SII-SWORD/CoKE huggingface dataset:
ADAM10/ADAM17 catalytic domain (ADAM10_ADAM17)
Type: Domain

This entry includes proteins with reprolysin-like metallopeptidase domains and includes ADAM10 (also known as myelin-associated metalloendopeptidase, MEROPS identifier M12.210), ADAM17 (also known as tumour necrosis factor alpha-convertase, MEROPS identifier M12.217), kuzbanian (MEROPS identifiers M12.211 and M12.322) and ADM-4 (MEROPS identifier M12.329) .
ESAT-6 secretion machinery protein EssA (EssA)
Type: Family

Mycobacterium tuberculosis secretes ESAT-6, a virulence factor belonging to the WXG100 family. Other Gram-positive human pathogens belonging to the phylum Firmicutes, e.g. Staphylococcus aureus, also secrete immune potent WXG100 proteins. S. aureus secretes ESAT-6-like proteins EsxA and EsxB. In S.aureus the WXG100 protein secretion system seems to be encoded by a locus of eight ORFs, called ess (eSAT-6 secretion system) . This locus encodes, amongst several other proteins, EssA, a protein predicted to possess one transmembrane domain. Due to its predicted membrane location and its absolute requirement for WXG100 protein secretion, it has been speculated that EssA could form a secretion apparatus. Proteins homologous to EssA are absent from mycobacteria .
Reprolysin domain, adamalysin-type (Reprolysin_adamalysin)
Type: Domain

This entry includes the reprolysin-like domain found in snake venom metallopeptidases such as adamalysin and membrane-anchored metalloendopeptidases known as ADAMs (A Disintegrin And Metalloprotease), which are glycoproteins and play roles in cell signaling, cell fusion, and cell-cell interactions . Peptidase activity depends on the presence of an extended zinc-binding motif known as HEXXHXXGXXH in which the histidines are zinc ligands, the glutamic acid is a catalytic residue and the glycine maintains an important turn. There are a number of proteins in which one or more of these essential residues are not conserved, and these do not have proteolytic activity.
Fungal reprolysin domain (ZnMc_ADAM_fungal)
Type: Domain

The ADAM (A Disintegrin And Metalloprotease) family of metalloproteases are integral membrane proteases acting on a variety of extracellular targets. They are involved in shedding soluble peptides or proteins from the cell surface . This entry contains fungal ADAMs, whose precise function has yet to be determined, including ADAM-B.
Tumour necrosis factor receptor 10A/B, death domain (TNFRSF10A/B_death)
Type: Domain

This death domain (DD) is found in Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) receptors. In mammals, this family includes TRAILR1 (also called DR4 or TNFRSF10A) and TRAILR2 (also called DR5, TNFRSF10B, or KILLER). They function as receptors for the cytokine TRAIL and are involved in apoptosis signaling pathways. TRAIL preferentially induces apoptosis in cancer cells while exhibiting little toxicity in normal cells .

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 .
Salivary gland reprolysin domain (ZnMc_salivary_gland_MPs)
Type: Domain

This entry includes reprolysin-like domains of metalloproteases secreted by the salivary glands of arthropods .
Tumor necrosis factor receptor 14/UL144, N-terminal (TNFRSF14/UL144_N)
Type: Domain

Tumor necrosis factor receptor superfamily member 14 (TNFRSF14), also known as herpes virus entry mediator or HVEM, ATAR, CD270, HVEA, LIGHTR or TR2, regulates T-cell immune responses by activating inflammatory, as well as inhibitory signaling pathways. HVEM acts as a receptor for the canonical TNF-related ligand LIGHT (lymphotoxin-like), which exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM . It also acts as a ligand for the immunoglobulin superfamily proteins BTLA (B and T lymphocyte attenuator) and CD160, a feature distinguishing HVEM from other immune regulatory molecules, thus, creating a functionally diverse set of intrinsic and bidirectional signaling pathways .

HVEM is highly expressed in the gut epithelium. Genome-wide association studies have shown that HVEM is an inflammatory bowel disease (IBD) risk gene, suggesting that HVEM could have a regulatory role influencing the regulation of epithelial barrier, host defense, and the microbiota . Mouse models have revealed that HVEM is involved in colitis pathogenesis, mucosal host defense, and epithelial immunity, thus acting as a mucosal gatekeeper with multiple regulatory functions in the mucosa. HVEM plays a critical role in both tumor progression and resistance to antitumor immune responses, possibly through direct and indirect mechanisms. It is known to be expressed in several human malignancies, including esophageal squamous cell carcinoma, follicular lymphoma and melanoma. HVEM network may therefore be an attractive target for drug intervention .

TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family .

