TMPRSS2

Last updated
TMPRSS2
Identifiers
Aliases TMPRSS2 , PP9284, PRSS10, transmembrane protease, serine 2, transmembrane serine protease 2
External IDs OMIM: 602060 MGI: 1354381 HomoloGene: 4136 GeneCards: TMPRSS2
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001135099
NM_005656
NM_001382720

NM_015775

RefSeq (protein)

NP_001128571
NP_005647
NP_001369649

NP_056590

Location (UCSC) Chr 21: 41.46 – 41.53 Mb Chr 16: 97.37 – 97.41 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Transmembrane protease, serine 2 is an enzyme that in humans is encoded by the TMPRSS2 gene. [5] [6] [7] It belongs to the TMPRSS family of proteins, whose members are transmembrane proteins which have a serine protease activity. [8] 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. [8]

Contents

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. [8]

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. [6] TMPRSS2 participates in proteolytic cascades necessary for normal physiological function of the prostate. [7] Gene knockout mice lacking TMPRSS2 show no abnormalities. [9]

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). Image made in Chimera. His296, Asp345, and Ser441 catalytic triad.png
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). Image made in Chimera.
Solved structure of TMPRSS2 is shown here (PDB: 7MEQ), the entire protein is oriented with the extracellular side towards the top and the cytoplasmic side towards the bottom. 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. TMPRSS2- Solved Structure.png
Solved structure of TMPRSS2 is shown here (PDB: 7MEQ), the entire protein is oriented with the extracellular side towards the top and the cytoplasmic side towards the bottom. 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. [12] This serine protease activity is orchestrated by a catalytic 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 or arginine residues)— consistent with what is observed in the S1/S2 cleavage site found in SARS-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 another motif in the stem region: the scavenger receptor cysteine-rich domain (SRCR). [12] This domain may be implicated in the binding of extracellular 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 overall virulence of SARS-CoV-2. [15] [12] [16]

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. [17]

Coronaviruses

Some coronaviruses, e.g. SARS-CoV-1, MERS-CoV, and SARS-CoV-2 (although less well by the omicron variant [18] ), are activated by TMPRSS2 and can thus be inhibited by TMPRSS2 inhibitors. [19] [20] SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. [21]

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. [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 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. [23] By not releasing soluble ACE2, TMPRSS2 cleavage is more harmful. [23]

A TMPRSS2 inhibitor such as camostat 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 of COVID-19, is the over-the-counter (in most countries) mucolytic cough medicine bromhexine, [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 in prostate epithelium than any tissue, suggests a role for TMPRSS2 in the gender difference. [26] [27] Prostate cancer patients receiving androgen deprivation therapy have a lower risk of SARS-CoV-2 infection than those not receiving that therapy. [26] [27]

Inhibitors

Camostat is an inhibitor of the serine protease activity of TMPRSS2. It is used to treat pancreatitis and reflux 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]

Related Research Articles

<span class="mw-page-title-main">SARS-related coronavirus</span> Species of coronavirus causing SARS and COVID-19

Severe-acute-respiratory-syndrome–related coronavirus is a species of virus consisting of many known strains. Two strains of the virus have caused outbreaks of severe respiratory diseases in humans: severe acute respiratory syndrome coronavirus 1, which caused the 2002–2004 outbreak of severe acute respiratory syndrome (SARS), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is causing the ongoing pandemic of COVID-19. There are hundreds of other strains of SARSr-CoV, which are only known to infect non-human mammal species: bats are a major reservoir of many strains of SARSr-CoV; several strains have been identified in Himalayan palm civets, which were likely ancestors of SARS-CoV-1.

<span class="mw-page-title-main">Serine protease</span> Class of enzymes

Serine proteases are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Serine proteases fall into two broad categories based on their structure: chymotrypsin-like (trypsin-like) or subtilisin-like.

<span class="mw-page-title-main">Urokinase</span> Human protein

Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947. Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.

