiose/UDP-D-xylose synthases, such as AXS1/2 from Arabidopsis thaliana. AXS1 catalyses the conversion of UDP-D-glucuronate to a mixture of UDP-D-apiose and UDP-D-xylose
[].ArnA is an enzyme involved in the modification of outer membrane protein lipid A of gram-negative bacteria. It is a bifunctional enzyme that catalyses the NAD-dependent decarboxylation of UDP-glucuronic acid and N-10-formyltetrahydrofolate-dependent formylation of UDP-4-amino-4-deoxy-l-arabinose; its NAD-dependent decaboxylating activity is in the C-terminal 360 residues. This subgroup belongs to the extended SDR family, however the NAD binding motif is not a perfect match and the upstream Asn of the canonical active site tetrad is not conserved. Extended SDRs are distinct from classical SDRs. In addition to the Rossmann fold (alpha/beta folding pattern with a central β-sheet) core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids. Extended SDRs are a diverse collection of proteins, and include isomerases, epimerases, oxidoreductases, and lyases; they typically have a TGXXGXXG cofactor binding motif [
,
,
]. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they catalyse a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing [].
Type-F conjugative transfer system protein TraW N-terminal domain
Type:
Domain
Description:
This entry represents the N-terminal domain of TraW, an essential component of the F-type conjugative transfer system for plasmid DNA transfer [
]. There is a single completely conserved residue G that may be functionally important.
Salmonella invasion protein A, C-terminal actin-binding domain superfamily
Type:
Homologous_superfamily
Description:
Salmonella invasion protein A (SipA) is a virulence factor that is translocated into host cells by a type III secretion system. In the host cell it binds to actin, stimulates actin polymerisation and counteracts F-actin destabilising proteins. This contributes towards cytoskeletal rearrangements that allow the entry of the pathogen into the host cell [
]. The actin-binding domain forms a heart-shaped helical structure that appears to be unrelated to that of other actin-binding domains [
]. Disordered regions are present on both sides of the structural domain, forming nonglobular arms. SipA polymerises actin by stapling filaments with these nonglobular arms.
Protein phosphatase 2A regulatory subunit PR55, conserved site
Type:
Conserved_site
Description:
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase implicated
in many cellular processes, including the regulation of metabolic enzymes and proteins involved in signal transduction [
,
]. PP2A is a trimercomposed of a 36kDa catalytic subunit, a 65kDa regulatory subunit
(subunit A) and a variable third subunit (subunit B) [,
].One form of the third subunit is a 55kDa protein (PR55), which exists in
Drosophila melanogaster and yeast, and has up to three forms in mammals [,
]. PR55 may actas a substrate recognition unit, or may help to target the enzyme to the
correct subcellular location [].This entry represents conserved regions found in the N-terminal region and the centre of these proteins.
This entry represents the second OB-fold domain found in cell division control protein 24 (Cdc24). The OB-fold domains are nucleic acid binding domains. Cdc24 plays an essential role in the progression of normal DNA replication and is required to maintain genomic integrity [
]. Cdc24 has been reported to interact with replication factor C (RFC) as well as proliferating cell nuclear antigen (PCNA), and has been suggested to act as a target for the regulation of damage repair DNA synthesis [].
This entry represents the first OB-fold domain found in cell division control protein 24 (Cdc24).The OB-fold domains are nucleic acid binding domains. Cdc24 plays an essential role in the progression of normal DNA replication and is required to maintain genomic integrity [
]. Cdc24 has been reported to interact with replication factor C (RFC) as well as proliferating cell nuclear antigen (PCNA), and has been suggested to act as a target for the regulation of damage repair DNA synthesis [].
This entry represents the third OB-fold domain found in cell division control protein 24 (Cdc24).The OB-fold domains are nucleic acid binding domains. Cdc24 plays an essential role in the progression of normal DNA replication and is required to maintain genomic integrity [
]. Cdc24 has been reported to interact with replication factor C (RFC) as well as proliferating cell nuclear antigen (PCNA), and has been suggested to act as a target for the regulation of damage repair DNA synthesis [].
Small G protein signalling modulator 1/2, PH domain
Type:
Domain
Description:
Small G-protein signalling modulator 1/2 (also known as RUTBC2/1) bind to Rab9A via their Pleckstrin homology (PH) domain [,
]. RUTBC1 stimulates GTP hydrolysis by Rab32 and Rab33B [], while RUTBC2 appears to be a GAP for Rab36, Rab9A and associated proteins controling the recycling of mannose-6-phosphate receptors from late endosomes to the trans-Golgi [,
,
]. This entry represents the PH domain of RUTBC1/2.
Bridge-like lipid transfer protein family member 1, N-terminal
Type:
Domain
Description:
This entry represents the N-terminal domain of BLTP1 from animals and the orthologue from yeast Csf1 [
].Bridge-like lipid transfer protein family member 1 (BLTP1, formerly known as Tweek/KIAA1109 in human) is a tube-forming lipid transport protein which provides phosphatidylethanolamine for glycosylphosphatidylinositol (GPI) anchor synthesis in the endoplasmic reticulum. It plays a role in endosomal trafficking and endosome recycling and it is also involved in the actin cytoskeleton and cilia structural dynamics [
,
]. BLTP1 also acts as a regulator of phagocytosis []. In humans, it has been associated with rheumatoid arthritis [,
]. Mutations of the BLTP1 gene has been associated with Alkuraya-Kucinskas syndrome (MIM 617822), a severe disorder of brain development and arthrogryposis [].Members of this entry belong to the repeating β-groove (RBG) superfamily together with VPS13, ATG2, SHIP164, BLTP2/FMP27, which are all conserved lipid transfer proteins containing long hydrophobic grooves [
]. They all share the same structure comprising multiple repeating modules consisting of five β-sheets followed by a loop.