This entry represents the N-terminal domain of TNFRSF14, and is also found in the orphan TNFR, UL144, present in human Cytomegalovirus. UL144 binds BTLA, but not LIGHT, and inhibits T cell proliferation, selectively mimicking the inhibitory cosignaling function of HVEM .
Bacterial MMP-like domain (Zn_MMP-like_bac)
Type: Domain

This entry consists of uncharacterised matrix-metallopeptidase (MMP)-like zinc-dependent metalloprotease domains from bacteria.
Serralysin-like metallopeptidase domain (Serralysin-like)
Type: Domain

This entry includes zinc-dependent metalloprotease domains from the serralysin and related proteins such as PbrA from Pseudomonas . Serralysins and related proteases are important virulence factors in pathogenic bacteria. They may be secreted into the medium via a mechanism found in Gram-negative bacteria, that does not require N-terminal signal sequences which are cleaved after the transmembrane translocation. A calcium-binding domain C-terminal to the metalloprotease domain, which contains multiple tandem repeats of a nine-residue motif including the pattern GGxGxD, and which forms a parallel β roll may be involved in the translocation mechanism and/or substrate binding. Serralysin family members may have a broad spectrum of substrates each, including host immunoglobulins, complement proteins, cell matrix and cytoskeletal proteins, as well as antimicrobial peptides .
Tumor necrosis factor receptor 21, N-terminal (TNFRSF21_N)
Type: Domain

Tumor necrosis factor receptor superfamily member 21 (TNFRSF21), also known as death receptor 6 (DR6), CD358, or BM-018, plays a role in neuronal apoptosis, including apoptosis in response to amyloid peptides derived from APP, and is required for both normal cell body death and axonal pruning. It also acts as a regulator of pyroptosis sa it recruits CASP8 in response to reactive oxygen species (ROS) and subsequent oxidation, leading to activation of gasdermin C (GSDMC). DR6 negatively regulates neuron, axon, and oligodendrocyte survival, hinders axondendrocyte and oligodendrocyte regeneration and its inhibition has a neuroprotective effect in nerve injury . It activates nuclear factor kappa-B (NFkB) and mitogen-activated protein kinase 8 (MAPK8, also called c-Jun N-terminal kinase 1), and induces cell apoptosis by associating with TNFRSF1A-associated via death domain (TRADD), which is known to mediate signal transduction of tumor necrosis factor receptors . TNFRSF21 plays a role in T-helper cell activation, and may be involved in inflammation and immune regulation . It binds alpha-amyloid precursor protein (APP); when released, APP binds in an autocrine/paracrine manner to activate a caspase-dependent self-destruction program that removes unnecessary or connectionless axons . Increasing beta-catenin levels in brain endothelium upregulates TNFRSF21 and TNFRSF19, indicating that these death receptors are downstream target genes of Wnt/beta-catenin signaling, which has been shown to be required for blood-brain barrier development . DR6 is up-regulated in numerous solid tumors as well as in tumor vascular cells, including ovarian cancer and may be a clinically useful diagnostic and predictive serum biomarker for some adult sarcoma subtypes .

This entry represents the N-terminal domain of TNFRSF21. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family .
Astacin-like metallopeptidase domain (Astacin-like_dom)
Type: Domain

This entry includes the peptidase domain of zinc-dependent metalloproteases in the astacin-like subfamily (peptidase subfamily M12A), a group of zinc-dependent proteolytic enzymes with a HExxHxxGxxH zinc-binding site/active site . Members of this family may have an amino terminal propeptide, which is cleaved to yield the active protease domain, which is consequently always found at the N terminus in multi-domain architectures. This family includes: astacin (MEROPS identifier M12.001) , a digestive enzyme from crayfish and the sea urchin SPAN protein (MEROPS identifier M12.013), which may also play a role in development.
Tolloid/BMP1 peptidase domain (ZnMP_TLD/BMP1)
Type: Domain

This entry includes the zinc-dependent metalloprotease domain of BMP1 and tolloid-like proteins. Procollagen C-peptidase (BMP1, Bone morphogenetic protein 1; MEROPS identifier M12.005) and TLD (tolloid)-like metalloproteases play vital roles in extracellular matrix formation, by cleaving precursor proteins such as enzymes, structural proteins, and proteins involved in the mineralization of the extracellular matrix. The Drosophila protein tolloid (MEROPS identifier M12.010) and its Xenopus homologue xolloid (MEROPS identifier M12.015) cleave and inactivate Sog and chordin, respectively, which are inhibitors of Dpp (the Drosophila decapentaplegic gene product) and its homologue BMP4, involved in dorso-ventral patterning .
Tumor necrosis factor receptor 21, death domain (TNFRSF21_death)
Type: Domain

This death domain (DD) is found in tumor necrosis factor receptor superfamily member 21 (TNFRSF21), also called death receptor-6, or DR6. DR6 is an orphan receptor that is expressed ubiquitously, but shows high expression in lymphoid organs, heart, brain and pancreas . Results from DR6(-/-) mice indicate that DR6 plays an important regulatory role for the generation of adaptive immunity. It may also be involved in tumor cell survival and immune evasion. In neuronal cells, it binds beta-amyloid precursor protein (APP) and activates caspase-dependent cell death .