<span class="mw-page-title-main">Fusion gene</span>

A fusion gene is a hybrid gene formed from two previously independent genes. It can occur as a result of translocation, interstitial deletion, or chromosomal inversion. Fusion genes have been found to be prevalent in all main types of human neoplasia. The identification of these fusion genes play a prominent role in being a diagnostic and prognostic marker.

<span class="mw-page-title-main">Enteropeptidase</span> Class of enzymes

Enteropeptidase is an enzyme produced by cells of the duodenum and is involved in digestion in humans and other animals. Enteropeptidase converts trypsinogen into its active form trypsin, resulting in the subsequent activation of pancreatic digestive enzymes. Absence of enteropeptidase results in intestinal digestion impairment.

<span class="mw-page-title-main">Angiotensin-converting enzyme 2</span> Exopeptidase enzyme that acts on angiotensin I and II

Angiotensin-converting enzyme 2 (ACE2) is an enzyme that can be found either attached to the membrane of cells (mACE2) in the intestines, kidney, testis, gallbladder, and heart or in a soluble form (sACE2). Both membrane bound and soluble ACE2 are integral parts of the renin–angiotensin–aldosterone system (RAAS) that exists to keep the body's blood pressure in check. mACE2 is cleaved by the enzyme ADAM17 that releases its extracellular domain, creating soluble ACE2 (sACE2). ACE2 enzyme activity opposes the classical arm of the RAAS by lowering blood pressure through catalyzing the hydrolysis of angiotensin II into angiotensin (1–7). Angiotensin (1-7) in turns binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure. This decrease in blood pressure makes the entire process a promising drug target for treating cardiovascular diseases.

<span class="mw-page-title-main">Cathepsin L1</span> Protein-coding gene in the species Homo sapiens

Cathepsin L1 is a protein that in humans is encoded by the CTSL1 gene. The protein is a cysteine cathepsin, a lysosomal cysteine protease that plays a major role in intracellular protein catabolism.

<span class="mw-page-title-main">ST14</span> Protein-coding gene in the species Homo sapiens

Suppressor of tumorigenicity 14 protein, also known as matriptase, is a protein that in humans is encoded by the ST14 gene. ST14 orthologs have been identified in most mammals for which complete genome data are available.

<i>ERG</i> (gene) Protein-coding gene in the species Homo sapiens

ERG is an oncogene. ERG is a member of the ETS family of transcription factors. The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis.

<span class="mw-page-title-main">KLK4</span> Mammalian protein found in Homo sapiens

Kallikrein-related peptidase 4 is a protein which in humans is encoded by the KLK4 gene.

<span class="mw-page-title-main">PRSS8</span> Protein-coding gene in the species Homo sapiens

Prostasin is a protein that in humans is encoded by the PRSS8 gene.

<span class="mw-page-title-main">HPN (gene)</span> Protein-coding gene in humans

Serine protease hepsin is an enzyme that in humans is encoded by the HPN gene.

<span class="mw-page-title-main">MALT1</span> Protein-coding gene in the species Homo sapiens

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 is a protein that in humans is encoded by the MALT1 gene. It's the human paracaspase.

<span class="mw-page-title-main">LMTK2</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase LMTK2 also known as Lemur tyrosine kinase 2 (LMTK2) is an enzyme that in humans is encoded by the LMTK2 gene.

<span class="mw-page-title-main">Camostat</span> Serine protease inhibitor

Camostat is a serine protease inhibitor. Serine protease enzymes have a variety of functions in the body, and so camostat has a diverse range of uses. Camostat is approved in Japan for the treatment of chronic pancreatitis and postoperative reflux esophagitis. The oral proteolytic enzyme inhibitor has been on the market since 1985 under the trade name Foipan Tablets. The manufacturer is Ono Pharmaceutical. The drug is used in the treatment of some forms of cancer and is also effective against some viral infections, as well as inhibiting fibrosis in liver or kidney disease or pancreatitis.