Bacteriophage T4, Gp59, helicase assembly protein domain superfamily
Type:
Homologous_superfamily
Description:
The Bacteriophage T4 gene 59 helicase assembly protein (Gp59) is required for recombination-dependent DNA replication and repair, which is the predominant mode of DNA replication in the late stage of T4 infection. Gp59 accelerates the loading of the T4 gene 41 helicase during DNA synthesis by the T4 replication system in vitro. This protein binds to both T4 gene 41 helicase and T4 gene 32 single-stranded DNA binding protein, and to single and double-stranded DNA [
].The structure of Gp59 helicase assembly protein reveals a novel α-helical bundle fold with two domains of similar size. Surface residues are predominantly basic (pI 9.37) with clusters of acidic residues but exposed hydrophobic residues suggest sites for potential contact with DNA and with other protein molecules [
]. The N-terminal domain shares structural homology with the high mobility group (HMG) proteins from eukaryotic organisms and it has been suggested that it plays a role in duplex DNA binding ahead of the fork. The C-terminal domain interacts with the helicase (T4 gp41) and with SSB (single-stranded binding protein T4 gp32) [].
Ankyrin repeat and zinc finger domain-containing protein 1/VMS1
Type:
Family
Description:
This entry represents a group of proteins predominantly found in eukaryotes, including Ankyrin repeat and zinc finger domain-containing protein 1 from human (ANKZF1) and VMS1 from Saccharomyces cerevisiae which belong to the VLRF1 (Vms1-Like Release Factor-1) clade [
]. They have been identified as peptidyl-tRNA hydrolases that release nascent chains from stalled ribosomes []. ANKZF1, VMS1 orthologue in human, plays a role in the cellular response to hydrogen peroxide and in the maintenance of mitochondrial integrity under conditions of cellular stress []. VMS1 is a component of an evolutionarily conserved system for ubiquitin-mediated mitochondria-associated protein degradation (MAD), which is necessary to maintain mitochondrial, cellular, and organismal viability. It is involved in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway [,
].
KN motif and ankyrin repeat domain-containing protein 1-4
Type:
Family
Description:
This entry represents KN motif and ankyrin repeat domain-containing protein 1 (KANK1-4) from humans and similar animal proteins. KANK1 is involved in the control of cytoskeleton formation by regulating actin polymerization. It inhibits actin fibre formation, cell migration and fibronectin-mediated cell spreading. This protein is involved in the establishment and persistence of cell polarity during directed cell movement in wound healing. [
,
]. KANK2 is involved in regulation of caspase-independent apoptosis, in the negative control of vitamin D receptor signalling pathway and in actin stress fibres formation [,
,
,
]. These proteins have been associated with nephrotic syndrome [].
Bromodomain adjacent to zinc finger domain protein 1A
Type:
Family
Description:
Bromo adjacent to zinc finger 1A (also known as ACF1) is the regulatory subunit of the ATP-dependent ACF-1 and ACF-5 ISWI chromatin remodeling complexes, which form ordered nucleosome arrays on chromatin and regulates spacing of nucleosomes using ATP to generate evenly spaced nucleosomes along the chromatin, to facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair [
,
,
,
].
This family of phage proteins is functionally uncharacterised. The family includes bacteriophage Sf6 gene 66 (
) as well as phage N4 GP49 protein (
). Proteins in this family are typically between 87 and 154 amino acids in length. There is a conserved NGF sequence motif.
This entry represents a group of four and a half LIM domains proteins (FHLs), including FHL2/3/5. The LIM domain is a conserved cysteine-rich module that provides protein-protein binding interfaces. FHL2 is one of the best studied FHL proteins. It is involved in a wide range of cellular processes, such as transcriptional regulation, signal transduction, and cell survival by binding to various protein partners [
,
].
