SII-SWORD/CoKE huggingface dataset:
Exocyst complex component EXOC6/Sec15, C-terminal, domain 1 (EXOC6/Sec15_C_dom1)
Type: Homologous_superfamily

Subunits of the vesicle tethering complex (such as Tip20 and Dsl1) share protein sequence similarity with known subunits of the exocyst complex, establishing a structural connection among several multi-subunit tethering complexes and implying that many of their subunits are derived from a common progenitor.

Proteins containing this domain includes EXOC6/PINT-1 from animals, Tip20 from budding yeast, Sec15 from fission yeasts and MAIGO2 (Mag2) from plants. Sec15 (EXOC6 homologue) is an exocyst complex component that links Sec4 and downstream fusion effectors at discrete cellular locations. Its C-terminal domain mediates Rab GTPases binding which occurs in a GTP-dependent manner . PINT-1/Tip20/MAIGO2 play a role in anterograde transport from the endoplasmic reticulum (ER) to the Golgi and/or retrograde transport from the Golgi to the ER. They share a similar domain organisation with an N-terminal leucine heptad repeat rich coiled coil and an ~500-residue C-terminal RINT1/TIP20 domain, which might be a protein-protein interaction module necessary for the formation of functional complexes.

This superfamily represents the domain 1 found in the C-terminal domain of the exocyst complex subunit Sec15.
Lepidopteran low molecular weight lipoprotein, N-terminal domain (Lipoprotein_11_N)
Type: Homologous_superfamily

This superfamily represents the Lepidopteran low molecular weight lipoprotein N-terminal domain. It consists of 5 α-helices. The all-α N-terminal domain contains a putative lipid-binding cavity .

Lepidopteran low molecular weight (30 kD) lipoproteins are involved in the innate immune response and transportation of lipid and/or sugar. Structurally, those proteins have two distinct domains: an all-α N-terminal domain (NTD) and an all-β C-terminal domain (CTD) .
Cell wall hydrolase SleB, domain 1 (SleB_dom1)
Type: Homologous_superfamily

This superfamily represents the domain 1 found in the catalytic domain of cell wall hydrolase SleB . The function of the cell wall hydrolase SleB domain involves degradation of peptidoglycan (PG), process required for spore germination, mainly in Bacillus species. Its structure is similar to other transglycosylases but has unique topological features reflecting its unusual specificity for muramic-delta-lactam-containing PG . This domain 1 represents the α helices of the catalytic domain and contains a catalytic glutamate residue .
Heat shock 70kDa protein 13 (HSPA13)
Type: Family

Human HSPA13 (also called 70kDa heat shock protein 13, STCH, or 'stress 70 protein chaperone, microsome-associated, 60kDa') belongs to the heat shock protein 70 (HSP70) family of chaperones that assist in protein folding and assembly and can direct incompetent 'client' proteins towards degradation. Typically, HSP70s have a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). The nucleotide sits in a deep cleft formed between the two lobes of the NBD. STCH contains an NBD but lacks an SBD . STCH may function to regulate cell proliferation and survival, and modulate the TRAIL-mediated cell death pathway. The HSPA13 gene is a candidate stomach cancer susceptibility gene; a mutation in the NBD coding region of HSPA13 has been identified in stomach cancer cells . The NBD of HSPA13 interacts with the ubiquitin-like proteins Chap1 and Chap2, implicating HSPA13 in regulating cell cycle and cell death events . HSPA13 is induced by the Ca2+ ionophore A23187 .
Heat shock 70kDa protein 14, nucleotide-binding domain (HSPA14_NBD)
Type: Domain

Human HSPA14 (also known as 70kDa heat shock protein 14 or HSP70L1), is ribosome-associated and belongs to the heat shock protein 70 (HSP70) family of chaperones that assist in protein folding and assembly, and can direct incompetent 'client' proteins towards degradation. Typically, HSP70s have a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). The nucleotide sits in a deep cleft formed between the two lobes of the NBD. The two subdomains of each lobe change conformation between ATP-bound, ADP-bound, and nucleotide-free states. ATP binding opens up the substrate-binding site; substrate-binding increases the rate of ATP hydrolysis. HSP70 chaperone activity is regulated by various co-chaperones: J-domain proteins and nucleotide exchange factors (NEFs). HSPA14 interacts with the J-protein MPP11 to form the mammalian ribosome-associated complex (mRAC) . HSPA14 participates in a pathway along with Nijmegen breakage syndrome 1 (NBS1, also known as p85 or nibrin), heat shock transcription factor 4b (HSF4b), and HSPA4 (belonging to a different subfamily), that induces tumor migration, invasion, and transformation . HSPA14 is a potent T helper cell (Th1) polarizing adjuvant that contributes to antitumor immune responses .
Endoplasmic reticulum chaperone BIP, nucleotide-binding domain (BIP_NBD)
Type: Domain