<span class="mw-page-title-main">SLC45A3</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 45 member 3 (SLC45A3), also known as prostate cancer-associated protein 6 or prostein, is a protein that in humans is encoded by the SLC45A3 gene.

<span class="mw-page-title-main">Rhomboid protease</span>

The rhomboid proteases are a family of enzymes that exist in almost all species. They are proteases: they cut the polypeptide chain of other proteins. This proteolytic cleavage is irreversible in cells, and an important type of cellular regulation. Although proteases are one of the earliest and best studied class of enzyme, rhomboids belong to a much more recently discovered type: the intramembrane proteases. What is unique about intramembrane proteases is that their active sites are buried in the lipid bilayer of cell membranes, and they cleave other transmembrane proteins within their transmembrane domains. About 30% of all proteins have transmembrane domains, and their regulated processing often has major biological consequences. Accordingly, rhomboids regulate many important cellular processes, and may be involved in a wide range of human diseases.

<span class="mw-page-title-main">Collagen, type XXIII, alpha 1</span> Mammalian protein found in humans

Collagen α-1 (XXIII) chain is a protein encoded by COL23A1 gene, which is located on chromosome 5q35 in humans, and on chromosome 11B1+2 in mice. The location of this gene was discovered by genomic sequence analysis.

<span class="mw-page-title-main">Coronavirus spike protein</span> Glycoprotein spike on a viral capsid or viral envelope

Spike (S) glycoprotein is the largest of the four major structural proteins found in coronaviruses. The spike protein assembles into trimers that form large structures, called spikes or peplomers, that project from the surface of the virion. The distinctive appearance of these spikes when visualized using negative stain transmission electron microscopy, "recalling the solar corona", gives the virus family its main name.