Insulin-like growth factor binding protein-related protein (IGFBP-rP), MAC25
Type:
Family
Description:
The insulin family of proteins groups together several evolutionarily related active peptides [
]: these include insulin [,
], relaxin [,
], insect prothoracicotropic hormone (bombyxin) [], insulin-like growth factors (IGF1 and IGF2) [,
], mammalian Leydig cell-specific insulin-like peptide (gene INSL3), early placenta insulin-like peptide (ELIP) (gene INSL4), locust insulin-related peptide (LIRP), molluscan insulin-related peptides (MIP), and Caenorhabditis elegans insulin-like peptides. The 3D structures of a number of family members have been determined [,
,
]. The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of 4 cysteines in their A chain, the first of which is linked by a disulphide bond to the third, while the second and fourth are linked by interchain disulphide bonds to cysteines in the B chain. Insulin is found in many animals, and is involved in the regulation of normal glucose homeostasis. It also has other specific physiological effects, such as increasing the permeability of cells to monosaccharides, amino acids and fatty acids, and accelerating glycolysis and glycogen synthesis in the liver [
]. Insulin exerts its effects by interaction with a cell-surface receptor, which may also result in the promotion of cell growth []. Insulin is synthesised as a prepropeptide from which an endoplasmic reticulum-targeting sequence is cleaved to yield proinsulin. The sequence of prosinsulin contains 2 well-conserved regions (designated A and B), separated by an intervening connecting region (C), which is variable between species [
]. The connecting region is cleaved, liberating the active protein, which contains the A and B chains, held together by 2 disulphide bonds []. Insulin-like Growth Factor Binding Proteins (IGFBP) are a group of vertebrate secreted proteins, which bind to IGF-I and IGF-II with high affinity and modulate the biological actions of IGFs. The IGFBP family has six distinct subgroups, IGFBP-1 through 6, based on conservation of gene (intron-exon) organisation, structural similarity, and binding affinity for IGFs. Across species, IGFBP-5 exhibits the most sequence conservation, while IGFBP-6 exhibits the least sequence conservation. The IGFBPs contain inhibitor domain homologues, which are related to MEROPS protease inhibitor family I31 (equistatin, clan IX). All IGFBPs share a common domain architecture (
:
). While the N-terminal (
, IGF binding protein domain), and the C-terminal (
, thyroglobulin type-1 repeat) domains are conserved across vertebrate species, the mid-region is highly variable with respect to protease cleavage sites and phosphorylation and glycosylation sites. IGFBPs contain 16-18 conserved cysteines located in the N-terminal and the C-terminal regions, which form 8-9 disulphide bonds [
]. As demonstrated for human IGFBP-5, the N terminus is the primary binding site for IGF. This region, comprised of Val49, Tyr50, Pro62 and Lys68-Leu75, forms a hydrophobic patch on the surface of the protein [
]. The C terminus is also required for high affinity IGF binding, as well as for binding to the extracellular matrix [] and for nuclear translocation [,
] of IGFBP-3 and -5. IGFBPs are unusually pleiotropic molecules. Like other binding proteins, IGFBP can prolong the half-life of IGFs via high affinity binding of the ligands. In addition to functioning as simple carrier proteins, serum IGFBPs also serve to regulate the endocrine and paracrine/autocrine actions of IGF by modulating the IGF available to bind to signalling IGF-I receptors [
,
]. Furthermore, IGFBPs can function as growth modulators independent of IGFs. For example, IGFBP-5 stimulates markers of bone formation in osteoblasts lacking functional IGFs []. The binding of IGFBP to its putative receptor on the cell membrane may stimulate the signalling pathway independent of an IGF receptor, to mediate the effects of IGFBPs in certain target cell types. IGFBP-1 and -2, but not other IGFBPs, contain a C-terminal Arg-Gly-Asp integrin-binding motif. Thus, IGFBP-1 can also stimulate cell migration of CHO and human trophoblast cells through an action mediated by alpha 5 beta 1 integrin []. Finally, IGFBPs transported into the nucleus (via the nuclear localisation signal) may also exert IGF-independent effects by transcriptional activation of genes.This group represents an insulin-like growth factor binding protein related protein (IGFBP-rP), MAC25 type. This is a secreted protein which binds IGF-I and IGF-II with a relatively low affinity and stimulates prostacyclin (PGI2) production[
].
Receptor of activated protein kinase C 1 RACK1/Asc1
Type:
Family
Description:
This entry includes Asc1 from yeasts and RACK1 from animals. They are core 40S ribosomal proteins that repress gene expression
[] and involved in induction of the ribosome quality control (RQC) pathway, a pathway that degrades nascent peptide chains during problematic translation [,
]. The seven-bladed β-propeller structure of RACK1 is located near the mRNA exit tunnel where it makes contacts with the ribosomal RNA through lysine and arginine residues and neighbouring ribosomal proteins []. Asc1/RACK1 are key factors in phosphosignaling and functions as a control point at the head of the ribosomal 40S subunit itself regulated through posttranslational modification []. RACK1 also serves as a scaffold protein that can recruit other proteins to the ribosome and also for a wide range of kinases and membrane bound receptors [,
]. It has been shown to regulates axonal growth [] and is essential for development in mice, Drosophila melanogaster and Arabidopsis thaliana [,
,
].
Type III secretion system flagellar brake protein YcgR
Type:
Family
Description:
This entry represents YcgR a member of the T3SS. It acts as a flagellar brake, regulating swimming and swarming in a bis-(3'-5') cyclic diguanylic acid (c-di-GMP)-dependent manner. Increasing levels of c-di-GMP lead to decreased motility. YcgR binds 1 c-di-GMP dimer per subunit. YcgR is composed of two domains: an N-terminal domain of unknown function and a C-terminal PilZ domain. The PilZ domain binds c-di-GMP in vitro with an affinity that is high enough to allow it to respond to small changes in intracellular c-di-GMP levels. This domain organisation is conserved in a large number of proteobacteria. Therefore, the function of YcgR in motility control is likely to be conserved. Higher concentrations of c-di-GMP in the presence of YcgR slows motor speed and inhibit chemotaxis by inhibiting ClockWise (CW) rotation. YcgR, when bound to c-di-GMP, interacts strongly with the flagellar motor proteins FliG and FliM. Interaction with FliG disrupts the organisation of the C-terminal domain altering the rotor-stator interface in a way that reduces the efficiency of torque generation and induces a CCW motor bias [
].
Phenylacetic acid degradation operon negative regulatory protein PaaX
Type:
Family
Description:
This transcriptional regulator is always found in association with operons believed to be involved in the degradation of phenylacetic acid [
]. The gene product has been shown to bind to the promoter sites and repress their transcription [].
Deleted in lung and esophageal cancer (DLEC1) is a tumour suppressor that is frequently silenced by promoter methylation in various kinds of cancer [
,
,
]. However, in head and neck squamous cell carcinoma, DLEC1 is not silenced solely by promoter methylation []. It has been shown to repress NF-kB signalling in prostate cancer [].