This entry includes human endoplasmic reticulum chaperone BIP (also known as 70kDa heat shock protein 5, HSPA5, glucose-regulated protein 78/GRP78, and immunoglobulin heavy chain-binding protein), yeast Kar2p (also known as Grp78p) , hsp-3 from C. elegans and related proteins.

BIP/HSPA5 belongs to the heat shock protein 70 (HSP70) family of chaperones that assist in protein folding and assembly and can direct incompetent 'client' proteins towards degradation. HSPA5 and Kar2p are chaperones of the endoplasmic reticulum (ER). Typically, HSP70s have a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). The nucleotide sits in a deep cleft formed between the two lobes of the NBD. The two subdomains of each lobe change conformation between ATP-bound, ADP-bound, and nucleotide-free states. ATP binding opens up the substrate-binding site; substrate-binding increases the rate of ATP hydrolysis. HSP70 chaperone activity is regulated by various co-chaperones: J-domain proteins and nucleotide exchange factors (NEFs). Multiple ER DNAJ domain proteins have been identified and may exist in distinct complexes with HSPA5 in various locations in the ER, for example DNAJC3-p58IPK in the lumen . HSPA5-NEFs include SIL1, whose disruption causes the Marinesco-Sjogren syndrome, and an atypical HSP70 family protein HYOU1/ORP150 . The ATPase activity of Kar2p is stimulated by the NEFs: Sil1p and Lhs1p .
HSPA4, nucleotide-binding domain (HSPA4_NBD)
Type: Domain

Human HSPA4 (also known as 70kDa heat shock protein 4, APG-2, HS24/P52, hsp70 RY, and HSPH2) responds to acidic pH stress, is involved in the radioadaptive response, is required for normal spermatogenesis and is overexpressed in hepatocellular carcinoma . It participates in a pathway along with NBS1 (Nijmegen breakage syndrome 1, also known as p85 or nibrin), heat shock transcription factor 4b (HDF4b), and HSPA14 (belonging to a different HSP70 subfamily) that induces tumor migration, invasion, and transformation . HSPA4 expression in sperm was increased in men with oligozoospermia, especially in those with varicocele . HSPA4 belongs to the 105/110kDa heat shock protein (HSP105/110) subfamily of the HSP70-like family . HSP105/110s are believed to function generally as co-chaperones of HSP70 chaperones, acting as nucleotide exchange factors (NEFs), to remove ADP from their HSP70 chaperone partners during the ATP hydrolysis cycle. HSP70 chaperones assist in protein folding and assembly, and can direct incompetent 'client' proteins towards degradation. Like HSP70 chaperones, HSP105/110s have an N-terminal nucleotide-binding domain (NBD) and a C-terminal substrate-binding domain (SBD) .

This entry represents the N-terminal nucleotide-binding domain of HSPA4.
HSPH1, nucleotide-binding domain (HSPH1_NBD)
Type: Domain

Human HSPH1 (also known as heat shock 105kDa/110kDa protein 1, HSP105; HSP105A; HSP105B) suppresses the aggregation of denatured proteins caused by heat shock in vitro, and may substitute for HSP70 family proteins to suppress the aggregation of denatured proteins in cells under severe stress . It reduces the protein aggregation and cytotoxicity associated with Polyglutamine (PolyQ) diseases, including Huntington's disease, which are a group of inherited neurodegenerative disorders sharing the characteristic feature of having insoluble protein aggregates in neurons . The expression of HSPH1 is elevated in various malignant tumors, including malignant melanoma, and there is a direct correlation between HSPH1 expression and B-cell non-Hodgkin lymphomas (B-NHLs) aggressiveness and proliferation . HSPH1 belongs to the 105/110kDa heat shock protein (HSP105/110) subfamily of the HSP70-like family. HSP105/110s are believed to function generally as co-chaperones of HSP70 chaperones, acting as nucleotide exchange factors (NEFs), to remove ADP from their HSP70 chaperone partners during the ATP hydrolysis cycle. HSP70 chaperones assist in protein folding and assembly, and can direct incompetent 'client' proteins towards degradation. Like HSP70 chaperones, HSP105/110s have an N-terminal nucleotide-binding domain (NBD) and a C-terminal substrate-binding domain (SBD) .

