SII-SWORD/CoKE huggingface dataset:
Sorting nexin-4, BAR domain (SNX4_BAR)
Type: Domain

SNX4 is involved in recycling traffic from the sorting endosome (post-Golgi endosome) back to the late Golgi. It shows a similar domain architecture as SNX1-2, among others, containing a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain . SNX4 is implicated in the regulation of plasma membrane receptor trafficking and interacts with receptors for EGF, insulin, platelet-derived growth factor and the long form of the leptin receptor .

This entry represents the BAR domain of SNX4 from Metazoa. BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions .
RNA exonuclease 4, DEDDh 3'-5' exonuclease domain (REX4_DEDDh_dom)
Type: Domain

This entry represent the DEDDh 3'-5' exonuclease domain found in RNA exonuclease 4 (REX4 or Rex4p) . It is a DEDDh-type DnaQ-like 3'-5' exonuclease containing three conserved sequence motifs termed ExoI, ExoII and ExoIII, with a specific Hx(4)D conserved pattern at ExoIII. These motifs are clustered around the active site and contain four conserved acidic residues that serve as ligands for the two metal ions required for catalysis . REX proteins function in the processing and maturation of many RNA species, similar to the function of Escherchia coli RNase T .
Exonuclease Mut-7, DEDDy 3'-5' exonuclease domain (Mut-7_DEDDy_dom)
Type: Domain

This entry represents the DEDDy domain found in Caenorhabditis elegans mut-7 and similar proteins found in metazoans. Mut-7 is implicated in posttranscriptional gene silencing . It contains a DEDDy-type DnaQ-like 3'-5' exonuclease domain possessing three conserved sequence motifs, termed ExoI, ExoII and ExoIII, with a specific YX(3)D pattern at ExoIII. These motifs are clustered around the active site and contain four conserved acidic residues that serve as ligands for the two metal ions required for catalysis .
ISG20, DEDDh 3'-5' exonuclease domain (ISG20_DEDDh)
Type: Domain

Interferon (IFN) Stimulated Gene product of 20kDa (ISG20) is an IFN-induced antiviral exonuclease with a strong preference for single-stranded RNA and minor activity towards single-stranded DNA . It was also independently identified by its response to estrogen and was called HEM45 (human estrogen regulated transcript) . ISG20 may be a major effector of innate immunity against pathogens including viruses, bacteria, and parasites. It is located in promyelocytic leukemia (PML) nuclear bodies, sites for oncogenic DNA viral transcription and replication. It may carry out its function by degrading viral RNAs as part of the IFN-regulated antiviral response .

ISG20 is a DEDDh-type DnaQ-like 3'-5' exonuclease containing three conserved sequence motifs termed ExoI, ExoII and ExoIII with a specific Hx(4)D conserved pattern at ExoIII. These motifs are clustered around the active site and contain four conserved acidic residues that serve as ligands for the two metal ions required for catalysis .
Fosfomycin resistance protein FosX (FosX)
Type: Family

FosX is a Mn(II)-dependent fosfomycin-specific epoxide hydrolase . Fosfomycin inhibits the enzyme UDP-Nacetylglucosamine-3-enolpyruvyltransferase (MurA), which catalyzes the first committed step in bacterial cell wall biosynthesis. FosX catalyzes the addition of a water molecule to the C1 position of the antibiotic with inversion of the configuration at C1 in the presence of Mn(II). The hydrated fosfomycin loses the inhibition activity . FosX is evolutionarily related to glyoxalase I and type I extradiol dioxygenases.
14-3-3 protein sigma (14-3-3_sigma)
Type: Family

14-3-3 protein sigma isoform, also known as stratifin or human mammary epithelial marker (HME) 1, has been most directly linked to tumour development . In humans, it is expressed by the SFN gene, strictly in stratified squamous epithelial cells in response to DNA damage where it is transcriptionally induced in a p53-dependent manner, subsequently causing cell-cycle arrest at the G2/M checkpoint . Up-regulation and down-regulation of 14-3-3 sigma expression have both been described in tumours. For example, in human breast cancer, 14-3-3 sigma is predominantly down-regulated by CpG methylation, acting as both a tumour suppressor and a prognostic indicator , while in human scirrhous-type gastric carcinoma (SGC), it is up-regulated and may play an important role in SGC carcinogenesis and progression . Loss of 14-3-3 sigma expression sensitizes tumour cells to treatment with conventional cytostatic drugs, making this protein an attractive therapeutic target .
Sorting nexin-14, PX domain (SNX14_PX)
Type: Domain

SNX14 (sorting nexin-14) is expressed in the embryonic nervous system of mammals such as mice, being co-expressed with homoprotein islet-1 in several tissues . SNX14 levels increase progressively during neuronal development and its knockdown impairs both excitatory and inhibitory synaptic transmission, suggesting a role in neuronal development and function . SNX14 contains an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal PXC domain . Its RGS domain is non-functional as a GTPase activator for Galpha, but it binds to and sequesters Galpha, thus inhibiting downstream cAMP production .