Signal transduction histidine kinase/phosphatase, lantibiotic regulatory protein MprB
Type:
Family
Description:
Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions [
]. Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk []. These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more []. Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) []. The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response [
,
].Signal transducing histidine kinases are the key elements in two-component signal transduction systems, which control complex processes such as the initiation of development in microorganisms [
,
]. Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation [], and CheA, which plays a central role in the chemotaxis system []. Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water []. The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily. HKs can be roughly divided into two classes: orthodox and hybrid kinases [
,
]. Most orthodox HKs, typified by the Escherichia coli EnvZ protein, function as periplasmic membrane receptors and have a signal peptide and transmembrane segment(s) that separate the protein into a periplasmic N-terminal sensing domain and a highly conserved cytoplasmic C-terminal kinase core. Members of this family, however, have an integral membrane sensor domain. Not all orthodox kinases are membrane bound, e.g., the nitrogen regulatory kinase NtrB (GlnL) is a soluble cytoplasmic HK []. Hybrid kinases contain multiple phosphodonor and phosphoacceptor sites and use multi-step phospho-relay schemes instead of promoting a single phosphoryl transfer. In addition to the sensor domain and kinase core, they contain a CheY-like receiver domain and a His-containing phosphotransfer (HPt) domain.Pathogenic bacteria produce a number of virulence factors to facilitate host infection, and to combat competing species. Antibiotics are secreted by some pathogenic prokaryotes to lyse cells, some of which have been adapted by humans for use against virulent microbes. Amongst these are the lantibiotics, produced exclusively by Gram-positive bacteria. Lantibiotics are small, heavily post-translationally modified peptides that inhibit rival cell growth and are strongly cationic. Lantibiotic genes reside on the bacterial chromosome, where they cluster with genes that adapt and secrete them to the extracellular space. Many of these so-called 'pathogenicity islands' have been characterised, including the epidermin (epi) cluster in Staphylococcus epidermis, and the nisin (nis) cluster in Lactococcus lactis [
]. The gene encoding the lantibiotic is flanked by 3 regulatory genes: 2 that are usually involved in a 2-component regulatory system, and another that cleaves the signal peptide from the precursor to produce the mature lantibiotic.The archetypal example of lantibiotic synthesis is witnessed in the Lactococcus lactisnis operon. In this cluster, the 2-component regulatory system is controlled by the nisK/nisR genes. NisK is believed to function as a membrane-associated protein kinase that phosphorylates NisR in response to external stimuli [
]. It shows some similarity to other bacterial kinases, and contains a single histidine kinase domain.
African swine fever virus, Inner membrane protein p54
Type:
Family
Description:
This entry represents Inner membrane protein p54 from African swine fever virus (ASFV). This inner envelope protein is involved in the intracellular microtubule-dependent transport of viral capsid toward viral factories through its interaction with host dynein [
]. It sems to induce caspase-3 activation and apoptosis [].
Flagellar assembly protein FliH/Type III secretion system HrpE
Type:
Domain
Description:
This entry represents a region found in the flagellar assembly protein FliH, as well as in type III secretion system protein HrpE.Many flagellar proteins are exported by a flagellum-specific export pathway. Attempts have been made to characterise the apparatus responsible for this process, by designing assays to screen for mutants with export defects.
Experiments involving filament removal from temperature-sensitive flagellar mutants of Salmonella typhimurium have shown that, while most mutants were able to regrow filaments, flhA, fliH, fliI and fliN mutants showed no or greatly reduced regrowth. This suggests that the corresponding gene products are involved in the process of flagellum-specific export []. The sequence of fliH has been deduced and shown to encode a protein of molecular mass of 25,782 Da.Bacterial HrpE proteins are belived to function on the type III secretion system, specifically the secretion of HrpZ (harpinPss) [
].
Cytochrome b561, DM13 and DOMON domain-containing protein At5g54830
Type:
Family
Description:
This entry represents the Cytochrome b561, DM13 and DOMON domain-containing protein At5g54830 from Arabidopsis thaliana (b561A). This protein is thought to act as a catecholamine-responsive trans-membrane electron transporter [
]. Most members of this family are found in streptophytes.
Type III exporter system, secretion apparatus protein BsaZ
Type:
Family
Description:
This entry represents one of several families of proteins related to bacterial flagellar biosynthesis proteins and involved in bacterial type III protein secretion systems. This family is homologous to, but distinguished from, flagellar biosynthetic protein FlhB (
).
Type II secretion system protein TadB-like, N-terminal domain
Type:
Domain
Description:
This presumed domain, mainly found in Alphaproteobacteria, is functionally uncharacterised. It is found at the N-terminal of predicted type II secretion proteins, such as TadB. It is found in association with
.
PGC-1 and ERR-induced regulator in muscle protein 1
Type:
Family
Description:
Peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha (PGC-1 alpha) and PGC-1 beta are two members of the PGC-1 family and important regulators of mitochondrial metabolism. They are expressed at high levels in heart and skeletal muscle and can induce mitochondrial biogenesis and oxidative capacity. PGC-1 alpha and PGC-1 beta regulate DNA-binding transcription factors, such as estrogen-related receptors (ERRS). ERR beta and ERR gamma are orphan nuclear receptors that act both downstream and parallel to PGC-1 coactivators to control the expression of a broad set of genes important for energy homeostasis.PGC-1/ERR-induced regulator in muscle 1 (Perm1) is a downstream effector of PGC-1 and ERRs [
], regulating muscle-specific pathways important for energy metabolism and contractile function. Perm1 does not function as a classical coactivator, but has been suggested to act by regulating signalling pathways in a tissue-selective manner to enable PGC-1/ERRs to induce specific sets of genes. It has been shown that Perm1 is also required for the efficient expression of the glucose transporter Glut4, thus, it may affect glucose uptake, and of the mitochondrial creatine kinase Ckmt2 [].