This entry represents the N-terminal nucleotide-binding domain of HSPH1.
YegD-like (YegD-like)
Type: Family

This bacterial family includes the uncharacterised Escherichia coli YegD . It belongs to the heat shock protein 70 (HSP70) family of chaperones that assist in protein folding and assembly and can direct incompetent 'client' proteins towards degradation. Typically, HSP70s have a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). The nucleotide sits in a deep cleft formed between the two lobes of the NBD. The two subdomains of each lobe change conformation between ATP-bound, ADP-bound, and nucleotide-free states. ATP binding opens up the substrate-binding site; substrate-binding increases the rate of ATP hydrolysis. YegD lacks the SBD. HSP70 chaperone activity is regulated by various co-chaperones: J-domain proteins and nucleotide exchange factors (NEFs). Some family members are not chaperones but instead, function as NEFs for their Hsp70 partners, other family members function as both chaperones and NEFs .
CD9, extracellular domain (CD9_LEL)
Type: Domain

This entry represents the extracellular domain or large extracellular loop (LEL) of CD9. This extracellular domain lies between the 3rd and 4th trans-membrane segment. CD9 belongs to the tetraspanin family of membrane proteins and is found in virtually all tissues, it is potentially involved in developmental processes. It associates with the tetraspanins CD81 and CD63, as well as with some integrin, and has been shown to be involved in a variety of activation, adhesion, and cell motility functions, as well as cell-cell interactions - such as during fertilization .

Tetraspanins are a distinct family of cell surface proteins, containing four conserved transmembrane domains: a small outer loop (EC1), a larger outer loop (EC2), a small inner loop (IL) and short cytoplasmic tails. They contain characteristic structural features, including 4-6 conserved extracellular cysteine residues, and polar residues within transmembrane domains.

A fundamental role of tetraspanins appears to be organising other proteins into a network of multimolecular membrane microdomains, sometimes called the 'tetraspanin web'. Within this web there are primary complexes in which tetraspanins show robust, specific, and direct lateral associations with other proteins. The strong tendency of tetraspanins to associate with each other probably contributes to the assembly of a network of secondary interactions in which non-tetraspanin proteins are associated with each other via palmitoylated tetraspanins acting as linker proteins. In addition, the association of lipids, such as gangliosides and cholesterol, probably contributes to the assembly of even larger tetraspanin complexes, which have some lipid raft-like properties (e.g. resistance to solubilization in non-ionic detergents). Within the tetraspanin web, tetraspanin proteins can associate not only with integrins and other transmembrane proteins, but also with signalling enzymes such as protein kinase C and phosphatidylinositol-4 kinase. Thus, the tetraspanin web provides a mechanistic framework by which membrane protein signalling can be expanded into a lateral dimension .
E3 ubiquitin-protein ligase MIB1/2, zinc finger, ZZ-type (MIB1/2_ZZ)
Type: Domain

This entry represents the Zinc finger found in the mammalian MIB1/2 protein and Drosophila Mind bomb (D-mib) protein. The ZZ motif coordinates two zinc ions and most likely participates in ligand binding or molecular scaffolding. MIB1 and MIB2 are E3 ubiquitin-protein ligases . Mind bomb is an E3 ubiqitin ligase that has been shown to regulate signaling by the Notch ligand Delta in Drosophila melanogaster .
Plant lipoxygenase, PLAT/LH2 domain (Lipoxy_PLAT/LH2)
Type: Domain

This is the PLAT/LH2 domain of plant lipoxygenase related proteins. Lipoxygenases are nonheme, nonsulfur iron dioxygenases that act on lipid substrates containing one or more (Z,Z)-1,4-pentadiene moieties. In plants, the immediate products are involved in defense mechanisms against pathogens and may be precursors of metabolic regulators . The generally proposed function of PLAT/LH2 domains is to mediate interaction with lipids or membrane bound proteins .

