SII-SWORD/CoKE huggingface dataset:
Heparin cofactor II, serpin domain (HCII_serpin_dom)
Type: Domain

Heparin cofactor II (HCII) inhibits thrombin, the final protease of the coagulation cascade . HCII is allosterically activated by binding to cell surface glycosaminoglycans (GAGs). The specificity of HCII for thrombin is conferred by a highly acidic hirudin-like N-terminal tail, which becomes available after GAG binding for interaction with the anion-binding exosite I of thrombin . HCII belongs to clade D of the serpin superfamily; it is also known as Serpin D1 .
Pigment epithelium derived factor, serpin domain (PEDF_serpin_dom)
Type: Domain

Pigment epithelium-derived factor (PEDF) is a non-inhibitory member of the Serpin superfamily (MEROPS family I4; MEROPS identifier I04.979). It exhibits neurotrophic, neuroprotective and antiangiogenic properties and is widely expressed in the developing and adult nervous systems . This subgroup corresponds to clade F1 of the serpin superfamily .
Alpha2-antiplasmin, serpin domain (Alpha2AP_serpin_dom)
Type: Domain

Alpha2-antiplasmin (alpha2AP; plasmin inhibitor; MEROPS identifier I04.023) is the primary inhibitor of plasmin, a proteinase that digests fibrin, the main component of blood clots. Alpha2-antiplasmin forms an inactive 1:1 stoichiometric complex with plasmin. It also rapidly crosslinks to fibrin during blood clotting by activated coagulation factor XIII, and as a consequence fibrin becomes more resistant to fibrinolysis. Therefore alpha2AP is important in modulating the effectiveness and persistence of fibrin with respect to its susceptibility to digestion and removal by plasmin . Alpha2-antiplasmin corresponds to clade F2 of the serpin superfamily (MEROPS family I4) .
Angiotensinogen, serpin domain (Angiotensinogen_serpin_dom)
Type: Domain

Angiotensinogen is a component of the renin-angiotensin system (RAS), a hormone system that regulates blood pressure and fluid balance. It is also known as the renin substrate, and is a non-inhibitory member of the serpin family of proteinase inhibitors (MEROPS inhibitor family I4, clan ID, MEROPS identifier I04.953).

Angiotensinogen is catalytically cleaved by renin to produce angiotensin I in response to lowered blood pressure. Angiotensin converting enzyme (ACE), subsequently removes a dipeptide to produce angiotensin II, the physiologically active peptide, which functions in the regulation of volume and mineral balance of body fluids . Angiotensin I and angiotensin II can be further processed to generate angiotensin III, which stimulates aldosterone release , and angiotensin IV. Angiotensin 1-9 is cleaved from angiotensin-1 by ACE2 and can be further processed by ACE to produce angiotensin 1-7, angiotensin 1-5 and angiotensin 1-4 .

Angiotensinogen is synthesised in the liver and secreted in plasma . Angiotensinogen appears to be associated with a predisposition to essential hypertension; it is also associated with pregnancy-induced hypertension (pih) (preeclampsia), a heterogeneous disorder that complicates 5-7% of all pregnancies and remains a leading cause of maternal, foetal and neonatal morbidity and mortality .

This entry represents the serpin domain of angiotensinogen.
Protein Z-dependent peptidase inhibitor, serpin domain (PZI_serpin_dom)
Type: Domain

Protein Z-dependent protease inhibitor (ZPI; MEROPS identifier I04.005) is a member of the serpin superfamily of proteinase inhibitors, corresponding to clade A10 . ZPI inhibits coagulation factor Xa, dependent on protein Z (PZ), a vitamin K-dependent plasma protein . ZPI also inhibits factor XIa in a process that does not require PZ . In general, SERine Proteinase INhibitors (serpins) exhibit conformational polymorphism shifting from native to cleaved, latent, delta, or polymorphic forms .
Maspin, serpin domain (SERPINB5_serpin_dom)
Type: Domain

Maspin (mammary serine proteinase inhibitor; Serpin B5; MEROPS identifier I04.980) is a non-inhibitory member of the serpin superfamily (clade B) , with a multitude of effects on cells and tissues at an assortment of developmental stages. Maspin has tumor suppressing activity against breast and prostate cancer .

