Biology:TMPRSS2

From HandWiki

Transmembrane protease, serine 2 is an enzyme that in humans is encoded by the TMPRSS2 gene.[1][2][3] It belongs to the TMPRSS family of proteins, whose members are transmembrane proteins which have a serine protease activity.[4] The TMPRSS2 protein is found in high concentration in the cell membranes of epithelial cells of the lung and of the prostate, but also in the heart, liver and gastrointestinal tract.[4]

Mutations of the TMPRSS2 gene are often involved in prostate cancer. Several viruses, including SARS-CoV-2, use the protease activity of the TMPRSS2 protein in the process of entering cells.[4]

Function

The TMPRSS2 gene encodes a protein that belongs to the serine protease family. The encoded protein contains a type II transmembrane domain, a low density lipoprotein receptor class A domain, a scavenger receptor cysteine-rich domain and a protease domain. Serine proteases are known to be involved in many physiological and pathological processes. This gene is up-regulated by androgenic hormones in prostate cancer cells and down-regulated in androgen-independent prostate cancer tissue. The protease domain of this protein is thought to be cleaved and secreted into cell media after autocleavage.[2] TMPRSS2 participates in proteolytic cascades necessary for normal physiological function of the prostate.[3] Gene knockout mice lacking TMPRSS2 show no abnormalities.[5]

Structure

His296, Asp345, and Ser441 catalytic triad within the Serine Peptidase domain on TMPRSS2 that is characteristic of almost all Type II Serine proteases. The serine (green) engages in nucleophilic attack, the histidine (cyan) acts as a general base to reset the serine and the aspartate (magenta) neutralizes the histidine in transition states during reactions that cause proteolytic cleavage. This structure was solved via X-ray crystallography with a resolution of 1.95 Angstroms (PDB: 7MEQ).[6] Image made in Chimera.[7]
Solved structure of TMPRSS2 is shown here (PDB: 7MEQ)[1], the entire protein is oriented with the extracellular side towards the top and the cytoplasmic side towards the bottom.[6] Bound calcium ions are shown in blue and function as stabilizing cofactors. This view (generated in Chimera) illustrates the largely open conformation that exposes the catalytic triad.

As 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.[8] This serine protease activity is orchestrated by a catalytic triad containing the residues His296, Asp345, and Ser441.[8][6] 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.[8] A notable domain in the stem region that has been examined through mutational analysis is the low density lipoprotein receptor class A domain (LDLRA).[8] 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).[8] This domain may be implicated in the binding of extracellular molecules and other nearby cells.[9][10] Interestingly, SRCR may have a role in overall proteolytic activity of the protein, which could lead to implications on the overall virulence of SARS-CoV-2.[11][8][12]

Clinical significance

In prostate cancer

TMPRSS2 protein's function in prostate carcinogenesis relies on overexpression of ETS transcription factors, such as ERG and ETV1, through gene fusion. TMPRSS2-ERG fusion gene is the most frequent, present in 40% - 80% of prostate cancers in humans. ERG overexpression contributes to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling.[13]

Coronaviruses

Some coronaviruses, e.g. SARS-CoV-1, MERS-CoV, and SARS-CoV-2 (although less well by the omicron variant[14]), are activated by TMPRSS2 and can thus be inhibited by TMPRSS2 inhibitors.[15][16] SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.[17]

Cleavage of the SARS-CoV-2 S2 spike protein required for viral entry into cells can be accomplished by proteases TMPRSS2 located on the cell membrane, or by cathepsins (primarily cathepsin L) in endolysosomes.[18] Hydroxychloroquine inhibits the action of cathepsin L in endolysosomes, but because cathepsin L cleavage is minor compared to TMPRSS2 cleavage, hydroxychloroquine does little to inhibit SARS-CoV-2 infection.[18]

The enzyme Adam17 has similar ACE2 cleavage activity as TMPRSS2, but by forming soluble ACE2, Adam17 may actually have the protective effect of blocking circulating SARS‑CoV‑2 virus particles.[19] By not releasing soluble ACE2, TMPRSS2 cleavage is more harmful.[19]

A TMPRSS2 inhibitor such as camostat approved for clinical use blocked entry and might constitute a treatment option.[16][18] Another experimental candidate as a TMPRSS2 inhibitor for potential use against both influenza and coronavirus infections in general, including those prior to the advent of COVID-19, is the over-the-counter (in most countries) mucolytic cough medicine bromhexine,[20] which is also being investigated as a possible treatment for COVID-19 itself as well.[21] The fact that TMPRSS2 has no known irreplaceable function makes it a promising target for preventing SARS-CoV-2 virus transmission.[5]

The fact that severe illness and death from Sars-Cov-2 is more common in males than females, and that TMPRSS2 is expressed several times more highly in prostate epithelium than any tissue, suggests a role for TMPRSS2 in the gender difference.[22][23] Prostate cancer patients receiving androgen deprivation therapy have a lower risk of SARS-CoV-2 infection than those not receiving that therapy.[22][23]

Inhibitors

Camostat is an inhibitor of the serine protease activity of TMPRSS2. It is used to treat pancreatitis and reflux esophagitis.[24] It was found not to be effective against COVID-19.[25] A novel inhibitor of TMPRSS2 (N-0385) has been found to be effective against SARS-CoV-2 infection in cell and animal models.[26][27]