This entry represents the PX domain of SNX14. The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions .
Sorting nexin-13, PX domain (SNX13_PX)
Type: Domain

SNX13, also called RGS-PX1 or sorting nexin-13, contains an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal PXC domain . It specifically binds to the stimulatory subunit of the heterotrimeric G protein G(alpha)s, serving as its GTPase activating protein, through the RGS domain . It is involved in development and regulation of endocytosis dynamics . It influences the lysosomal targeting of the epidermal growth factor receptor, suggesting a role both in cell signaling and receptor trafficking .

This entry represents the PX domain of SNX13. The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions .
Talin-1/2, rod-segment (Talin1/2-RS)
Type: Domain

This entry represents the rod-segment of Talin-1/2. This domain interacts with its N-terminal FERM domain to mask its integrin-binding site and interferes with interactions between the FERM domain and the cellular membrane .

Talin is a cytoskeletal protein that interacts with integrins and lipids. It forms an antiparallel homodimer with an N-terminal globular head and a larger C-terminal rod . The head domain contains a FERM (4.1, ezrin, radixin, moesin) domain, which has been implicated in both integrin and actin-binding. Binding of integrin beta cytoplasmic tails to the FERM domain has been found to induce integrin activation . The rod domain also appears to mediate binding to both actin and integrins . The C-terminal rod contains an I/LWEQ domain. It has been shown that the I/LWEQ domains from mouse talin

and yeast Sla2p

interact with F-actin . The domain has four conserved blocks, the name of the domain is derived from the initial conserved amino acid of each of the four blocks .

In vivo, talin has been shown to play a critical role in the formation of cell adhesions and regulation of integrin signalling in numerous species . Talin localises to some neuromuscular junction and sites of cell-cell adhesions, as well as to focal adhesions, sites of attachment to the substratum.
1,4-alpha-glucan-branching enzyme (Branching_enzy)
Type: Family

This entry consists of glycogen branching enzyme GlgB from bacteria and GBE1 from eukaryotes, which are responsible for the transfer of chains of alpha(1,4)-linked glucosyl residues to other similar chains (in new alpha-(1,6) linkages) in the biosynthesis of glycogen . GlgB is responsible for the degree of alpha(1,6) branch linkages found in polysaccharides . GBE1 is required for normal glycogen accumulation in animals . Deficiency in GBE1 results in glycogen storage disease type IV .
Frizzled-5, CRD domain (FZ5_CRD)
Type: Domain

Frizzleds are seven transmembrane-spanning proteins that constitute an unconventional class of G protein-coupled receptors . They have important regulatory roles during embryonic development .

Frizzleds expose their large N terminus on the extracellular side. The N-terminal, extracellular cysteine-rich domain (CRD) has been implicated as the Wnt binding domain and its structure has been solved . The cysteine-rich domain of Frizzled (Fz) is shared with other receptor tyrosine kinases that have roles in development including the muscle-specific receptor tyrosine kinase (MuSK), the neuronal specific kinase (NSK2), and ROR1 and ROR2. The cytoplasmic side of many Fz proteins has been shown to interact with the PDZ domains of PSD-95 family members and is thought to have a role in the assembly of signalling complexes. The conserved cytoplasmic motif of Fz, Lys-Thr-X-X-X-Trp, is required for activation of the beta-catenin pathway, and for membrane localisation and phosphorylation of Dsh.

In Drosophila melanogaster, the frizzled locus is involved in planar cell polarity, which is the coordination of the cytoskeleton of epidermal cells to produce a parallel array of cuticular hairs and bristles . In the wild-type wing, all hairs point towards the distal tip , whereas in Fz mutants, the orientation of individual hairs with respect both to their neighbours and to the organism as a whole is altered. In the developing wing, Fz function is required for cells to respond to the extracellular polarity signal as well as the proximal-distal transmission of an intracellular polarity signal.

In Caenorhabditis elegans, protein mom-5 is the equivalent of frizzled .

