Mutations of theTMPRSS2 gene are often involved inprostate cancer. Several viruses, includingSARS-CoV-2, use the protease activity of the TMPRSS2 protein in the process of entering cells.[8]
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 innucleophilic attack, the histidine (cyan) acts as a generalbase to reset theserine and theaspartate (magenta) neutralizes thehistidine intransition states during reactions that cause proteolytic cleavage. This structure was solved viaX-ray crystallography with a resolution of 1.95Angstroms (PDB: 7MEQ).[10] Image made inChimera.[11]Solved structure of TMPRSS2 is shown here (PDB: 7MEQ)[1], the entire protein is oriented with theextracellular side towards the top and thecytoplasmic side towards the bottom.[10] Boundcalcium ions are shown in blue and function as stabilizingcofactors. This view (generated in Chimera) illustrates the largelyopen conformation that exposes thecatalytic triad.
As a type II transmembraneprotease, TMPRSS2 consists of an intracellularN-terminal domain, atransmembrane domain, a stem region that extends extracellularly and aC-terminal domain that catalyzes itsserine protease (SP) activity.[12] This serine protease activity is orchestrated by acatalytic triad containing the residues His296, Asp345, and Ser441.[12][10] This noted catalytic triad is typically responsible for the cleaving of basic amino acid residues (lysine orarginine residues)— consistent with what is observed in the S1/S2 cleavage site found inSARS-CoV-2.[12] A notable domain in the stem region that has been examined through mutational analysis is the low density lipoprotein receptor class A domain (LDLRA).[12] Experimental evidence suggests that this domain likely participates in enzymatic activity of the protein and has been examined alongside anothermotif in the stem region: the scavenger receptor cysteine-rich domain (SRCR).[12] This domain may be implicated in the binding ofextracellular molecules and other nearby cells.[13][14] Interestingly, SRCR may have a role in overall proteolytic activity of the protein, which could lead to implications on the overallvirulence of SARS-CoV-2.[15][12][16]
TMPRSS2 protein's function in prostate carcinogenesis relies on overexpression ofETS transcription factors, such asERG andETV1, throughgene 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 ofandrogen receptor signaling.[17]
Some coronaviruses, e.g.SARS-CoV-1,MERS-CoV, andSARS-CoV-2 (although less well by theomicron variant[18]), are activated by TMPRSS2 and can thus be inhibited by TMPRSS2 inhibitors.[19][20]SARS-CoV-2 uses the SARS-CoV receptorACE2 for entry and the serine protease TMPRSS2 for S protein priming.[21]
Cleavage of theSARS-CoV-2S2spike protein required for viral entry into cells can be accomplished byproteases TMPRSS2 located on the cell membrane, or bycathepsins (primarilycathepsin L) inendolysosomes.[22]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.[22]
The enzymeAdam17 has similarACE2 cleavage activity as TMPRSS2, but by forming soluble ACE2, Adam17 may actually have the protective effect of blocking circulating SARS‑CoV‑2 virus particles.[23] By not releasing soluble ACE2, TMPRSS2 cleavage is more harmful.[23]
A TMPRSS2 inhibitor such ascamostat approved for clinical use blocked entry and might constitute a treatment option.[20][22] Another experimental candidate as a TMPRSS2 inhibitor for potential use against both influenza and coronavirus infections in general, including those prior to the advent ofCOVID-19, is the over-the-counter (in most countries) mucolytic cough medicinebromhexine,[24] which is also being investigated as a possible treatment for COVID-19 itself as well.[25] The fact that TMPRSS2 has no known irreplaceable function makes it a promising target for preventing SARS-CoV-2 virus transmission.[9]
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 inprostateepithelium than any tissue, suggests a role for TMPRSS2 in the gender difference.[26][27]Prostate cancer patients receivingandrogen deprivation therapy have a lower risk of SARS-CoV-2 infection than those not receiving that therapy.[26][27]
Camostat is an inhibitor of the serine protease activity of TMPRSS2. It is used to treatpancreatitis andreflux esophagitis.[28] It was found not to be effective against COVID-19.[29] A novel inhibitor of TMPRSS2 (N-0385) has been found to be effective against SARS-CoV-2 infection in cell and animal models.[30][31]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE (September 1997). "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.PMID9325052.
^Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE (September 1997). "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.PMID9325052.
^Afar DE, Vivanco I, Hubert RS, Kuo J, Chen E, Saffran DC, et al. (February 2001). "Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia".Cancer Research.61 (4):1686–1692.PMID11245484.
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Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library".Gene.200 (1–2):149–156.doi:10.1016/S0378-1119(97)00411-3.PMID9373149.
Teng DH, Chen Y, Lian L, Ha PC, Tavtigian SV, Wong AK (June 2001). "Mutation analyses of 268 candidate genes in human tumor cell lines".Genomics.74 (3):352–364.doi:10.1006/geno.2001.6551.PMID11414763.
Soller MJ, Isaksson M, Elfving P, Soller W, Lundgren R, Panagopoulos I (July 2006). "Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer".Genes, Chromosomes & Cancer.45 (7):717–719.doi:10.1002/gcc.20329.PMID16575875.S2CID86518137.