Non-structural protein NSP3, SUD-N (Mac2) domain superfamily, betacoronavirus
Type:
Homologous_superfamily
Description:
This superfamily 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 [
].Non-structural protein Nsp3 contains at least seven different functional modules within its 1922-amino-acid polypeptide chain. One of these is the so-called SARS (severe acute respiratory syndrome)-unique domain (SUD), a stretch of about 338 residues that is completely absent from any other coronavirus. The SUD domain may be responsible for the high pathogenicity of the SARS coronavirus, compared to other viruses of this family [
,
]. Later, the NSP3 of MHV was shown by X-ray crystallography to contain a SUD-C-like fold, so it is no longer appropriate to call this domain "SARS-unique". This region has been renamed into "Domain Preceding Ubl2 and PL2pro"(DPUP) [
]. NSP3 has been shown to bind to viral RNA, nucleocapsid protein, as well as other viral proteins, and participates in polyprotein processing. It is a multifunctional protein comprising up to 16 different domains and regions [
]. SUD(core) exhibits a two-domain architecture. The N-terminal subdomain (SUD-N) and the C-terminal subdomain of SUDcore, also named middle SUD subdomain, or SUD-M [,
]. SUD-N has been shown to be dispensable for the SARS-CoV replication/transcription complex within the context of a SARS-CoV replicon []. 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 [].
Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus
Type:
Domain
Description:
The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface [
,
,
,
].This domain corresponds to the receptor-binding domain (RBD) of the Spike S1 subunit which binds to angiotensin-converting enzyme 2 (ACE2) in respiratory syndrome coronavirus (SARS-CoV) [
,
,
], but not in some bat-derived coronaviruses (BatCoV) [,
].This domain is composed of a core and an external subdomain. During evolution, the core subdomain is structurally preserved, whereas the external subdomain folds into variant structures to engage different receptors. The most conserved part lies in the core-centre sheet that is composed of five antiparallel strands and functions as the scaffold of the core subdomain. Additional conserved elements include the core-centre helices and core-peripheral structures. Characteristic cysteine residues form three disulfide bonds in the core subdomain, further stabilizing the core structure from the interior [
].
Spike (S) protein S1 subunit, receptor-binding domain, MERS-CoV-like
Type:
Domain
Description:
The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface [
,
,
,
].This entry represents the receptor-binding domain (RBD) of the S1 subunit of the Spike (S) proteins from betacoronaviruses in the merbecovirus subgenera (C lineage), including Bat coronavirus HKU5, Middle East respiratory syndrome (MERS) CoV and related bat CoVs.
Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2
Type:
Domain
Description:
The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface [
,
,
,
].This entry represents the RBD domain of Spike protein S1 subunit from SARS-CoV-2, which binds the extracellular peptidase domain of angiotensin-converting enzyme 2 (ACE2). It has been shown that the receptor binding induces the dissociation of the S1 with ACE2, prompting the S2 to transit from a metastable pre-fusion to a more-stable post-fusion state that is essential for membrane fusion [
,
,
,
]. Recent structures revealed that only a single RBD is necessary for ACE2 binding and it is not yet clear if protrusion of the RBD from the S protein trimer is necessary for binding to ACE2 or the interconversion of the RBD between closed and open states represents an intrinsic property of the S protein []. During the pandemic, many amino acid substitutions have been reported in the S1 segment, being D614G the most commonly observed amino acid change from the reference sequence. Although it was estimated to be slightly destabilizing, it was hypothesized that it increases virus infectivity by increasing the total amount of S protein incorporated into virions. The most prevalent RBD substitution in the RBD is the T478I, located in a portion of a loop that contacts ACE2. However, most substitutions in the interface with ACE2 appear to be neutral or destabilizing, with none improving binding affinity [].SARS-CoV-2 RBD has a core formed by a twisted five-stranded antiparallel β-sheet (β1-7) with short helices and loops connecting them. Between the β4 and β7 strands in the core, there is an extended insertion, the receptor-binding motif (RBM), containing the short β5 and β6 strands, α4 and α5 helices and loops, which contains most of the contacting residues for binding to ACE2. There are nine cysteine residues in the RBD, eight of which form four pairs of disulfide bonds. Among these four pairs, three are in the core which help to stabilise the β-sheet structure, while the remaining pair connects the loops in the distal end of the RBM [
].
Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV
Type:
Domain
Description:
The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface [
,
,
,
].This is the receptor-binding domain (RBD) of Spike protein S1 subunit from SARS-CoV which binds the extracellular peptidase domain of angiotensin-converting enzyme 2 (ACE2). It has been shown that the receptor binding induces the dissociation of the S1 with ACE2, prompting the S2 to transit from a metastable pre-fusion to a more-stable post-fusion state that is essential for membrane fusion [
,
].
Spike (S) protein S1 subunit, receptor-binding domain, HCoV-OC43-like
Type:
Domain
Description:
The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface [,
,
,
].This entry represents the receptor-binding domain (RBD) of the S1 subunit of the Spike (S) protein from several lineage A betacoronaviruses in the embecovirus genera, including human coronavirus OC43 (HCoV-OC43) and bovine respiratory coronavirus (BCoV), among others. HCoV-OC43 is of zoonotic origin and is endemic in the human population, causing mild respiratory tract infections and possible severe complications or fatalities in young children, the elderly, and immunocompromised individuals. HCoV-OC43 uses 9-O-acetyl-sialic acid (9-O-Ac-Sia) as a receptor, which is terminally linked to oligosaccharides decorating glycoproteins and gangliosides at the host cell surface. HCoV-OC43 appears to bind 9-O-Ac-Sia at the NTD [
].
