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.

Crystal structure of human TMPRSS2 in complex with nafamostat

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 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 prevalent 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. Specifically, the TMPRSS2-ERG fusion has been identified in approximately 50% of PC cases, responsible for driving carcinogenesis. This 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. 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 (viral spike protein). 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).SARS-CoV-2 S protein presents two functional domains S1, the receptor binding domain, and S2, that contains functional elements involved in membrane fusion. There are multiple sites in which this protein can be cleaved; one of these is at the S1/S2 boundary and another within S2. The S1/S2 cleavage site contains multiple arginine residues, which allows the action of serine proteases. Coronaviridae family tend to prefer "TMPRSS2" for the cleavage of S protein over other proteases, such as the endosomal cathepsins. As this protease is expressed in SARS-CoV-2 target cells throughout the human respiratory tract, it is also required for the spread of this virus. However, it has been demonstrated to be dispensable for the development or homeostasis of mice models, so it can be considered a potential target to fight the infection of these viruses. 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. It 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: TMPRSS2 protein 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) Expression Autocatalytic cleavage As TMPRSS2 is synthesized as a single-chain proenzyme, or zymogen, it requires cleavage at a conserved Arg255-Ile256 peptide bond within its SRQSR255↓IVGGE activation motif (cleavage site denoted with an arrow) to achieve full maturation of its enzymatic activity. This autocatalytic cleavage activates the 492-residue long TMPRSS2 zymogen. This modification enables the binding of Ile256 into a putative allosteric pocket (A-pocket), which induces a conformational rearrangement of the catalytic site. After the cleavage, TMPRSS2 remains bound to the transmembrane N-terminal domains by a conserved disulfide bond, although a small fraction of the protein can be detected into the extracellular environment, the protease domain of this protein is thought to be cleaved and secreted into cell media after autocleavage. Regulation The human TMPRSS2 gene promoter has a 15-bp androgen response element. The upregulation of TMPRSS2 mRNA by androgens appears to be mediated by the androgen receptor Pharmacological therapeutic approaches Inhibitors of TMPRSS2 Nafamostat mesylate Nafamostat mesylate (FUT-175; CAS number: 81525-10-2) is an artificial serine protease inhibitor clinically approved in Japan for the treatment of acute pancreatitis, intravascular coagulation dissemination, and extracorporeal circulation antioxidation. This drug is a competitive inhibitor of the binding active site, as well as Camostat. Both are reactive esters that form the same slowly-reversible phenylguanidino covalent complex with the catalytic serine (Ser441) residue of trypsin-like serine proteases. Nafamostat demonstrated enhanced potency over camostat with IC50 values of (1.7±0.2) and (17±4) nM, respectively. Although nafamostat potently neutralizes TMPRSS2 activity, it is non-selective and disables trypsin-like serine proteases involved in coagulation such as plasmin, FXa, and FXIIa, as well as other TTSPs through its generic arginine-like engagement with the S1 subsite. Also it requires continuous intravenous infusion to approach therapeutic concentrations for COVID-19 owing to its short biological half-life of 8 minutes. Bromhexine Repurposing of the mucolytic agent called bromhexine, a TMPRSS2 inhibitor, has been also proposed for COVID-19 therapy. Transcriptional inhibition Transcriptional inhibition of TMPRSS2 has been proposed as a new therapeutic option. As TMPRSS2 expression seems to be modulated by estrogens and androgens, data suggest that the activation of estrogen pathways or inhibition of androgen pathways may be a new target for therapeutic clinical intervention for symptom amelioration in COVID-19 patients. Using computational and experimental methods, estrogen and androgen-related compounds such as genistein, estradiol, and enzatulamide have been shown to reduce TMPRSS2 expression. Structural highlights 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.

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