Three main signalling pathways are activated by agonist-activated Frizzled proteins: the Fz/beta-catenin pathway, the Fz/Ca2+ pathway and the Fz/PCP (planar cell polarity) pathway . The Wnt/beta-catenin pathway is the best studied signalling pathway involving Fz receptors. In the Wnt/beta-catenin pathway the first downstream cytoplasmic components activated by Fz signalling include Dishevelled (Dsh) and/or its regulatory kinases.

This entry represents the cysteine-rich Wnt-binding domain (CRD) of Frizzled-5 (Fz5). The cysteine-rich domain (CRD) is an essential extracellular portion of the Fz5 receptor, and is required for binding Wnt proteins .
Melanophilin, FYVE-related domain (Melanophilin_FYVE-rel_dom)
Type: Domain

Melanophilin, also termed SlaC2-a, or exophilin-3, is a GTP-bound form of Rab27A-, myosin Va-, and actin-binding protein present on melanosomes. It is involved in the control of transferring of melanosomes from microtubules to actin filaments. It also functions as a melanocyte type myosin Va (McM5) binding partner and directly activates the actin-activated ATPase activity of McM5 through forming a tripartite protein complex with Rab27A and an actin-based motor myosin Va .
Leucine rich adaptor protein 1 (LURAP1)
Type: Family

This family of proteins activate the canonical NF-kappa-B pathway, promote proinflammatory cytokine production and promote the antigen presenting and priming functions of dendritic cells .
Glycerol kinase 5 (GK5)
Type: Family

This entry includes Glycerol kinase 5 (GK5). Sequence comparison shows members of this group are homologues of bacterial GKs, and they retain all functionally important residues. However, GK-like proteins in this family do not have detectable GK activity. The reason remains unclear. It has been suggested that the conserved catalytic residues might facilitate them performing a distinct function. GKs belong to the FGGY family of carbohydrate kinases, the monomers of which contain two large domains, which are separated by a deep cleft that forms the active site .

These proteins are skin-specific kinases expressed predominantly in sebaceous glands. It can form a complex with the sterol regulatory element-binding proteins (SREBPs) through their C-terminal regulatory domains, inhibiting SREBP processing and activation . GK5 also promotes gefitinib resistance by inhibiting apoptosis and cell cycle arrest .
Melanoma-associated antigen (MAGE)
Type: Family

The melanoma antigen (MAGE) protein family contains more than 25 members that share a conserved MAGE homology domain (MHD) .

Proteins known to contain a MAGE domain are listed below:

Human MAGE-A, -B and -C proteins. MAGE-A, -B and -C genes are silent in all normal tissues with the exception of testis.

Human MAGE-D to -L proteins. MAGE-D to -L genes are expressed in normal adult tissues.

Mouse Mage-a and -b proteins.

Mouse Mage-d, -e, -g, -h, -k and -l.

Mammalian Necdin. The human Necdin gene is a candidate for the Prader-Willi syndrome.

Human Trophinin mediates apical cell adhesion between trophoblastic cells and luminal epithelial cells of the endometrium and is implicated in the initial attachment during the process of human embryo implantation .
Histidine acid phosphatase, VIP1 family (His_Pase_VIP1)
Type: Family

This entry represents the VIP1 subfamily of the histidine acid phosphatase family. Budding yeast Vip1 is a inositol hexakisphosphate and inositol heptakisphosphate kinase . The N-terminal domain of yeast Vip1 has inositol-hexakisphosphate kinase activity and is followed by a phosphatase domain of as yet unknown specificity, but which is very likely to act on multiply phosphorylated inositol species .

The histidine phosphatase superfamily is so named because catalysis centres on a conserved His residue that is transiently phosphorylated during the catalytic cycle. Other conserved residues contribute to a 'phosphate pocket' and interact with the phospho group of substrate before, during and after its transfer to the His residue. Structure and sequence analyses show that different families contribute different additional residues to the 'phosphate pocket' and, more surprisingly, differ in the position, in sequence and in three dimensions, of a catalytically essential acidic residue. The superfamily may be divided into two main branches. The relationship between the two branches is not evident by (PSI-)BLAST but is clear from more sensitive sequence searches and structural comparisons .
Small ribosomal subunit protein eS10 (Ribosomal_eS10)
Type: Family

Eukaryotic ribosomes consist of a small 40S subunit and a large 60S subunit. This entry represents the ribosomal subunit protein eS10 (also known as Rps10), a component of the 40S ribosomal subunit . It plays an important role in mammalian ribosome-associated QC pathways .
Zwei Ig domain protein zig-8 (Zig-8)
Type: Family

C. elegans Zig-8 is a immunoglobulin (Ig) domain-containing protein involved in maintaining neuronal soma and axon position .
Formin-binding protein 1, F-BAR domain (FNBP1_F-BAR)
Type: Domain