Spike (S) protein S1 subunit, receptor-binding domain, HKU1-like
Type:
Domain
Description:
The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface [,
,
,
].This domain corresponds to the receptor binding domain (RBD) of the Spike S1 subunit from human coronavirus (CoV) HKU1, isolates N5 and N2. HKU1 is a human lineage A betacoronavirus that causes mild yet prevalent respiratory disease, and is related to the zoonotic SARS and MERS betacoronaviruses. These viruses use 9-O-acetyl-sialic acid (9-O-Ac-Sia) as a receptor which is terminally linked to oligosaccharides decorating glycoproteins and gangliosides at the host cell surface [
,
].
Spike (S) protein S1 subunit, receptor-binding domain, MERS-CoV
Type:
Domain
Description:
The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface [
,
,
,
].This entry represents the RDB domain of Spike protein S1 subunit from MERS-CoV. MERS-CoV causes severe pulmonary disease in humans. It binds to its receptor, human dipeptidyl peptidase 4 (DPP4), also called CD26, through the RBD of its S1 subunit and then fuses viral and host membranes through its S2 subunit [
,
]. The RBD consists of a core subdomain and a unique strand-dominated external receptor binding motif (RBM) that recognises blades IV and V of the CD26 β-propeller [].
Spike (S) protein S1 subunit, receptor-binding domain, HKU4-like
Type:
Domain
Description:
The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface [
,
,
,
].This entry represents the receptor-binding domain (RBD) of the S1 subunit of the spike (S) protein from Tylonycteris bat coronavirus HKU4 and other Middle East Respiratory Syndrome (MERS)-related coronaviruses which are phylogenetically closely related, sharing high sequence similarity. HKU4 is able to bind the MERS-CoV receptor, human dipeptidyl peptidase 4 (DPP4), also called CD26 but with lower affinity than MERS-CoV which indicates that HKU4 is less adapted to human DPP4 [].
Spike (S) protein S1 subunit, receptor-binding domain, HEV
Type:
Domain
Description:
The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface [
,
,
,
].This entry represents the receptor-binding domain (RDB) of the Spike protein S1 subunit from the porcine hemagglutinating encephalomyelitis virus (HEV), which is related to SARS and MERS betacoronaviruses and is associated with acute outbreaks of wasting and encephalitis in nursing piglets from pig farms. Porcine HEV uses 9-O-acetyl-sialic acid (9-O-Ac-Sia) as a receptor, like the closely related HCoV-OC43 and HCoV-HKU1 viruses [
].
Granule associated Rac and RHOG effector protein 1
Type:
Family
Description:
This entry represents the granule associated Rac and RHOG effector protein 1 (GARRE1), also known as KIAA0355, associates with proteins found in RNA processing bodies [
]. GARRE1 is found in vertebrates and has been shown to be an effector specific to the Rac subfamily of proteins [].
Conserved hypothetical protein CHP01519, Plasmodium falciparum (isolate 3D7)
Type:
Family
Description:
These sequences represent an uncharacterised family consisting of a small number of hypothetical proteins of the malaria parasite Plasmodium falciparum (isolate 3D7).
RNA-binding protein MEX-3, second type I KH domain
Type:
Domain
Description:
This entry represents the second type I KH domain of MEX3 proteins.
The MEX-3 protein family includes four members, MEX3A/RKHD4, MEX3B/RKHD3/RNF195, MEX3C/ RKHD2/RNF194, and MEX3D/RKHD1/RNF193/TINO [
,
,
]. They are homologous of Caenorhabditis elegans MEX-3 protein, a translational regulator that specifies the posterior blastomere identity in the early embryo and contributes to the maintenance of the germline totipotency [,
]. MEX-3 proteins are RNA-binding phosphoproteins involved in post-transcriptional regulatory mechanisms [,
,
]. It has been shown that these proteins are deregulated in several cancers and affects apoptosis regulation, antigen processing, and presentation, which, therefore, contribute to the immune evasion of tumour cells [
,
].They are characterised by containing two K-homology (KH) RNA-binding domains and a C-terminal RING finger [
]. They bind RNA through their KH domains and shuttle between the nucleus and the cytoplasm via the CRM1-dependent export pathway [].
This entry represents the first type I KH domain of MEX3 proteins.
The MEX-3 protein family includes four members, MEX3A/RKHD4, MEX3B/RKHD3/RNF195, MEX3C/ RKHD2/RNF194, and MEX3D/RKHD1/RNF193/TINO [
,
,
]. They are homologous of Caenorhabditis elegans MEX-3 protein, a translational regulator that specifies the posterior blastomere identity in the early embryo and contributes to the maintenance of the germline totipotency [,
]. MEX-3 proteins are RNA-binding phosphoproteins involved in post-transcriptional regulatory mechanisms [,
,
]. It has been shown that these proteins are deregulated in several cancers and affects apoptosis regulation, antigen processing, and presentation, which, therefore, contribute to the immune evasion of tumour cells [,
].They are characterised by containing two K-homology (KH) RNA-binding domains and a C-terminal RING finger [
]. They bind RNA through their KH domains and shuttle between the nucleus and the cytoplasm via the CRM1-dependent export pathway [].