In general, SERine Proteinase INhibitors (serpins) exhibit conformational polymorphism shifting from native to cleaved, latent, delta, or polymorphic forms . Many serpins, such as antitrypsin and antichymotrypsin, function as serine protease inhibitors which regulate blood coagulation cascades. Non-inhibitory serpins perform many diverse functions such as chaperoning proteins or transporting hormones .
Ubiquitinyl hydrolase-L5 (UCH37)
Type: Domain

The ubiquitin C-terminal hydrolase (UCH; ubiquitinyl hydrolase; ubiquitin thiolesterase; MEROPS family C12) family of deubiquitinating enzymes (DUBs) consists of several members including: UCH-L1, UCH-L3, UCH-L5 (UCH37) and BRCA1-associated protein-1 (BAP1), all containing a conserved catalytic domain with cysteine peptidase activity .
Colicin V processing peptidase (CvaB_peptidase)
Type: Domain

This entry includes the processing peptidase for the bacteriocin colicin V (MEROPS identifier C39.005) . The cysteine peptidases in family C39 cleave the "double-glycine" leader peptides from the precursors of various bacteriocins (mostly non-lantibiotic). The cleavage is mediated by the transporter as part of the secretion process. Bacteriocins are antibiotic proteins secreted by some species of bacteria that inhibit the growth of other bacterial species. The bacteriocin is synthesized as a precursor with an N-terminal leader peptide, and processing involves removal of the leader peptide by cleavage at a Gly-Gly bond, followed by translocation of the mature bacteriocin across the cytoplasmic membrane. Most endopeptidases of family C39 are N-terminal domains in larger proteins (ABC transporters) that serve both functions . The proposed protease active site is conserved in members of this entry .

This entry also includes the N-terminal peptidase domain of secretion/processing ATP-binding protein MchF, which processes microcin H47 and is closely related to that of colicin V .
Lacticin 481 processing peptidase (Lacticin_481_peptidase)
Type: Domain

This entry includes the processing peptidase for the bacteriocin lacticin 481 (MEROPS identifier C39.007) . The cysteine peptidases in family C39 cleave the "double-glycine" leader peptides from the precursors of various bacteriocins (mostly non-lantibiotic). The cleavage is mediated by the transporter as part of the secretion process. Bacteriocins are antibiotic proteins secreted by some species of bacteria that inhibit the growth of other bacterial species. The bacteriocin is synthesized as a precursor with an N-terminal leader peptide, and processing involves removal of the leader peptide by cleavage at a Gly-Gly bond, followed by translocation of the mature bacteriocin across the cytoplasmic membrane. Most endopeptidases of family C39 are N-terminal domains in larger proteins (ABC transporters) that serve both functions . The proposed protease active site is conserved in members of this entry .
Ubiquitin-specific peptidase 38 (USP38)
Type: Domain

Ubiquitin carboxyl-terminal hydrolases (UCH) (

) are thiol proteases that recognise and hydrolyse the peptide bond at the C-terminal glycine of ubiquitin. These enzymes are involved in the processing of poly-ubiquitin precursors as well as that of ubiquinated proteins. The deubiquitinsing proteases can be split into 2 size ranges, 20-30kDa
(

) and 100-200kDa : the second class consist of large proteins (800 to 2000 residues) that belong to the peptidase family C19, and this group is currently represented by yeast UBP1 .

This entry includes the peptidase domain of ubiquitin-specific peptidase 38 (USP38; MEROPS identifier C19.056), which belongs to the second group of deubiquitinsing proteases. It has specificity for 'Lys-63'-linked ubiquitin chains .
USP48, peptidase domain (Pep_USP48)
Type: Domain

This entry contains the peptidase domain for ubiquitin-specific peptidase 48 (USP48; MEROPS identifier C19.068).

In animals, USP48 is found in the nucleus, where it trims long Lys48-linked free and substrate-anchored ubiquitin chains, rather than completely disassembling them; a catalytic property only shared with ataxin-3 and otubain-1. USP48 ubiquitin-chain-trimming activity is regulated by casein-kinase-2-mediated phosphorylation in response to cytokine stimulation. USP48 controls the turnover of activated NF-kB/RelA in the nucleus together with the CSN and contributes to a timely control of immune responses . In plants, the gene name is USP26, which should not be confused with USP26 from mammals. USP26 deubiquitinates histone H2B and is required for heterochromatin silencing .