Formin-binding protein 1 (FNBP1, also known as formin-binding protein 17) contains a N-terminal FER-CIP4 homology (FCH) domain and a C-terminal SH3 domain. It belongs to the CIP4 (Cdc42 interacting protein-4) subfamily of the F-BAR protein family. F-BAR proteins (F for FCH, Fer-CIP4 homology domain) are proteins with an extended CIP4-Fer domain. The F-BAR proteins have been implicated in cell membrane processes such as membrane invagination, tubulation and endocytosis . FNBP1 was originally isolated as a molecule that binds to the proline-rich region of formin . It induces tubular membrane invaginations and participates in endocytosis . It interacts with sorting nexin, SNX2, and is linked to acute myelogeneous leukemia .

This entry represents the F-BAR domain of FNBP1. F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization .
Sulphur relay, TusC (Sulphur_relay_TusC)
Type: Family

This entry includes TusC protein.

The three proteins TusB, TusC, and TusD form a heterohexamer responsible for a sulphur relay reaction. In large numbers of proteobacterial species, this complex acts on a Cys-derived persulphide moiety, delivered by the cysteine desulphurase IscS to TusA, then to TusBCD. The activated sulphur group is then transferred to TusE (DsrC), then by MnmA (TrmU) for modification of an anticodon nucleotide in tRNAs for Glu, Lys, and Gln .
SLIT-ROBO Rho GTPase-activating protein 1, F-BAR domain (srGAP1_F-BAR)
Type: Domain

The SLIT-ROBO Rho GTPase-activating protein (srGAP) family consists of four members: srGAP1, -2, -3 and -4. They contain F-BAR, RhoGAP and SH3 domains. Their RhoGAP domain is involved in negative regulation of Rho GTPase activities important for cytoskeleton rearrangement . The srGAP family members have an "inverse F-BAR" or IF-BAR domain that is distinct from other F-BAR domains such as FBP17. They are multifunctional adaptor proteins involved in various aspects of neuronal development .

This entry represents the F-BAR domain of srGAP1. srGAP1, also called Rho GTPase-Activating Protein 13 (ARHGAP13), is a Cdc42- and RhoA-specific GAP and is expressed later in the development of CNS (central nervous system) tissues. It is an important downstream signaling molecule of Robo1 .
Tyrosine-protein kinase Fer, F-BAR domain (Fer_F-BAR)
Type: Domain

Fer (

) is a tyrosine-protein kinase that acts downstream of cell surface receptors for growth factors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, lamellipodia formation, cell adhesion, cell migration and chemotaxis . In non-small cell lung cancer cells, Fer kinase expression has been linked to cell invasion and tumour metastasis . It also acts downstream of EGFR (EGF receptor) to promote activation of NF-kappa-B and cell proliferation .

This entry represents the F-BAR domain of Fer. F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization .
PACSIN2, F-BAR domain (PACSIN2_F-BAR)
Type: Domain

PACSIN2 (protein kinase C and casein kinase substrate in neurons protein 2, also known as Syndapin-2) belongs to the PACSIN family that contains a N-terminal F-BAR (FCH-BAR) domain and a C-terminal SH3 domain . They are cytoplasmic phosphoproteins that play a role in vesicle formation and transport .

This entry represents the F-BAR domain of PACSIN2. F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization .
PACSIN1, F-BAR (PACSIN1_F-BAR)
Type: Domain

PACSIN1 (protein kinase C and casein kinase substrate in neurons protein 1, also known as SYNDAPIN1) belongs to the PACSIN family that contains a N-terminal F-BAR (FCH-BAR) domain and a C-terminal SH3 domain . There are three tissue-specific isoforms of PACSIN1 found in mammals: PACSIN11 is enriched in neurons, PACSIN12 is ubiquitously expressed, and PACSIN13 is found mainly in muscle . They are cytoplasmic phosphoproteins that play a role in vesicle formation and transport .

PACSIN1 is upregulated upon differentiation into neuronal cells . The SH3 domain of PACSIN1 mediates activation of neural WASP (N-WASP), which is required to regulate actin polymerisation and is essential for proper neuromorphogenesis and cellular motility . Two phosphorylation sites within the F-BAR domain of PACSIN1 are used for membrane tubulation regulation .

