The transmembrane protease serine system 3, TMPRSS3 (ECHOS1, TADG12, UNQ323/PRO382) of 454 aas and 1 very large hydrophobic N-terminal TMS. It is involved in activation of ENaC in the inner ear (Guipponi et al. 2002). The C-terminal half of the protein is homologous to part of the multidomain serine protease/channel protein with TC# 1.A.17.3.1, but no other protein in this latter family. A short sequence in the N-terminal region shows similarity with members of TC family 9.B.87.  Mutations in the gene encoding TMPRSS3 cause human hearing loss. Tang et al. 2019 investigate the role of TMPRSS3, showing that a defect leads to hair cell apoptosis without altering the development of hair cells and the formation of the mechanotransduction apparatus. Prior to degeneration, Tmprss3-KO hair cells show reduced numbers of BK channels and lower expression of genes encoding calcium ion-binding proteins, suggesting disruption in intracellular homeostasis. A proteolytically active TMPRSS3 was detected on cell membranes in addition to the ER of cells in inner ear organoids (Tang et al. 2019). TMPRSS3 regulates cell viability and apoptosis processes via regulation of the circ-Slc4a2, miR-182 and Akt cascade (Zhang et al. 2019).

TMPRSS3 of Homo sapiens

Transmembrane protease serine 4 isoform X1 of 433 aas and 1 N-terminal TMS.

Protease of Physeter catodon (sperm whale)

Hepsin, Hpn or IMPRESS1, of 417 aas and 1 N-terminal TMS. The N-glycan in the scavenger receptor cysteine-rich domain of hepsin promotes intracellular trafficking and cell surface expression (Sun et al. 2020). Hpn is a serine protease that cleaves extracellular substrates, and contributes to the proteolytic processing of growth factors, such as HGF and MST1/HGFL (Ganesan et al. 2011, Herter et al. 2005). It plays a role in cell growth and maintenance of cell morphology (Torres-Rosado et al. 1993), Ganesan et al. 2011), and also in the proteolytic processing of ACE2 (Heurich et al. 2014). It mediates the proteolytic cleavage of urinary UMOD that is required for UMOD polymerization (Brunati et al. 2015).

Hpn of Homo sapiens

Transmembrane protease serine 13, TMPRSS13. of 586 aas. Posttranslational modifications of serine protease TMPRSS13 regulate zymogen activation, proteolytic activity, and cell surface localization (Martin et al. 2021).

TMPRSS13 of Homo sapiens

Serine protease 30, SP30 or PRSS30; Distal intestinal serine protease; Transmembrane serine protease 1, TMSP-1; Transmembrane serine protease 8, Tmprss8, of 304 aas with at least two TMSs, N- and C-terminal, and possibly two more at residues 60 and 235. It is a sodium channel activator (Okumura et al. 2013).

SP30 of Rattus norvegicus

Haptoglobin, HP(T), or zonulin (a modulator of tight junctions; see TC# 1.H.1) of 406 aas and 0 TMSs. As a result of hemolysis, hemoglobin is found to accumulate in the kidney and is secreted in the urine. Haptoglobin captures and combines with free plasma hemoglobin to allow hepatic recycling of heme iron and to prevent kidney damage. Haptoglobin also acts as an antioxidant, has antibacterial activity, and plays a role in modulating many aspects of the acute phase response. Hemoglobin/haptoglobin complexes are rapidly cleared by the macrophage CD163 scavenger receptor expressed on the surface of liver Kupfer cells through an endocytic lysosomal degradation pathway. The uncleaved form of allele alpha-2 (2-2), known as zonulin, plays a role in intestinal permeability (Fasano 2011), allowing intercellular tight junction disassembly, and controlling the equilibrium between tolerance and immunity to non-self antigens (Zengil and Laloğlu 2023). Zonulin and occludin levels in bipolar disorder (BD) increase independently of the disease stage. Consideration of the role of IP in the pathogenesis of BD may be helpful in determining the appropriate treatment modality (Zengil and Laloğlu 2023).

Haptoglobulin/zonulin of Homo sapiens

Thrombin-like enzyme gyroxin B1.3 or VSP13 of 262 aas and 1 N-terminal TMS.  It is a thrombin-like snake venom serine protease that displays a specificity similar to trypsin and releases only fibrinopeptide A in the conversion of fibrinogen to fibrin. It reversibly increases the permeability of the blood brain barrier (BBB) in mice (Alves da Silva et al. 2011). It also induces the barrel rotation syndrome in mice, which is manifested by gyroxin-like, rapid rolling motions (Camillo et al. 2001, Alves da Silva et al. 2011). This syndrome may be due to its effect on BBB permeability, and certainly also to other actions affecting endogenous substrates present in the endothelium, nervous tissues or blood.  It also shows a moderate inhibitory activity on the human voltage-gated potassium channel Kv10.1/KCNH1/EAG1 (58% current inhibition at 5 uM) (Boldrini-França et al. 2020).  It blocks Kv10.1/KCNH1/EAG1 in a time and dose-dependent manner and with a mechanism independent of its enzymatic activity.  It may have a preference in interacting with Kv10.1/KCNH1/EAG1 in its closed state, since the inhibitory effect of the toxin is decreased at more depolarized potentials.