Lipoxygenases can be classified as 9- and 13-lipoxygenases, according to the position of oxygen incorporation in linoleic acid and linolenic acid, the most important substrates for LOX catalysis in plants. There are six A. thaliana lipoxygenases identified: AtLOX1-6, among which AtLOX-1 and AtLOX-5 are 9S-lipoxygenases, and AtLOX-2, AtLOX-3, AtLOX-4 and AtLOX-6 are 13S-lipoxygenases .
UNC5D, Death domain (UNC5D_Death)
Type: Domain

This entry represents the Death Domain (DD) found in Uncoordinated-5D (UNC5D), which is part of the UNC-5 homologue family. It is a receptor for the secreted netrin-1 and plays a role in axonal guidance, angiogenesis, and apoptosis . UNC5 proteins are transmembrane proteins with an extracellular domain consisting of two immunoglobulin repeats, two thrombospondin type-I modules and an intracellular region containing a ZU-5 domain, UPA domain and a DD .

In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes .
SUSD5, Link domain (SUSD5_Link_domain)
Type: Domain

This entry represents the Link domain found in SUSD5. The link domain is a hyaluronan-binding (HA) domain. However, the function of SUSD5 is still not clear.
Polycystin-1 like, PLAT/LH2 domain (PLAT_polycystin1)
Type: Domain

This is the PLAT/LH2 domain of polycystin-1 like proteins. Polycystins are a large family of membrane proteins composed of multiple domains, present in fish, invertebrates, mammals, and humans that are widely expressed in various cell types and whose biological functions remain poorly defined. In human, mutations in polycystin-1 (PKD1) and polycystin-2 (PKD2) have been shown to be the cause for autosomal dominant polycystic kidney disease (ADPKD) . The generally proposed function of PLAT/LH2 domains is to mediate interaction with lipids or membrane bound proteins .
Peregrin, ePHD domain (Peregrin_ePHD)
Type: Domain

This entry represents the ePHD finger of Peregrin (also known as BRPF1), which is a multi-domain protein that binds histones, mediates monocytic leukaemic zinc-finger protein (MOZ) -dependent histone acetylation, and is required for Hox gene expression and segmental identity . It is a close partner of the MOZ histone acetyltransferase (HAT) complex and a novel Trithorax group (TrxG) member with a central role during development . BRPF1 is primarily a nuclear protein that has a broad tissue distribution and is abundant in testes and spermatogonia. It contains a plant homeodomain (PHD) zinc finger followed by a non-canonical ePHD finger, a bromodomain and a proline-tryptophan-tryptophan-proline (PWWP) domain. This PHD finger binds to methylated lysine 4 of histone H3 (H3K4me), the bromodomain interacts with acetylated lysines on N-terminal tails of histones and other proteins, and the PWWP domain shows histone-binding and chromatin association properties. BRPF1 may be involved in chromatin remodelling. The extended plant homeodomain (ePHD) zinc finger is characterised as Cys2HisCys5HisCys2His .
Lipoxygenase, vertebrates, PLAT domain (PLAT_LOX_verte)
Type: Domain

Lipoxygenases (LOXs, LOs) catalyze the the dioxygenation of polyunsaturated fatty acids, including arachidonic acid. Animal LO enzymes include 5-LO, 12-LO (epidermal-, platelet-, and leukocyte-type), 15-LO, and eLOX-3 (epidermis-type LO-3). 12-LO and 15-LO and its metabolites participate in apoptosis, autophagy and ferroptosis, and have been implicated in the development of insulin resistance and diabetes .

This entry represents the PLAT domain of vertebrate LOs . 12-LO and 15-LO are cytosolic but need this domain to access their sequestered membrane or micelle bound substrates .
Ubiquitin-activating enzyme E1, SCCH domain (Ubi_acti_E1_SCCH)
Type: Homologous_superfamily

The E1 enzyme that catalyses carboxy-terminal Ub adenylation, thioester bond formation to a catalytic cysteine in the E1 Cys domain, together with thioester transfer to a catalytic cysteine in E2 conjugating enzymes are responsible for the Ubiquitin (Ub) conjugation initiation . There are several homologues of this enzyme with one of them being ThiF .

The catalytic cysteine domain contains the E1 active site cysteine, and is divided in two half-domains, FCCH and SCCH, for 'first' and 'second' catalytic cysteine half-domain, respectively. This superfamily represents the domain 5 found in Ub-activating enzyme E1, the SCCH in which resides the catalytic cysteine . This domain has an α-helical structure and likely to exist in equilibrium of open (adenylation active) and closed (thioester bond formation active) conformations. SCCH, FCCH (the first catalytic cysteine half-domain) and UFD (ubiquitin fold domain) are connected to the AAD (active adenylation domain) through flexible loops that allow the conformational changes and rotations of these domains essential for catalysis of Ub activation and transfer of activated UB from E1 to E2 .
POLG2, C-terminal (POLG2_C)
Type: Domain