This entry represents the F-BAR domain of PACSIN1. F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization .
Aerobactin siderophore biosynthesis, IucA/IucC-like (LucA/IucC-like)
Type: Family

Bacteria solve the iron supply problem caused by the insolubility of Fe(3) by synthesizing iron-complexing compounds, called siderophores, and by using iron sources of their hosts, such as haem and iron bound to transferrin and lactoferrin. Escherichia coli, as an example of a Gram-negative bacterium, forms sophisticated Fe(3)-siderophore and haem transport systems across the outer membrane. IucA and IucC catalyse discrete steps in biosynthesis of the siderophore aerobactin from N epsilon-acetyl-N epsilon-hydroxylysine and citrate .

This entry also includes SbnC, SbnE and SbnF from Staphylococcus aureus. They are involved in staphyloferrin B biosynthesis. SbnC is a staphyloferrin B synthase. SbnE is a L-2,3-diaminopropanoate--citrate ligase. SbnF is a 2-[(L-alanin-3-ylcarbamoyl)methyl]-3-(2-aminoethylcarbamoyl)-2-hydroxypropanoate synthase .

It also includes Bisucaberin biosynthesis protein C that is involved in the biosynthesis of the siderophore bisucaberin , as well as AnkE which is responsible of the production of NK13650 B via ligation of citrate to the ankD product .
MA1715-like (MA1715-like)
Type: Family

A member of this archaeal family, MA1715 from Methanosarcina acetivorans, is required for optimal growth with sulfide as the sole sulfur source and has been shown to support both cysteine and homocysteine biosynthesis .
M28 Zn-Peptidase Glutaminyl Cyclase (M28_QC)
Type: Domain

This entry represents a domain found in proteins belonging to the glutaminyl cyclase (QC) subfamily of the peptidase M28 family. QC is involved in N-terminal glutamine cyclization of many endocrine peptides and is typically abundant in brain tissue. N-terminal glutamine residue cyclization is an important post-translational event in the processing of numerous bioactive proteins, including neuropeptides, hormones, and cytokines during their maturation in the secretory pathway. The N-terminal pGlu protects them from exopeptidase degradation and/or enables them to have proper conformation for binding to the receptors .

QCs are highly conserved from yeast to human . Mammalian QCs have evolved likely from a bacterial zinc-dependent aminopeptidase and have been originally proposed to be Zn-dependent metalloenzymes based on structural similarities to bacterial aminopeptidases and the observation that it can bind Zn ions in a 1:1 stoichiometry . However, a Zn-independent catalytic mechanism has also been proposed. In humans, several genetic diseases, such as osteoporosis, appear to result from mutations of the QC gene. N-terminal glutamate cyclization into pyroglutamate (pGlu) is a reaction that may be related to the formation of several plaque-forming peptides, such as amyloid-(A) peptides and collagen-like Alzheimer amyloid plaque component, which play a pivotal role in Alzheimer's disease .
L-mandelate/L-lactate dehydrogenase, FMN-binding domain (L-MDH/L-LDH_FMN-bd)
Type: Domain

L-Lactate dehydrogenase (L-LDH) Fcb2 from Saccharomyces cerevisiae and L-mandelate dehydrogenase (L-MDH) from Rhodotorula graminis are both flavocytochromes b2. L-LDH is a respiratory enzyme located in the intermembrane space of fungal mitochondria which catalyzes the oxidation of L-lactate to pyruvate. It is composed of 2 domains: a C-terminal flavin-binding domain, which includes the active site for lactate oxidation, and an N-terminal b2-cytochrome domain, required for efficient cytochrome c reduction. Despite their similarities these enzymes have distinct substrate specificities; L-LDH is unable to oxidize mandelate, whereas L-MDH is unable to oxidize lactate .

Fcb2 is composed of 2 domains: a C-terminal FMN-binding domain, which includes the active site for lacate oxidation, and an N-terminal b2-cytochrome domain, required for efficient cytochrome c reduction. Fcb2 is a homotetramer and contains two noncovalently bound cofactors, FMN and heme per subunit. This entry represents the FMN-binding domain .
Rhamnogalacturonan acetylesterase RhgT-like (RhgT-like)
Type: Family

This entry includes rhamnogalacturonan acetylesterase RhgT and related proteins.
Rhamnogalacturan acetylesterase removes acetyl esters from rhamnogalacturonan substrates, and renders them susceptible to degradation by rhamnogalacturonases. Rhamnogalacturonans are highly branched regions in pectic polysaccharides, consisting of repeating -(1,2)-L-Rha-(1,4)-D-GalUA disaccharide units, with many rhamnose residues substituted by neutral oligosaccharides such as arabinans, galactans and arabinogalactans. Extracellular enzymes participating in the degradation of plant cell wall polymers, such as Rhamnogalacturonan acetylesterase, would typically be found in saprophytic and plant pathogenic fungi and bacteria .