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 .
Meprin peptidase domain (ZnMP_meprin)
Type: Domain

This entry includes the peptidase domain of the zinc-dependent metalloprotease meprin. Meprin can be either membrane-bound or secreted, and cleaves a variety of targets, including peptides such as parathyroid hormone, gastrin, and cholecystokinin, cytokines such as osteopontin, and proteins such as collagen IV, fibronectin, casein and gelatin. Meprin may also be able to release proteins from the cell surface. Closely related meprin alpha- (MEROPS identifier M12.002) and beta-subunits (MEROPS identifier M12.004) form homo- and hetero-oligomers ; these complexes are found on epithelial cells of the intestine, for example, and are also expressed in certain cancer cells .
Hatching enzyme, peptidase domain (ZnMP_hatching_enz)
Type: Domain

This entry represents the peptidase domain of the zinc-dependent metalloprotease hatching enzyme. Hatching enzymes are secreted by embryos to digest the egg envelope or chorion. In some teleosts, the hatching enzyme may be a system consisting of two evolutionary related metalloproteases, choriolysin H (high choriolytic enzyme, HCE; MEROPS identifier M12.007) and choriolysin L (low choriolytic enzyme, LCE; MEROPS identifier M12.006), which may have different substrate specificities and cooperatively digest the chorion . Other embryonic hatching enzymes included in this entry are from quail (MEROPS identifier M12.324) , Xenopus and crayfish (MEROPS identifier M12.014) . Also included in this entry is nephrosin (MEROPS identifier M12.008) from the carp whose function is unknown but has been isolated from kidney .
Tumor necrosis factor receptor 11A, N-terminal (TNFRSF11A_N)
Type: Domain

Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A), also known as RANK, FEO, OFE, ODFR, OSTS, PDB2, CD26, OPTB7, TRANCER, or LOH18CR1, induces the activation of NF-kappa B and MAPK8/JNK through interactions with various TRAF adaptor proteins . This receptor and its ligand are important regulators of the interaction between T cells and dendritic cells. The receptor is also an essential mediator for osteoclast and lymph node development. Mutations at this locus have been associated with familial expansile osteolysis, autosomal recessive osteopetrosis, and Juvenile Paget's disease (JPD) of bone . Alternatively spliced transcript variants have been described for this locus . Mutation analysis may improve diagnosis, prognostication, recurrence risk assessment, and perhaps treatment selection among the monogenic disorders of RANKL/OPG/RANK activation.

This entry represents the N-terminal domain of TNFRSF11A. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family .
STABLE peptidase domain (STABLE_peptidase)
Type: Domain

This entry contains the peptidase domain of the subtilisin STABLE and close homologues. STABLE is a glycoprotein from the archaean Staphylothermus marinus which is found in geothermally heated marine environments. The endopeptidase is membrane-anchored and the extracellular portion is a component of the glycoprotein S-layer that forms outside the cell membrane. The peptidase is active at pH 3.2 to 12.7, and stable to 95 degrees Celsius and is one of the most stable peptidases known .
PARN, R3H domain (PARN_R3H)
Type: Domain

This is the R3H domain of Poly(A)-specific ribonuclease (PARN). PARN is a poly(A)-specific 3' exonuclease from the RNase D family which, in Xenopus deadenylates a specific class of maternal mRNAs that results in their translational repression . The name of the R3H domain comes from the characteristic spacing of the most conserved arginine and histidine residues. The function of the domain is predicted to bind ssDNA or ssRNA .
Tumor necrosis factor receptor 11B, N-terminal, teleost (TNFRSF11B_N_teleost)
Type: Domain

This entry represents the N-terminal domain of TNFRSF11B form teleost. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family .

Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), also known as Osteoprotegerin, OPG, TR1, or OCIF, is found in teleosts. It is a secreted glycoprotein that regulates bone resorption . It binds to two ligands, RANKL (receptor activator of nuclear factor kappaB ligand, also known as osteoprotegerin ligand, OPGL, TRANCE, TNF-related activation induced cytokine), a critical cytokine for osteoclast differentiation, and TRAIL (TNF-related apoptosis-inducing ligand), involved in immune surveillance. Therefore, acting as a decoy receptor for RANKL and TRAIL, OPG inhibits the regulatory effects of nuclear factor-kappaB on inflammation, skeletal, and vascular systems, and prevents TRAIL-induced apoptosis . Studies in mice counterparts suggest that this protein and its ligand also play a role in lymph-node organogenesis and vascular calcification . Circulating OPG levels have emerged as independent biomarkers of cardiovascular disease in patients with acute or chronic heart disease. OPG has also been implicated in various inflammations and linked to diabetes and poor glycemic control . Genetic analysis of the Japanese rice fish medaka (Oryzias latipes) has shown that entire networks for bone formation are conserved between teleosts and mammals, enabling medaka to be used as a genetic model to monitor bone homeostasis in vivo .
CspA-like domain (Pep_S8_CspA-like)
Type: Domain