References

  1. ↑ "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. September 1997. doi:10.1006/geno.1997.4845. PMID 9325052. 
  2. ↑ 2.0 2.1 "Entrez Gene: TMPRSS2 transmembrane protease, serine 2". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=7113. 
  3. ↑ 3.0 3.1 "UniProt Protein: TMPS2_HUMAN transmembrane protease". https://www.uniprot.org/uniprot/O15393#function. 
  4. ↑ 4.0 4.1 4.2 "Gene of the month: TMPRSS2 (transmembrane serine protease 2)". Journal of Clinical Pathology 73 (12): 773–776. December 2020. doi:10.1136/jclinpath-2020-206987. PMID 32873700. 
  5. ↑ 5.0 5.1 "A Review on Expression, Pathological Roles, and Inhibition of TMPRSS2, the Serine Protease Responsible for SARS-CoV-2 Spike Protein Activation". Scientifica 2021. 2021. doi:10.1155/2021/2706789. PMID 34336361. 
  6. ↑ 6.0 6.1 6.2 "Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation". Nature Chemical Biology 18 (9): 963–971. September 2022. doi:10.1038/s41589-022-01059-7. PMID 35676539. 
  7. ↑ "Supplemental Information 4: UCSF Chimera". doi:10.7717/peerj.4593/supp-4. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 "The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment". International Journal of Molecular Sciences 23 (3): 1351. January 2022. doi:10.3390/ijms23031351. PMID 35163273. 
  9. ↑ "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. September 1997. doi:10.1006/geno.1997.4845. PMID 9325052. 
  10. ↑ "The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment". International Journal of Molecular Sciences 23 (3): 1351. January 2022. doi:10.3390/ijms23031351. PMID 35163273. 
  11. ↑ "TMPRSS3, a type II transmembrane serine protease mutated in non-syndromic autosomal recessive deafness". Frontiers in Bioscience 13 (13): 1557–1567. January 2008. doi:10.2741/2780. PMID 17981648. 
  12. ↑ "Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia". Cancer Research 61 (4): 1686–1692. February 2001. PMID 11245484. 
  13. ↑ "An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression". Cancer Cell 17 (5): 443–454. May 2010. doi:10.1016/j.ccr.2010.03.018. PMID 20478527. 
  14. ↑ "Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity". Nature 603 (7902): 706–714. March 2022. doi:10.1038/s41586-022-04474-x. PMID 35104837. Bibcode: 2022Natur.603..706M. 
  15. ↑ "Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2". Journal of Molecular Graphics & Modelling 100. November 2020. doi:10.1016/j.jmgm.2020.107710. PMID 32829149. Bibcode: 2020JMGM..100j7710H. 
  16. ↑ 16.0 16.1 "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor". Cell 181 (2): 271–280.e8. April 2020. doi:10.1016/j.cell.2020.02.052. PMID 32142651. 
    • Lay summary in: "Preventing spread of SARS coronavirus-2 in humans". German Primate Center (Press release). March 5, 2020.
  17. ↑ "Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2)". Molecules 25 (10): 2271. May 2020. doi:10.3390/molecules25102271. PMID 32408547. 
  18. ↑ 18.0 18.1 18.2 "Mechanisms of SARS-CoV-2 entry into cells". Nature Reviews. Molecular Cell Biology 23 (1): 3–20. January 2022. doi:10.1038/s41580-021-00418-x. PMID 34611326. 
  19. ↑ 19.0 19.1 "ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19". Frontiers in Immunology 11. 2020. doi:10.3389/fimmu.2020.576745. PMID 33117379. 
  20. ↑ "TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections". Biochimie 142: 1–10. November 2017. doi:10.1016/j.biochi.2017.07.016. PMID 28778717. 
  21. ↑ "Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?". Internal and Emergency Medicine 15 (5): 801–812. August 2020. doi:10.1007/s11739-020-02383-3. PMID 32458206. 
  22. ↑ 22.0 22.1 "The pivotal role of TMPRSS2 in coronavirus disease 2019 and prostate cancer". Future Oncology 16 (27): 2029–2033. September 2020. doi:10.2217/fon-2020-0571. PMID 32658591. 
  23. ↑ 23.0 23.1 "The secret identities of TMPRSS2: Fertility factor, virus trafficker, inflammation moderator, prostate protector and tumor suppressor". Tumour Biology 43 (1): 159–176. 2021. doi:10.3233/TUB-211502. PMID 34420994. 
  24. ↑ "Camostat mesylate against SARS-CoV-2 and COVID-19-Rationale, dosing and safety". Basic & Clinical Pharmacology & Toxicology 128 (2): 204–212. February 2021. doi:10.1111/bcpt.13533. PMID 33176395. 
  25. ↑ "ACTG announces Camostat will not advance to phase 3 in outpatient treatment study for COVID-19" (in en). https://www.eurekalert.org/pub_releases/2021-06/actg-aac062421.php. 
  26. ↑ "A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic". Nature 605 (7909): 340–348. March 2022. doi:10.1038/s41586-022-04661-w. PMID 35344983. Bibcode: 2022Natur.605..340S. 
  27. ↑ "Nanomolar anti-SARS-CoV-2 Omicron activity of the host-directed TMPRSS2 inhibitor N-0385 and synergistic action with direct-acting antivirals". Antiviral Research 225. May 2024. doi:10.1016/j.antiviral.2024.105869. PMID 38548023. 

Further reading



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