This entry represents the C-terminal domain of mitochondrial DNA polymerase gamma B subunit (also known as POLG2), which is required for processivity. Polymerase gamma replicates and repairs mitochondrial DNA. The C-terminal domain of its B subunit is strikingly similar to the anticodon-binding domain of glycyl tRNA synthetase .
E3 ubiquitin-protein ligase ELL-like (E3_ELL-like)
Type: Homologous_superfamily

This superfamily can be found in two different types of proteins, RNA polymerase II elongation factor ELL and E3 ubiquitin protein ligases UBR1 and UBR2. ELL functions as an E3 ubiquitin ligase and targets c-Myc for proteasomal degradation .
Spt6, Death-like domain (Spt6_death-like)
Type: Homologous_superfamily

This superfamily represents the death-like domain (DLD) of Spt6 (Suppressor of Ty 6, originally discovered in Saccharomyces cerevisiae), a gene that influences general transcription through manipulation of chromatin structure at upstream promoter elements .

This DLD domain maintains the characteristic overall topology of death domains, as it consists of a six-helix bundle with three stacked antiparallel helices and an additional helix inserted between the final two helices of the bundle. The Spt6 DLD prominent location and the observation that it displays the most highly conserved region of the Spt6 surface suggest that it mediates important intermolecular interactions .
Sip3, PH domain (Sip3_PH)
Type: Domain

This entry represents the pleckstrin homology (PH) domain found in Sip3 and its paralogue, Lam1 (also known as Ysp1), from budding yeasts. They have an N-terminal Bin/Amphiphysin/Rvs (BAR) domain followed by a PH domain, and a C-terminal StART-like domain. They may be involved in sterol transfer between intracellular membranes . This domain can also be found in uncharacterised protein C19A8.02 from fission yeasts.

PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner . They share little sequence conservation, but all have a common fold, which is electrostatically polarised. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity . PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane . A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signalling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes .
Semaphorin-1A, sema domain (SEM1A_sema_dom)
Type: Domain

This entry represents the Sema domain found in Sema1A, which is a transmembrane protein. Sema1A binds to its receptor plexin A (PlexA), which in turn triggers downstream signaling events involving the receptor tyrosine kinase Otk, the evolutionarily conserved flavoprotein monooxygenase molecule interacting with CasL (MICAL), and the A kinase anchoring protein Nervy, leading to repulsive growth-cone response . Sema1A has also been shown to be involved in synaptic formation .

Sema1A belongs to the semaphorin family, whose members are regulatory molecules in the development of the nervous system and in axonal guidance . They also play important roles in other biological processes, such as angiogenesis, immune regulation, respiration systems and cancer . The Sema domain is located at the N terminus and contains four disulfide bonds formed by eight conserved cysteine residues. It serves as a receptor-recognition and -binding module .
CLIC5, C-terminal GST domain (CLIC5_C_GST)
Type: Domain

This entry represents the C-terminal glutathione S-transferase (GST) domain found in chloride intracellular channel 5 (CLIC5) protein. CLIC5 exists in two alternatively-spliced isoforms, CLIC5A or CLIC5B (also called p64) . It is expressed at high levels in hair cell stereocilia and is associated with the actin cytoskeleton and ezrin . A recessive mutation in the CLIC5 gene in mice led to the lack of coordination and deafness, due to a defect in the basal region of the hair bundle causing stereocilia to degrade. CLIC5 is therefore essential for normal inner ear function . CLIC5 is also highly expressed in podocytes where it is colocalized with the ezrin/radixin/moesin (ERM) complex. It is essential for foot process integrity, and for podocyte morphology and function .

CLICs are auto-inserting, self-assembling intracellular anion channels involved in a wide variety of functions including regulated secretion, cell division, and apoptosis. They can exist in both water-soluble and membrane-bound states and are found in various vesicles and membranes, and they may play roles in the maintenance of these intracellular membranes. The membrane localization domain is present in the N-terminal part of the protein. Structures of soluble CLICs reveal that they adopt a fold similar to GSTs, containing an N-terminal domain with a thioredoxin fold and a C-terminal α helical domain .
PucR C-terminal helix-turn-helix domain superfamily (PucR_C-HTH_sf)
Type: Homologous_superfamily

This superfamily represents a helix-turn-helix domain often found at the C terminus of PucR-like transcriptional regulators, such as

, and is likely to be DNA-binding .