Transmembrane protease serine 2

TMPRSS2 is a membrane protein belonging to the type II transmembrane serine protease (TTSP) family. It is functionally classified as a trypsin-like protease (TLP). Serine proteases are known to be involved in many physiological and pathological processes.

spinqualitylabelsall models Caption for this structure Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Protease activity TMPRSS2, as a serine protease, cleaves peptide bonds present after positively charged residues (lysine or arginine). The main player in the catalytic mechanism is the catalytic triad formed by His296, Asp345, and Ser441. This three aminoacids are located in the active site of the enzyme. The substrate specificity is achieved with the presence of a negatively charged Asp residue at the bottom of a cavity usually indicated as “S1 specificity pocket”. General function In terms of normal function, TMPRSS2 has been associated with physiological and pathological processes such as digestion, tissue remodelling, blood coagulation, fertility, inflammatory responses, tumour cell invasion, apoptosis and pain. Prostate cancer Prostate cancer (PC) is the most common form of cancer found in American men and the second leading cause of cancer death. This means that approximately 28.5% of cancers and 3.5% of cancer related deaths in men are due to PC. The most common chromosomal aberration causing this pathology is the fusion of the the promoter of transmembrane protease, serine 2 (TMPRSS2) gene and the coding sequence of the erythroblastosis virus E26 (Ets) gene family members. Ets family members are oncogenic transcription factors. Therefore, the fusion of these genes leads to the production of Ets transcription factors under the control of the androgen sensitive promoter elements of TMPRSS2. The most common of these fusions is with ERG (erythroblast-specific-related gene), a member of the Ets family, resulting in the TMPRSS2-ERG fusion. The TMPRSS2-ERG fusion has been identified in approximately 50% of PC cases. The mutation occurs through chromosomal translocation or intergenic deletion, with both genes on the same arm of chromosome 21, and results in overexpression of chimeric mRNA of ERG in response to androgens. The coding sequence of TMPRSS2 is not involved in the gene fusion. Consequently, there is no resultant recombinant protein for the TMPRSS2-ETS gene fusion and the promoterless copy of TMPRSS2 is silenced. There is impairment of apoptosis in TMPRSS2-ERG positive cancer cells, possibly due to disruption of the intracellular death domain or decoy receptors. The high prevalence of these gene fusions, in particular TMPRSS2-ERG, makes them attractive as potential diagnostic and prognostic indicators, as well as making them a potential target for tailored therapies. Viral entry TMPRSS2 facilitates the entry of viruses into host cells by proteolytically cleaving and activating viral envelope glycoproteins. As human TMPRSS2 is expressed in cells of the respiratory tracts, in addition to the epithelia of the gastrointestinal and urogenital systems, it mediates the entry of several viruses related to respiratory diseases into the host cells, including Influenza virus and the human coronaviruses HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2 (COVID-19 virus). SARS-CoV-2 SARS-CoV-2 entry is achieved by a receptor-mediated endocytosis pathway in which the spike (S) glycoprotein, located on the outer envelope of the virus, interacts with the host angiotensin-converting enzyme 2 (ACE2), a receptor located in the surface of host cells, which allows the virus to infect cells. Prior to this interaction, S protein is needed to be cleaved by different protease enzymes (furins, cathepsins, serine proteases). In this respect, cleavage of S protein by TMPRSS2 is preferred for Coronaviridae family infection over other proteases, such as the endosomal cathepsins. Structure Gene The TMPRSS2 gene resides on chromosome 21 at the band 21q22.3, extends aproximately 43.59 kb and is split into 14 exons. This gene is conserved in a wide variety of animals, such as chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, Caenorhabditis elegans and frog. This gene presents two alternative splicing variants resulting in a 3.25 kb and 3.21 kb transcripts, respectively. Protein TMPRSS2 is a 492 amino acid single-pass type II membrane protein. This protein is defined by the presence of an N-terminal cytoplasmic domain, a transmembrane helical domain, and three extracellular domains: Low-density lipoprotein (LDL)-receptor class A domain: which forms a binding site for calcium Scavenger receptor cysteine-rich domain (SRCR) Peptidase S1 domain, also known as serine protease domain (SPD) Structural highlights spinqualitylabelsall models Crystal structure of human TMPRSS2 in complex with Nafamostat Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D This is a sample scene created with SAT to color by Group, and another to make a transparent representation of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

Proteopedia Page Contributors and Editors (what is this?)

Ines Muniesa-Martinez, Paula R. Mallavibarrena, Laura Aleixos Juan, Michal Harel, Jaime Prilusky