DNA processing protein A, sterile alpha motif domain
Type:
Domain
Description:
This is the N-terminal domain found in DNA processing protein A (DprA) present in Streptococcus pneumoniae. DprA has recently been discovered to be a transformation-dedicated RecA loader. Transformation is believed to play a major role in genetic plasticity. This domain is known as the sterile alpha motif (SAM) domain. DprAs are able to form a type of dimer through SAM-SAM interactions, also known as N/N interactions [
].
Centromere DNA-binding protein complex CBF3 subunit B, C-terminal
Type:
Domain
Description:
This entry represents the C-terminal domain of Cep3, one of the major components of the CBF3. The Cep3 dimer forms a large central channel that is large enough to accommodate duplex B-form DNA. The dimerisation region is followed by a linker to the zinc-finger domain at the C terminus. The CBF3 complex is an essential core component of the budding yeast kinetochore and is required for the centromeric localisation of all other kinetochore proteins. Cep3 is the only component with DNA-binding properties [
].
This entry represents the RGS (Regulator of G-protein Signaling) domain of Regulator of G-protein signaling 9 (RGS9) [
], a member of the R7 subfamily of the RGS protein family (Neuronal RGS). RGS is a diverse group of multifunctional proteins that regulate cellular signalling events downstream of G-protein coupled receptors (GPCRs). As a major G-protein regulator, RGS domain containing proteins are involved in many crucial cellular processes such as regulation of intracellular trafficking, glial differentiation, embryonic axis formation, skeletal and muscle development, and cell migration during early embryogenesis [,
,
,
].RGS9 forms constitutive complexes with G-beta-5 subunit and controls such fundamental functions as vision and behaviour [
]. RGS9 exists in two splice isoforms: RGS9-1 which regulates phototransduction in rods and cones and RGS9-2 which regulates dopamine and opioid signalling in the basal ganglia. In addition, RGS9 was found to bind many other proteins outside of G protein signalling pathways including: mu-opioid receptor, beta-arrestin, alpha-actinin-2, NMDAR, polycystin, spinophilin, and guanylyl cyclase, among others.
Zinc finger CCCH-type with G patch domain-containing protein
Type:
Family
Description:
This entry represents the zinc finger CCCH-type with G patch domain-containing protein (ZIP) that acts as a transcription repressor through the recruitment of the Mi-2/nucleosome remodelling and deacetylase (NuRD) complex to target promoters. ZIP regulates several cellular signalling pathways like the epidermal growth factor receptor (EGFR) pathways, critically involved in cell proliferation, survival, and migration.ZIP contains several domains: a CCCH zinc finger, a TUDOR domain, a G-patch and a coiled-coil domain. The coiled-coil domain is responsible for the ZIP interaction with Mi-2 to recruit the NuRD complex, while its zinc finger structure specifically recognises the consensus sequence in the 5' upstream region of EGFR. The TUDOR domain is a chromatin-presenting module reading the methylated histone marks. ZIP is also involved in the recognition of RNA and other proteins, suggesting that it may coordinate an active coupling between transcription regulation and pre-mRNA splicing, especially considering that ZIP contains a CCCH-type of zinc finger and a G-patch domain, both of which have been featured in proteins functioning in mRNA processing. Additionally, ZIP inhibits cell proliferation and suppresses breast carcinogenesis, while its depletion leads to a drastic tumour growth in vivo. ZIP is downregulated in breast carcinomas and that its level of expression is negatively correlated with that of EGFR [
].
Coiled-coil and C2 domain-containing protein 1, DM14 domain
Type:
Domain
Description:
This is a short helical domain found in multiple copies in most members of this entry. In CC2D1A/B proteins is present four times. Its function is not yet known [
].This entry includes coiled-coil and C2 domain-containing protein 1A/B (CC2D1A/B, also known as Freud-1/2). CC2D1A is involved in many pathways, including nuclear factor kappaB, PDK1/Akt, cAMP/PKA, Notch and bone morphogenetic protein [
]. It is a calcium-regulated repressor of serotonine receptor 5-HT1A and dopamine-D2 receptor expression [,
]. CC2D1B binds to the 5-HT1A DRE and represses the human 5-HT1A receptor gene to regulate its expression in non-serotonergic cells and neurons [].CC2D1A and CC2D1B have also been shown to interact with the CHMP4 family of proteins, the major subunit of the ESCRT-III complex. They may regulate degradation and signaling of EGFR and TLR4 [
].CC2D1A and CC2D1B share conserved domains, including several DM14 domains that are specific to this protein family, a C-terminal helix-loop-helix domain, and a C2 domain. The CC2D1A C2 domain is thought to be calcium insensitive and it lacks several acidic residues that mediate calcium binding of the PKC C2 domain. In addition, it contains a poly-basic insert that is not present in calcium-dependent C2 domains and may function as a nuclear localization signal [
]. The CC2D1B C2 domain appears to be essential for its DNA binding and repressor function; it may mediate protein-protein interactions []. Mutations in the CC2D1A gene has been linked to nonsyndromic mental retardation [
,
].
Band 4.1-like protein 3, FERM domain, F1 sub-domain
Type:
Domain
Description:
Band 4.1-like protein 3, also known as 4.1B or DAL-1, belongs to the protein 4.1
family. Members of the 4.1 family contain a 4.1/ezrin/adixin/moesin (FERM) domain, which is involved in the linkage of cytoplasmic proteins to the membrane [].Protein 4.1B has been described to be a growth suppressor [
,
]. It localises to the cell membrane to sites of cell-cell contact, and functions as an adapter protein, linking the plasma membrane to the cytoskeleton [
,
]. It is involved in cytoskeleton-associated processes, such as cell motility and adhesion, and also plays a role in the regulation of cell growth, differentiation, and the establishment of epithelial-like cell structures [].The FERM domain of Band4.1-L3 is made up of three sub-domains, F1, F2, and F3. This entry represents the N-terminal F1 subdomain.