Ubiquitin carboxyl-terminal hydrolases (UCH) (

) are thiol proteases that recognise and hydrolyse the peptide bond at the C-terminal glycine of ubiquitin. These enzymes are involved in the processing of poly-ubiquitin precursors as well as that of ubiquinated proteins. The deubiquitinsing proteases can be split into 2 size ranges, 20-30kDa
(

) and 100-200kDa : the second class consist of large proteins (800 to 2000 residues) that belong to the peptidase family C19, and this group is currently represented by yeast UBP1 .
Carboxypeptidase M, N-terminal domain (CPM_N)
Type: Domain

Carboxypeptidase M (CPM; MEROPS identifier M14.006;

) is an extracellular glycoprotein, bound to cell membranes via a glycosyl-phosphatidylinositol on the C terminus of the protein . It specifically removes C-terminal basic residues (Arg or Lys) from peptides and proteins . The highest levels of CPM have been found in human lung and placenta, but significant amounts are present in kidney, blood vessels, intestine, brain, and peripheral nerves. CPM has also been found in soluble form in various body fluids, including amniotic fluid, seminal plasma and urine. Due to its wide distribution in a variety of tissues, it is believed that it plays an important role in the control of peptide hormones and growth factor activity on the cell surface and in the membrane-localized degradation of extracellular proteins. For example, it hydrolyses the C-terminal arginine of epidermal growth factor (EGF) resulting in des-Arg-EGF which binds to the EGF receptor (EGFR) with an equal or greater affinity than native EGF. CPM is a required processing enzyme that generates specific agonists for the B1 receptor .

This entry represents the carboxypeptidase (N-terminal) domain of carboxypeptidase M.
Carboxypeptidase A6 (CPAH)
Type: Domain

Carboxypeptidase (CP) A6 (CPA6, also known as CPAH; MEROPS identifier M14.018;

), belongs to the carboxypeptidase A/B subfamily of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. CPA6 prefers large hydrophobic C-terminal amino acids as well as histidine, while peptides with a penultimate glycine or proline are very poorly cleaved.

Several neuropeptides are processed by CPA6, including Met- and Leu-enkephalin, angiotensin I, and neurotensin. CPA6 converts enkephalin and neurotensin into forms known to be inactive toward their receptors, but converts inactive angiotensin I into the biologically active angiotensin II. Thus, CPA6 plays a possible role in the regulation of neuropeptides in the extracellular environment within the olfactory bulb where it is highly expressed . It is also broadly expressed in embryonic tissue, being found in neuronal tissues, bone, skin as well as the lateral rectus eye muscle . A disruption in the CPA6 gene is linked to Duane syndrome, a defect in the abducens nerve/lateral rectus muscle connection . Mutations in the CPA6 gene have been identified in patients with epilepsy .
Asparaginase-like 1, metazoa (ASRGL1_meta)
Type: Family

Human asparaginase-like protein 1 (ASRGL1) and similar proteins constitute a subfamily of the L-Asparaginase type 2-like enzymes. The wider family includes Glycosylasparaginase, Taspase 1, and L-Asparaginase type 2 enzymes. The proenzymes undergo autoproteolytic cleavage before a threonine to generate alpha and beta subunits. The threonine becomes the N-terminal residue of the beta subunit and is the catalytic residue . Because of this autolytic cleavage, the ASRGL1 precursor is considered a peptidase (MEROPS identifier T02.002). ASRGL1, or asparaginase-like 1, has been cloned from mammalian testis cDNA libraries. It has been identified as a sperm antigen that may induce the production of autoantibodies following obstruction of the male reproductive tract, e.g. vasectomy .
p-Aminobenzoyl-glutamate hydrolase subunit A (AbgA)
Type: Family

This entry includes p-aminobenzoyl-glutamate hydrolase subunit A (AbgA; MEROPS identifier M20.020). Together with subunit B it forms the heterodimer AbgAB, which has been shown not to be a dipeptidase, but to hydrolyse p-aminobenzoyl-glutamate (PABA-GLU) to form p-aminobenzoate (PABA) and glutamate .

AbgA is greatly similar to indole-3-acetyl-aspartic acid hydrolase from Enterobacter agglomerans , also included in this family.
YxeP peptidase-like (YxeP-like)
Type: Family

This entry includes N-acetylcysteine deacetylase (also known as YxeP protein) from Bacillus subtilis (MEROPS identifier M20.015) and its close homologues. YxeP probably catalyses the deacetylation of N-acetylcysteine (NAC) to acetate and cysteine. It is involved in a S-(2-succino)cysteine (2SC) degradation pathway that allows B.subtilis to grow on 2SC as a sole sulfur source, via its metabolization to cysteine . N-acetyl-L-cysteine deacetylase SndA is involved in a cysteine salvage pathway from S-alkylcysteine, catalysing the last step in this pathway. This pathway is likely important in the catabolism of alkylated cysteine generated by proteolysis of alkylated glutathione formed in the detoxification of a wide range of electrophiles .
ATP-citrate lyase/succinyl-CoA ligase, conserved site (Citrt_syn/SCS-alpha_CS)
Type: Conserved_site

There are four different enzymes that share a similar catalytic mechanism which involves the phosphorylation by ATP (or GTP) of a specific histidine residue in the active site. These enzymes are:

ATP citrate-lyase (

) , the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues, catalyses the formation of acetyl-CoA and oxaloacetate from citrate and CoA with the concomitant hydrolysis of ATP to ADP and phosphate. ATP-citrate lyase is a tetramer of identical subunits.