This entry includes the peptidase domain of the subtilisin homologues CspA (MEROPS identifier S08.159), CspB (MEROPS identifier S08.108) and CspC (MEROPS identifier S08.158) from Clostridium species. These peptidases are important for the initiation of spore germination by activation of the hydrolase hydrolase SleC, which degrades the protective cortex layer of the spore, allowing it to germinate. In Clostridium perfringens, all three subtilisin homologues are active peptidases, but in C. difficile, CspA and CspC are described as "pseudopeptidases" , because active site residues have been mutated. In C. difficile, dormant spores are activated by the binding of bile salts, especially taurocholate, to CspC. SleC is activated by a CspA/CspB fusion protein .

This domain is part of a family of domains found in serine peptidases belonging to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin)) and S53 (sedolisin), both of which are members of clan SB .

Peptidases S8 (or subtilases serine endo- and exo-peptidase clan) have an Asp/His/Ser catalytic triad similar to that found in trypsin-like proteases, but do not share their three-dimensional structure and are not homologous to trypsin. The stability of subtilases may be enhanced by calcium; some members have been shown to bind up to 4 ions via binding sites with different affinities. Some members of this clan contain disulfide bonds. These enzymes can be intra- and extracellular; some function at extreme temperatures and pH values .
Tumor necrosis factor receptor 16, N-terminal (TNFRSF16_N)
Type: Domain

Tumor necrosis factor receptor superfamily member 16 (TNFRSF16), also known as nerve growth factor receptor (NGFR) or p75 neurotrophin receptor (p75NTR or p75), CD271, or Gp80-LNGFR, is a common receptor for both neurotrophins and proneurotrophins, and plays a diverse role in many tissues, including the nervous system. It has been shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency . p75NTR owes its signaling to the recruitment of intracellular binding proteins, leading to the activation of different signaling pathways . It binds nerve growth factor (NGF) and the complex can initiate a signaling cascade which has been associated with both neuronal apoptosis and neuronal survival of discrete populations of neurons, depending on the presence or absence of intracellular signaling molecules downstream of p75NTR (e.g. NF-kB, JNK, or p75NTR intracellular death domain). p75NTR can also bind NGF in concert with the neurotrophic tyrosine kinase receptor type 1 (TrkA) protein where it is thought to modulate the formation of the high-affinity neurotrophin binding complex .

In melanoma cells, p75NTR is an immunosuppressive factor, induced by interferon (IFN)-gamma, and mediates down-regulation of melanoma antigens . It can interact with the aggregated form of amyloid beta (Abeta) peptides, and plays an important role in etiopathogenesis of Alzheimer's disease by influencing protein tau hyper-phosphorylation . p75NTR is involved in the formation and progression of retina diseases; its expression is induced in retinal pigment epithelium (RPE) cells and its knockdown rescues RPE cell proliferation activity and inhibits RPE apoptosis induced by hypoxia . It can therefore be a potential therapeutic target for RPE hypoxia or oxidative stress diseases.

This entry represents the N-terminal domain of TNFRSF16. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family .
Tumor necrosis factor receptor 19, N-terminal (TNFRSF19_N)
Type: Domain

TNFRSF19 (also known as TAJ; TROY; TRADE; TAJ-alpha) is expressed in progenitor cells of the hippocampus, thalamus, and cerebral cortex and highly expressed during embryonic development. It has been shown to interact with TRAF family members, and to activate JNK signaling pathway when overexpressed in cells . It is frequently overexpressed in colorectal cancer cell lines and primary colorectal carcinomas. TNFRSF19 is a beta-catenin target gene, in mesenchymal stem cells, and also activates NF-kappaB signaling, showing that beta-catenin regulates NF-kappaB activity via TNFRSF19. Since Wnt/beta-catenin signaling plays a crucial role in the regulation of colon tissue regeneration and the development of colon tumors, TNFRSF19 may contribute to the development of colorectal tumors . These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development . TNFRSF19 has been shown to promote glioblastoma (GBM) survival signaling and therefore targeting it may increase tumor vulnerability and improve therapeutic response in glioblastoma . It may play an important role in myelin-associated inhibitory factors (MAIFs)-induced inhibition of neurite outgrowth in the postnatal central nervous system (CNS) or on axon regeneration following CNS injury .

This entry represents the N-terminal domain of TNFRSF19. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family .