Band 4.1-like protein 4A, FERM domain, F1 sub-domain
Type:
Domain
Description:
Band 4.1-like protein 4A (also named NBL4) belongs to the protein 4.1 family. Members of the 4.1 family contain a FERM (4.1/Ezrin/radixin/moesin) domain, which is involved in the linkage of cytoplasmic proteins to the membrane [
]. NBL4 is an important component of the Wnt/beta-catenin pathway and may be involved in the cell polarity determination or proliferation []. It might have a role in embryogenesis [].The FERM domain of NBL4 is made up of three sub-domains, F1, F2, and F3. This entry represents the N-terminal F1 subdomain.
Band 4.1-like protein 4B, FERM domain, F1 sub-domain
Type:
Domain
Description:
Band 4.1-like protein 4B (EHM2) belongs to the protein 4.1 family. Members of the 4.1 family contain a FERM (4.1/Ezrin/radixin/moesin) domain, which is involved in the linkage of cytoplasmic proteins to the membrane [
]. EHM2 shows highest homology to band 4.1-like protein 4A (NBL4), which may be involved in the cell polarity determination or proliferation [,
]. EHM2 is expressed in high-metastatic K1735 murine melanoma cells [].The FERM domain of EHM2 is made up of three sub-domains, F1, F2, and F3. This entry represents the N-terminal F1 subdomain.
Type IV pilin-like putative secretion pathway protein G/H
Type:
Family
Description:
This entry represents a family from Cyanobacteria. All the proteins are putatively annotated as being general secretion pathway proteins G and H, and are likely to be pilins of the type IV secretory pathway.
Spindle pole body-associated protein Vik1/Cik1, microtubule binding domain
Type:
Domain
Description:
This domain can be found in the C-terminal of the yeast spindle pole body-associated protein Vik1 and its paralogue, Cik1. This domain is a motor homology domain that retains microtubule binding properties but lacks a nucleotide binding site [
,
].
Bridge-like lipid transfer protein family member 1, C-terminal
Type:
Domain
Description:
This is the conserved domain found at the C-terminal BLTP1.Bridge-like lipid transfer protein family member 1 (BLTP1, formerly known as Tweek/KIAA1109 in human) is a tube-forming lipid transport protein which provides phosphatidylethanolamine for glycosylphosphatidylinositol (GPI) anchor synthesis in the endoplasmic reticulum. It plays a role in endosomal trafficking and endosome recycling and it is also involved in the actin cytoskeleton and cilia structural dynamics [
,
]. BLTP1 also acts as a regulator of phagocytosis []. In humans, it has been associated with rheumatoid arthritis [,
]. Mutations of the BLTP1 gene has been associated with Alkuraya-Kucinskas syndrome (MIM 617822), a severe disorder of brain development and arthrogryposis [].Members of this entry belong to the repeating β-groove (RBG) superfamily together with VPS13, ATG2, SHIP164, BLTP2/FMP27, which are all conserved lipid transfer proteins containing long hydrophobic grooves [
]. They all share the same structure comprising multiple repeating modules consisting of five β-sheets followed by a loop.
Type II secretion system (T2SS) pilotin, S protein
Type:
Family
Description:
This entry represents pilotin AspS from Vibrio and some E.coli and Shigella. This entry also includes YghG from E. coli. AspS is part of the Vibrio-type T2SS secretin system that drives the secretion of fully-folded protein substrates across the bacterial outer membrane. The structure of AspS has been revealed [
,
]. 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 [
].
PDZ and LIM domain protein 1 (PDZ-LIM1, also known as CLP-36) is a member of the PDZ-LIM family of adapter proteins that have been implicated in cytoskeleton organisation, neuronal signalling, cell lineage specification, organ development, and oncogenesis [
]. Several PDZ-LIM proteins are predominantly expressed in striated muscle. However, CLP36 is expressed in several nonmuscle tissues []. CLP36 binds to alpha-actinin-1 and may direct alpha-actinin-1 to specific actin structures [
]. CLP36 also recruits the Clik1 kinase to actin stress fibres in nonmuscle cells [].This entry represents the C-terminal Lim domain of PDLIM1, which function as an adaptor or scaffold to support the assembly of multimeric protein. This domain shows two characteristic zinc finger motifs. The two zinc fingers contain eight conserved residues, mostly cysteines and histidines, which coordinately bond to two zinc atoms [
,
].
Nuclear pore complex protein Nup214, phenylalanine-glycine (FG) domain
Type:
Domain
Description:
CRM1 is the major nuclear export receptor. During translocation through the nuclear pore, transport complexes transiently interact with phenylalanine-glycine (FG) repeats of multiple nucleoporins. On the cytoplasmic side of the nuclear pore, CRM1 tightly interacts with the nucleoporin Nup214. Nup214 binds to N- and C-terminal regions of CRM1, thereby clamping CRM1 in a closed conformation and stabilizing the export complex. This entry represents an FG repeat region within the C terminus of Nup214 which is required for its interaction with CRM1 [
].
PHD finger protein 12, MRG binding domain superfamily
Type:
Homologous_superfamily
Description:
This superfamily represents a domain found in PHF12 (PHD finger protein 12, also known as Pf1) binds to the MRG domain of mortality factor 4-like protein 1 (MORF4L1, also known as MRG15) [
]. In mammals, the corepressor Sin3B, the histone deacetylase HDAC1, MRG15 and Pf1 form a complex that plays important roles in regulation of transcription [].
