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Structural Insights
editAs a type II transmembrane protease, TMPRSS2 consists of an intracellular N-terminal domain, a Transmembrane domain, a stem region that extends extracellularly and a C-terminal domain that catalyzes its Serine protease (SP) activity[1]. This serine protease activity is orchestrated by a catalytic triad containing the residues His296, Asp345, and Ser441.[1][2] This noted catalytic triad is typically responsible for the cleaving of basic amino acid residues (lysine or arginine residues)— consistent with what is observed in the S1/S2 cleavage site found in SARS-CoV-2.[1] A notable domain in the stem region that has been examined through mutational analysis is the low density lipoprotein receptor class A domain (LDLRA).[1] Experimental evidence suggests that this domain likely participates in enzymatic activity of the protein and has been examined alongside another motif in the stem region: the scavenger receptor cysteine-rich domain (SRCR).[1] This domain may be implicated in the binding extracellular molecules and other nearby cells.[3][4] Interestingly, SRCR could have a role in overall proteolytic activity of the protein, which could lead to implications on the overall virulence of SARS-CoV-2.[5][1][6]
- ^ a b c d e f Wettstein, Lukas; Kirchhoff, Frank; Münch, Jan (2022-01-25). "The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment". International Journal of Molecular Sciences. 23 (3): 1351. doi:10.3390/ijms23031351. ISSN 1422-0067. PMC 8836196. PMID 35163273.
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: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Fraser, Bryan J.; Beldar, Serap; Seitova, Almagul; Hutchinson, Ashley; Mannar, Dhiraj; Li, Yanjun; Kwon, Daniel; Tan, Ruiyan; Wilson, Ryan P.; Leopold, Karoline; Subramaniam, Sriram; Halabelian, Levon; Arrowsmith, Cheryl H.; Bénard, François (2022-09). "Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation". Nature Chemical Biology. 18 (9): 963–971. doi:10.1038/s41589-022-01059-7. ISSN 1552-4450.
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(help) - ^ Paoloni-Giacobino, Ariane; Chen, Haiming; Peitsch, Manuel C.; Rossier, Colette; Antonarakis, Stylianos E. (1997-09). "Cloning of the TMPRSS2 Gene, Which Encodes a Novel Serine Protease with Transmembrane, LDLRA, and SRCR Domains and Maps to 21q22.3". Genomics. 44 (3): 309–320. doi:10.1006/geno.1997.4845.
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(help) - ^ Wettstein, Lukas; Kirchhoff, Frank; Münch, Jan (2022-01-25). "The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment". International Journal of Molecular Sciences. 23 (3): 1351. doi:10.3390/ijms23031351. ISSN 1422-0067. PMC 8836196. PMID 35163273.
{{cite journal}}
: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Guipponi, Michel (2008). "TMPRSS3, a type II transmembrane serine protease mutated in non-syndromic autosomal recessive deafness". Frontiers in Bioscience. 13 (13): 1557. doi:10.2741/2780.
- ^ Afar, D. E.; Vivanco, I.; Hubert, R. S.; Kuo, J.; Chen, E.; Saffran, D. C.; Raitano, A. B.; Jakobovits, A. (2001-02-15). "Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia". Cancer Research. 61 (4): 1686–1692. ISSN 0008-5472. PMID 11245484.