Succinyl-CoA ligase (GDP-forming) (

) is a mitochondrial enzyme that catalyses the substrate level phosphorylation step of the tricarboxylic acid cycle: the formation of succinyl-CoA from succinate with a concomitant hydrolysis of GTP to GDP and phosphate. This enzyme is a dimer composed of an alpha and a beta subunits.

Succinyl-CoA ligase (ADP-forming) (

) is a bacterial enzyme that during aerobic metabolism functions in the citric acid cycle, coupling the hydrolysis of succinyl-CoA to the synthesis of ATP. It can also function in the other direction for anabolic purposes. This enzyme is a tetramer composed of two alpha and two beta subunits.

Malate-CoA ligase (

) (malyl-CoA synthetase) , is a bacterial enzyme that forms malyl-CoA from malate and CoA with the concomitant hydrolysis of ATP to ADP and phosphate. Malate-CoA ligase is composed of two different subunits.

This entry corresponds to a glycine-rich conserved region, located in the second half of ATP citrate lyase and in the alpha subunits of succinyl-CoA ligases and malate-CoA ligase.
Carboxypeptidase D, carboxypeptidase-like domain 3 (M14_CPD_III)
Type: Domain

This entry represents the third carboxypeptidase (CP)-like domain of Carboxypeptidase D (CPD; MEROPS identifier XM14.001; EC 3.4.17.22)(MEROPS identifier M14.950).

Carboxypeptidase D (CPD) differs from all other metallocarboxypeptidases in that it contains multiple CP-like domains . CPD belongs to the N/E-like subfamily (subfamily M14B) of the M14 family of metallocarboxypeptidases (MCPs) . CPD is a single-chain protein containing a signal peptide, three tandem repeats of CP-like domains separated by short bridge regions, followed by a transmembrane domain, and a C-terminal cytosolic tail. The first two CP-like domains of CPD contain all of the essential active site and substrate-binding residues, while the third CP-like domain lacks critical residues necessary for enzymatic activity and is inactive towards standard CP substrates. Domain I is optimally active at pH 6.3-7.5 and prefers substrates with C-terminal Arg, whereas domain II is active at pH 5.0-6.5 and prefers substrates with C-terminal Lys . CPD functions in the processing of proteins that transit the secretory pathway, and is present in all vertebrates as well as
Drosophila
. It is broadly distributed in all tissue types. Within cells, CPD is present in the trans-Golgi network and immature secretory vesicles, but is excluded from mature vesicles . It is thought to play a role in the processing of proteins that are initially processed by furin or related endopeptidases present in the trans-Golgi network, such as growth factors and receptors . CPD is implicated in the pathogenesis of lupus erythematosus (LE), it is regulated by TGF-beta in various cell types of murine and human origin and is significantly down-regulated in CD14 positive cells isolated from patients with LE. As down-regulation of CPD leads to down-modulation of TGF-beta, CPD may have a role in a positive feedback loop .

The carboxypeptidase A family can be divided into four subfamilies: M14A (carboxypeptidase A or digestive), M14B (carboxypeptidase H or regulatory), M14C (gamma-D-glutamyl-L-diamino acid peptidase I) and M14D (AGTPBP-1/Nna1-like proteins) . Members of subfamily M14B have longer C-termini than those of subfamily M14A , and carboxypeptidase M (a member of the H family) is bound to the membrane by a glycosylphosphatidylinositol anchor, unlike the majority of the M14 family, which are soluble . The zinc ligands have been determined as two histidines and a glutamate, and the catalytic residue has been identified as a C-terminal glutamate, but these do not form the characteristic metalloprotease HEXXH motif . Members of the carboxypeptidase A family are synthesised as inactive molecules with propeptides that must be cleaved to activate the enzyme. Structural studies of carboxypeptidases A and B reveal the propeptide to exist as a globular domain, followed by an extended α-helix; this shields the catalytic site, without specifically binding to it, while the substrate-binding site is blocked by making specific contacts .
Carboxypeptidase B2 (CPB2)
Type: Domain

Peptidase M14 Carboxypeptidase (CP) B2 (CPB2, also known as plasma carboxypeptidase B, carboxypeptidase U, CPU, and thrombin-activable fibrinolysis inhibitor, TAFI; MEROPS identifier M14.009;

), belongs to the carboxpeptidase A/B subfamily of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity.

