Transmembrane protease serine 2, also known as TMPRSS2, is a single-pass type II membrane protein in humans that is encoded by the TMPRSS2 gene. The TMPRSS2 gene was first discovered in 1997 on human chromosome 21 by systematic exon-trapping experiments. The protein encoded by this androgen-regulated gene belongs to the hepsin/TMPRSS subfamily, which contains an additional six proteolytically active TTSPs (type II transmembrane serine proteases). It is expressed in the lung, liver, and kidney tissues, with higher expression in the prostate, pancreatic, and colon tissues. Studies showed that TMPRSS2 is up-regulated by androgenic hormones in prostate cancer cells and down-regulated in androgen-independent prostate cancer tissue.
As a multidomain serine protease, TMPRSS2 harbors a type II transmembrane domain, a low-density lipoprotein receptor A (LDLRA) domain, a scavenger receptor cysteine-rich (SRDR) domain, a serine protease domain, and a cytoplasmic domain. The serine protease domain undergoes autocleaveage, secretion into the prostate epithelia, and interacts with cell surface proteins, the extracellular matrix, and proteins of neighboring cells. The LDLRA domain forms a binding site for LDA and calcium. The serine protease domain contains three catalytic residues histidine, aspartate, and serine.
The proteolytic cleavage and activation of the surface glycoprotein HA (haemagglutinin) of various influenza viruses by TMPRSS2 is essential for the ability of HA to facilitate the virus-endosome membranes fusion following receptor-mediated endocytosis of the virus, augmenting viral infectivity. And the priming of the spike glycoproteins of human coronaviruses such as SARS-CoV and SARS-CoV-2 entails the TMPRSS2, and this process promotes the viral entry into the host cell.
Additionally, TMPRSS2 also acts as a receptor for specific ligands to mediate environment-cells signals. Studies found that TMPRSS2 could regulate epithelial sodium currents in the lung by hydrolyzing epithelial sodium channels and inflammatory responses of the prostate by activating the protease-activated receptor 2 (PAR2). TMPRSS2-ERG gene fusion is common in about 50% of prostate cancer and 20% of HGPIN.
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