| Structural highlights
Function
TMPS2_HUMAN Plasma membrane-anchored serine protease that participates in proteolytic cascades of relevance for the normal physiologic function of the prostate (PubMed:25122198). Androgen-induced TMPRSS2 activates several substrates that include pro-hepatocyte growth factor/HGF, the protease activated receptor-2/F2RL1 or matriptase/ST14 leading to extracellular matrix disruption and metastasis of prostate cancer cells (PubMed:15537383, PubMed:26018085, PubMed:25122198). In addition, activates trigeminal neurons and contribute to both spontaneous pain and mechanical allodynia (By similarity).[UniProtKB:Q9JIQ8][1] [2] [3] (Microbial infection) Facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via two independent mechanisms, proteolytic cleavage of ACE2 receptor which promotes viral uptake, and cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry (PubMed:24227843, PubMed:32142651, PubMed:32404436). Proteolytically cleaves and activates the spike glycoproteins of human coronavirus 229E (HCoV-229E) and human coronavirus EMC (HCoV-EMC) and the fusion glycoproteins F0 of Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV). Essential for spread and pathogenesis of influenza A virus (strains H1N1, H3N2 and H7N9); involved in proteolytic cleavage and activation of hemagglutinin (HA) protein which is essential for viral infectivity.[4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
The human seasonal coronavirus HKU1-CoV, which causes common colds worldwide, relies on the sequential binding to surface glycans and transmembrane serine protease 2 (TMPRSS2) for entry into target cells. TMPRSS2 is synthesized as a zymogen that undergoes autolytic activation to process its substrates. Several respiratory viruses, in particular coronaviruses, use TMPRSS2 for proteolytic priming of their surface spike protein to drive membrane fusion upon receptor binding. We describe the crystal structure of the HKU1-CoV receptor binding domain in complex with TMPRSS2, showing that it recognizes residues lining the catalytic groove. Combined mutagenesis of interface residues and comparison across species highlight positions 417 and 469 as determinants of HKU1-CoV host tropism. The structure of a receptor-blocking nanobody in complex with zymogen or activated TMPRSS2 further provides the structural basis of TMPRSS2 activating conformational change, which alters loops recognized by HKU1-CoV and dramatically increases binding affinity.
Structural basis of TMPRSS2 zymogen activation and recognition by the HKU1 seasonal coronavirus.,Fernandez I, Saunders N, Duquerroy S, Bolland WH, Arbabian A, Baquero E, Blanc C, Lafaye P, Haouz A, Buchrieser J, Schwartz O, Rey FA Cell. 2024 Aug 8;187(16):4246-4260.e16. doi: 10.1016/j.cell.2024.06.007. Epub , 2024 Jul 3. PMID:38964326[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Lucas JM, Heinlein C, Kim T, Hernandez SA, Malik MS, True LD, Morrissey C, Corey E, Montgomery B, Mostaghel E, Clegg N, Coleman I, Brown CM, Schneider EL, Craik C, Simon JA, Bedalov A, Nelson PS. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov. 2014 Nov;4(11):1310-25. doi: 10.1158/2159-8290.CD-13-1010. Epub, 2014 Aug 13. PMID:25122198 doi:https://dx.doi.org/10.1158/2159-8290.CD-13-1010
- ↑ Ko CJ, Huang CC, Lin HY, Juan CP, Lan SW, Shyu HY, Wu SR, Hsiao PW, Huang HP, Shun CT, Lee MS. Androgen-Induced TMPRSS2 Activates Matriptase and Promotes Extracellular Matrix Degradation, Prostate Cancer Cell Invasion, Tumor Growth, and Metastasis. Cancer Res. 2015 Jul 15;75(14):2949-60. doi: 10.1158/0008-5472.CAN-14-3297. Epub , 2015 May 27. PMID:26018085 doi:https://dx.doi.org/10.1158/0008-5472.CAN-14-3297
- ↑ Shulla A, Heald-Sargent T, Subramanya G, Zhao J, Perlman S, Gallagher T. A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J Virol. 2011 Jan;85(2):873-82. doi: 10.1128/JVI.02062-10. Epub 2010 Nov 10. PMID:21068237 doi:https://dx.doi.org/10.1128/JVI.02062-10
- ↑ Glowacka I, Bertram S, Muller MA, Allen P, Soilleux E, Pfefferle S, Steffen I, Tsegaye TS, He Y, Gnirss K, Niemeyer D, Schneider H, Drosten C, Pohlmann S. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J Virol. 2011 May;85(9):4122-34. doi: 10.1128/JVI.02232-10. Epub 2011 Feb 16. PMID:21325420 doi:https://dx.doi.org/10.1128/JVI.02232-10
- ↑ Bertram S, Dijkman R, Habjan M, Heurich A, Gierer S, Glowacka I, Welsch K, Winkler M, Schneider H, Hofmann-Winkler H, Thiel V, Pohlmann S. TMPRSS2 activates the human coronavirus 229E for cathepsin-independent host cell entry and is expressed in viral target cells in the respiratory epithelium. J Virol. 2013 Jun;87(11):6150-60. doi: 10.1128/JVI.03372-12. Epub 2013 Mar 27. PMID:23536651 doi:https://dx.doi.org/10.1128/JVI.03372-12
- ↑ Abe M, Tahara M, Sakai K, Yamaguchi H, Kanou K, Shirato K, Kawase M, Noda M, Kimura H, Matsuyama S, Fukuhara H, Mizuta K, Maenaka K, Ami Y, Esumi M, Kato A, Takeda M. TMPRSS2 is an activating protease for respiratory parainfluenza viruses. J Virol. 2013 Nov;87(21):11930-5. doi: 10.1128/JVI.01490-13. Epub 2013 Aug 21. PMID:23966399 doi:https://dx.doi.org/10.1128/JVI.01490-13
- ↑ Shirato K, Kawase M, Matsuyama S. Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2. J Virol. 2013 Dec;87(23):12552-61. doi: 10.1128/JVI.01890-13. Epub 2013 Sep 11. PMID:24027332 doi:https://dx.doi.org/10.1128/JVI.01890-13
- ↑ Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pohlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2014 Jan;88(2):1293-307. doi: 10.1128/JVI.02202-13. Epub 2013 Nov 13. PMID:24227843 doi:https://dx.doi.org/10.1128/JVI.02202-13
- ↑ Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020, Mar 5. PMID:32142651 doi:https://dx.doi.org/10.1016/j.cell.2020.02.052
- ↑ Zang R, Gomez Castro MF, McCune BT, Zeng Q, Rothlauf PW, Sonnek NM, Liu Z, Brulois KF, Wang X, Greenberg HB, Diamond MS, Ciorba MA, Whelan SPJ, Ding S. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol. 2020 May 13;5(47). pii: 5/47/eabc3582. doi:, 10.1126/sciimmunol.abc3582. PMID:32404436 doi:https://dx.doi.org/10.1126/sciimmunol.abc3582
- ↑ Fernández I, Saunders N, Duquerroy S, Bolland WH, Arbabian A, Baquero E, Blanc C, Lafaye P, Haouz A, Buchrieser J, Schwartz O, Rey FA. Structural basis of TMPRSS2 zymogen activation and recognition by the HKU1 seasonal coronavirus. Cell. 2024 Aug 8;187(16):4246-4260.e16. PMID:38964326 doi:10.1016/j.cell.2024.06.007
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