CPB2 enzyme displays B-like activity; it only cleaves the basic residues lysine or arginine. It is produced and secreted by the liver as the inactive precursor, procarboxypeptidase U or PCPB2, commonly referred to as thrombin-activatable fibrinolysis inhibitor (TAFI). It circulates in plasma as a zymogen bound to plasminogen, and the active enzyme, TAFIa, inhibits fibrinolysis. It is highly regulated; increased TAFI concentrations are thought to increase the risk of thrombosis and coronary artery disease by reducing fibrinolytic activity while low TAFI levels have been correlated with chronic liver disease .
Carboxypeptidase O (Carboxypeptidase_O)
Type: Domain

Peptidase M14 carboxypeptidase (CP) O (CPO, also known as metallocarboxypeptidase C; MEROPS identifier M14.021; EC 3.4.17.) belongs to the carboxypeptidase A/B subfamily of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity . CPO releases acidic C-terminal residues. It is active at neutral pH and is membrane attached via a glycosylphosphatidinylinositol membrane anchor at the C terminus .
Mitochondrial intermediate peptidase (M3A_MIP)
Type: Family

Mitochondrial intermediate peptidase (MIP; MEROPS identifier M03.006;

) belongs to the widespread peptidase subfamily M3A . MIP shows similarity to the thimet oligopeptidase (TOP). These proteins are enriched in cysteine residues, two of which are highly conserved, suggesting their importance to stability as well as in formation of metal binding sites, thus playing a role in MIP activity .

MIP is one of three peptidases responsible for the proteolytic processing of both nuclear and mitochondrial encoded precursor polypeptides targeted to the various subcompartments of the mitochondria . It cleaves intermediate-size proteins initially processed by mitochondrial processing peptidase (MPP) to yield a processing intermediate with a typical N-terminal octapeptide that is sequentially cleaved by MIP to mature-size protein . MIP cleaves precursor proteins of respiratory components, including subunits of the electron transport chain and tri-carboxylic acid cycle enzymes, and components of the mitochondrial genetic machinery, including ribosomal proteins, translation factors, and proteins required for mitochondrial DNA metabolism. It has been suggested that the human MIP (HMIP polypeptide; gene symbol MIPEP) may be one of the loci predicted to influence the clinical manifestations of Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease caused by lack of human frataxin .
Cytosolic aminopeptidase 1/4 (CBPC1/4)
Type: Domain

The entry includes the peptidase M14-like domain of cytosolic carboxypeptidase 1 (CCP1; MEROPS identifier M14.028), also known as Nna-1 (Nervous system Nuclear protein induced by Axotomy) or ATP/GTP binding protein (AGTPBP-1), and ATP/GTP-binding protein-like 1 (also known as CCP4) . The peptidase M14 family of metallocarboxypeptidases are zinc-binding carboxypeptidases (CPs) which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. CCP1-like proteins are active metallopeptidases that are thought to act on cytosolic proteins such as alpha-tubulin, to remove a C-terminal tyrosine. CCP1-like proteins from the different phyla are highly diverse, but they all contain a unique N-terminal conserved domain right before the CP domain . It has been suggested that this N-terminal domain might act as a folding domain.

CCP1 is widely expressed in the developing and adult nervous systems, including cerebellar Purkinje and granule neurons, miral cells of the olfactory bulb and retinal photoreceptors. CCP1 is also induced in axotomized motor neurons . Mutations in CCP1 cause Purkinje cell degeneration (pcd) . The CCP1 CP domain is required to prevent the retinal photoreceptor loss and cerebellar ataxia phenotypes of pcd mice, and a functional zinc-binding domain is needed for CCP1 to support neuron survival in these mice.
Archaeal protein PH0471, N-terminal (PH1510-N)
Type: Domain

The N-terminal region of the the PH1510 protein (1510-N or PH1510-N) from archaebacterium Pyrococcus horikoshii has been shown to possess serine protease activity and has a Ser-Lys catalytic dyad, preferentially cleaving hydrophobic substrates. It is structurally related to ClpP. In the genome of Pyrococcus horikoshii, PH1510 is homologous to the genes nfed (nodulation formation efficiency D) .

PH1510 (MEROPS identifier S49.005) is thought to be a signal peptide peptidase, which degrades the membrane-bound signal peptide after it has been released from secreted proteins . The peptidase domain is followed by a C-terminal NfeD domain .