VSP13 of Crotalus durissus terrificus ( South American rattlesnake)

Serine protease 27-like protein of 321 aas and 1 N-terminal TMS.  This protein shows significant similarity with the TMEM106B protein with TC# 9.B.23.1.2.

Serine protease 27 of Electrophorus electricus

Serine protease 55 of 369 aas and 1 TMS.

Serine protease 55 of Neophocaena asiaeorientalis asiaeorientalis (Yangtze finless porpoise)

Suppressor of tumorigenicity 14 protein, ST-14 or St14 = Matriptase; membrane-type serine protease 1, MT-SP1; prostamin; serine protease 14; serine protease TADG-15; tumor-associated differentially-expressed gene 15 protein, of 855 aas and one N-terminal TMS (Alef et al. 2009). Mitochondrial localization of St14-encoding transmembrane serine protease is involved in neural stem/progenitor cell bioenergetics through binding to the F₀F₁-ATP synthase complex (Fang et al. 2019). Inhibitors include HAI-1 and HAI-2 (TC# 8.A.198). Mutations in ST-14 can give rise to congenital ichtyoses (Serra et al. 2022).

ST-14 of Homo sapiens

Kallikrein 3, KLK3, of 261 aas and 1 N-terminal TMS. It and TMPRSS2 (TC# 8.A.131.1.6) can be used for molecular lymph-node staging in prostate cancer patients undergoing prostatectomy (Lunger et al. 2020).

KLK3 of Homo sapiens

TMPRSS2 of 492 aas and one TMS near the N-terminus. It and kallikrein 3, KLK3 (TC# 8.A.131.1.5) can be used for molecular lymph-node staging in prostate cancer patients undergoing prostatectomy (Lunger et al. 2020). Camostat mesylate is a potent inhibitor of the human transmembrane protease, serine 2 (TMPRSS2) and is under investigation for its effectiveness in COVID-19 patients. Its active metabolite is 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA). OATP2B1 is inhibited by GBPA with an IC50 of 11 muM (Weiss et al. 2021). Although nafamostat and camostat have been identified as TMPRSS2 inhibitors, severe side effects such as cerebral hemorrhage, anaphylactoid reaction, and cardiac arrest shock greatly hamper their clinical use. Flupirtine, a selective neuronal potassium channel opener, is a potential TMPRSS2 inhibitor (Chen et al. 2021). TMPRSS2 proteolytically activates the epithelial sodium channel (ENaC) (TC# 1.A.6) by cleaving the channel's gamma-subunit (Sure et al. 2022). Dual inhibition of vacuolar-ATPase and TMPRSS2 is required for complete blockade of SARS-CoV-2 entry into cells (Icho et al. 2022). This is because an essential step in the infection life cycle of SARS-CoV-2 is the proteolytic activation of the viral spike (S) protein, which enables membrane fusion and entry into the host cell. Two distinct classes of host proteases have been implicated in S protein activation: cell-surface serine proteases, such as the cell-surface transmembrane protease, serine 2 (TMPRSS2), and endosomal cathepsins, leading to entry through either the cell-surface route or the endosomal route, respectively (Icho et al. 2022). Potential TMPRSS2 inhibitors for COVID-19 treatments have been identified in chinese medicines (Yang et al. 2023). Angiotensin converting enzyme 2 (ACE-2), transmembrane serine protease 2 (TMPRSS-2) and Neuropilin-1 cellular receptors support the entry of SARS-CoV-2 into susceptible human target cells including astrocytes in the blood brain barrier (BBB) (Malik et al. 2023).

TMPRSS2 of Homo sapiens

Transmembrane protease serine 11A, TMPRSS11A, ECRG1, HATL1, HESP, a Type II transmembrane serine proteases of 421 aas and one N-terminal TMS.  It may play a role in cellular senescence. Overexpression inhibits cell growth and induces G1 cell cycle arrest. It is expressed on the surface of airway epithelial cells and has been shown to cleave and activate spike proteins of the severe acute respiratory syndrome (SARS), SARS-2 and the Middle East respiratory syndrome (MERS) coronaviruses (CoVs). The activation cleavage of human TMPRSS11A is mediated by autocatalysis, and activation cleavage occurred before the protein reached the cell surface (Zhang et al. 2020). TMPRSS11a is an age-altered, tissue specific regulator of migration and wound healing (Fernandez et al. 2021).

ECRG1 of Homo sapiens

Corin (CRN) or TMPRESS10 or atrial natriuretic peptide-converting enzyme of 1042 aas with an N-terminal TMS. See family description for details.

Corin of Homo sapiens

Chmotrypsinogen-like protease of 263 aas and 1 N-terminal TMS.

Chmotrypsin-like protease of Chrysochloris asiatica (Cape golden mole)