SERTM2, also known as the Serine Rich And Transmembrane Domain Containing 2, is a protein which in humans is encoded by the SERTM2 gene. The SERTM2 protein is a transmembrane protein located in the intracellular membrane and active in membrane-bound organelles. SERTM2 expression has been linked to metastatic prostate tumors, prostate carcinomas and renal cell carcinomas.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000184012 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000000385 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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. PMID   9325052.
  6. 1 2 "Entrez Gene: TMPRSS2 transmembrane protease, serine 2".
  7. 1 2 "UniProt Protein: TMPS2_HUMAN transmembrane protease".
  8. 1 2 3 Thunders M, Delahunt B (December 2020). "Gene of the month: TMPRSS2 (transmembrane serine protease 2)". Journal of Clinical Pathology. 73 (12): 773–776. doi:10.1136/jclinpath-2020-206987. PMC   7470178 . PMID   32873700.
  9. 1 2 Sarker J, Das P, Sarker S, Roy AK, Momen AZ (2021). "A Review on Expression, Pathological Roles, and Inhibition of TMPRSS2, the Serine Protease Responsible for SARS-CoV-2 Spike Protein Activation". Scientifica. 2021: 2706789. doi: 10.1155/2021/2706789 . PMC   8313365 . PMID   34336361.
  10. 1 2 3 Fraser BJ, Beldar S, Seitova A, Hutchinson A, Mannar D, Li Y, et al. (September 2022). "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 . PMID   35676539.
  11. "Supplemental Information 4: UCSF Chimera". doi: 10.7717/peerj.4593/supp-4 .{{cite web}}: Missing or empty |url= (help)
  12. 1 2 3 4 5 6 Wettstein L, Kirchhoff F, Münch J (January 2022). "The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment". International Journal of Molecular Sciences. 23 (3): 1351. doi: 10.3390/ijms23031351 . PMC   8836196 . PMID   35163273.
  13. 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. PMID   9325052.
  14. Wettstein L, Kirchhoff F, Münch J (January 2022). "The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment". International Journal of Molecular Sciences. 23 (3): 1351. doi: 10.3390/ijms23031351 . PMC   8836196 . PMID   35163273.
  15. Guipponi M, Antonarakis SE, Scott HS (January 2008). "TMPRSS3, a type II transmembrane serine protease mutated in non-syndromic autosomal recessive deafness". Frontiers in Bioscience. 13 (13): 1557–1567. doi: 10.2741/2780 . PMID   17981648.
  16. 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. PMID   11245484.
  17. Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, et al. (May 2010). "An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression". Cancer Cell. 17 (5): 443–454. doi:10.1016/j.ccr.2010.03.018. PMC   2874722 . PMID   20478527.
  18. Meng B, Abdullahi A, Ferreira IA, Goonawardane N, Saito A, Kimura I, et al. (March 2022). "Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity". Nature. 603 (7902): 706–714. Bibcode:2022Natur.603..706M. doi:10.1038/s41586-022-04474-x. PMC   8942856 . PMID   35104837.
  19. Huggins DJ (November 2020). "Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2". Journal of Molecular Graphics & Modelling. 100: 107710. doi:10.1016/j.jmgm.2020.107710. PMC   7417922 . PMID   32829149.
  20. 1 2 Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. (April 2020). "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. doi: 10.1016/j.cell.2020.02.052 . PMC   7102627 . PMID   32142651.
  21. Rahman N, Basharat Z, Yousuf M, Castaldo G, Rastrelli L, Khan H (May 2020). "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. doi: 10.3390/molecules25102271 . PMC   7287752 . PMID   32408547.
  22. 1 2 3 Jackson CB, Farzan M, Chen B, Choe H (January 2022). "Mechanisms of SARS-CoV-2 entry into cells". Nature Reviews. Molecular Cell Biology. 23 (1): 3–20. doi:10.1038/s41580-021-00418-x. PMC   8491763 . PMID   34611326.
  23. 1 2 Zipeto D, Palmeira JD, Argañaraz GA, Argañaraz ER (2020). "ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19". Frontiers in Immunology. 11: 576745. doi: 10.3389/fimmu.2020.576745 . PMC   7575774 . PMID   33117379.
  24. Shen LW, Mao HJ, Wu YL, Tanaka Y, Zhang W (November 2017). "TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections". Biochimie. 142: 1–10. doi:10.1016/j.biochi.2017.07.016. PMC   7116903 . PMID   28778717.
  25. Depfenhart M, de Villiers D, Lemperle G, Meyer M, Di Somma S (August 2020). "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. doi:10.1007/s11739-020-02383-3. PMC   7249615 . PMID   32458206.
  26. 1 2 Mollica V, Rizzo A, Massari F (September 2020). "The pivotal role of TMPRSS2 in coronavirus disease 2019 and prostate cancer". Future Oncology. 16 (27): 2029–2033. doi:10.2217/fon-2020-0571. PMC   7359420 . PMID   32658591.
  27. 1 2 Epstein RJ (2021). "The secret identities of TMPRSS2: Fertility factor, virus trafficker, inflammation moderator, prostate protector and tumor suppressor". Tumour Biology. 43 (1): 159–176. doi: 10.3233/TUB-211502 . PMID   34420994. S2CID   237268413.
  28. Breining P, Frølund AL, Højen JF, Gunst JD, Staerke NB, Saedder E, Cases-Thomas M, Little P, Nielsen LP, Søgaard OS, Kjolby M (February 2021). "Camostat mesylate against SARS-CoV-2 and COVID-19-Rationale, dosing and safety". Basic & Clinical Pharmacology & Toxicology. 128 (2): 204–212. doi: 10.1111/bcpt.13533 . PMID   33176395.
  29. "ACTG announces Camostat will not advance to phase 3 in outpatient treatment study for COVID-19". EurekAlert!. Retrieved 2021-07-01.
  30. Shapira T, Monreal IA, Dion SP, Buchholz DW, Imbiakha B, Olmstead AD, et al. (March 2022). "A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic". Nature. 605 (7909): 340–348. Bibcode:2022Natur.605..340S. doi:10.1038/s41586-022-04661-w. PMC   9095466 . PMID   35344983.

Further reading