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| Line 7: |
Line 7: |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8ji0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ji0 OCA], [https://pdbe.org/8ji0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ji0 RCSB], [https://www.ebi.ac.uk/pdbsum/8ji0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ji0 ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8ji0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ji0 OCA], [https://pdbe.org/8ji0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ji0 RCSB], [https://www.ebi.ac.uk/pdbsum/8ji0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ji0 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Function == | + | <div style="background-color:#fffaf0;"> |
| - | [https://www.uniprot.org/uniprot/TMPS2_HUMAN TMPS2_HUMAN] Plasma membrane-anchored serine protease that participates in proteolytic cascades of relevance for the normal physiologic function of the prostate (PubMed:25122198). Androgen-induced TMPRSS2 activates several substrates that include pro-hepatocyte growth factor/HGF, the protease activated receptor-2/F2RL1 or matriptase/ST14 leading to extracellular matrix disruption and metastasis of prostate cancer cells (PubMed:15537383, PubMed:26018085, PubMed:25122198). In addition, activates trigeminal neurons and contribute to both spontaneous pain and mechanical allodynia (By similarity).[UniProtKB:Q9JIQ8]<ref>PMID:15537383</ref> <ref>PMID:25122198</ref> <ref>PMID:26018085</ref> (Microbial infection) Facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via two independent mechanisms, proteolytic cleavage of ACE2 receptor which promotes viral uptake, and cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry (PubMed:24227843, PubMed:32142651, PubMed:32404436). Proteolytically cleaves and activates the spike glycoproteins of human coronavirus 229E (HCoV-229E) and human coronavirus EMC (HCoV-EMC) and the fusion glycoproteins F0 of Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV). Essential for spread and pathogenesis of influenza A virus (strains H1N1, H3N2 and H7N9); involved in proteolytic cleavage and activation of hemagglutinin (HA) protein which is essential for viral infectivity.<ref>PMID:21068237</ref> <ref>PMID:21325420</ref> <ref>PMID:23536651</ref> <ref>PMID:23966399</ref> <ref>PMID:24027332</ref> <ref>PMID:24227843</ref> <ref>PMID:32142651</ref> <ref>PMID:32404436</ref>
| + | == Publication Abstract from PubMed == |
| | + | Hemorrhagic toxin (TcsH) is a major virulence factor produced by Paeniclostridium sordellii, which is a non-negligible threat to women undergoing childbirth or abortions. Recently, Transmembrane Serine Protease 2 (TMPRSS2) was identified as a host receptor of TcsH. Here, we show the cryo-EM structures of the TcsH-TMPRSS2 complex and uncover that TcsH binds to the serine protease domain (SPD) of TMPRSS2 through the CROP unit-VI. This receptor binding mode is unique among LCTs. Five top surface loops of TMPRSS2(SPD), which also determine the protease substrate specificity, constitute the structural determinants recognized by TcsH. The binding of TcsH inhibits the proteolytic activity of TMPRSS2, whereas its implication in disease manifestations remains unclear. We further show that mutations selectively disrupting TMPRSS2-binding reduce TcsH toxicity in the intestinal epithelium of the female mice. These findings together shed light on the distinct molecular basis of TcsH-TMPRSS2 interactions, which expands our knowledge of host recognition mechanisms employed by LCTs and provides novel targets for developing therapeutics against P. sordellii infections. |
| | + | |
| | + | Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin.,Zhou R, He L, Zhang J, Zhang X, Li Y, Zhan X, Tao L Nat Commun. 2024 Mar 4;15(1):1976. doi: 10.1038/s41467-024-46394-6. PMID:38438396<ref>PMID:38438396</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 8ji0" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| Structural highlights
Publication Abstract from PubMed
Hemorrhagic toxin (TcsH) is a major virulence factor produced by Paeniclostridium sordellii, which is a non-negligible threat to women undergoing childbirth or abortions. Recently, Transmembrane Serine Protease 2 (TMPRSS2) was identified as a host receptor of TcsH. Here, we show the cryo-EM structures of the TcsH-TMPRSS2 complex and uncover that TcsH binds to the serine protease domain (SPD) of TMPRSS2 through the CROP unit-VI. This receptor binding mode is unique among LCTs. Five top surface loops of TMPRSS2(SPD), which also determine the protease substrate specificity, constitute the structural determinants recognized by TcsH. The binding of TcsH inhibits the proteolytic activity of TMPRSS2, whereas its implication in disease manifestations remains unclear. We further show that mutations selectively disrupting TMPRSS2-binding reduce TcsH toxicity in the intestinal epithelium of the female mice. These findings together shed light on the distinct molecular basis of TcsH-TMPRSS2 interactions, which expands our knowledge of host recognition mechanisms employed by LCTs and provides novel targets for developing therapeutics against P. sordellii infections.
Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin.,Zhou R, He L, Zhang J, Zhang X, Li Y, Zhan X, Tao L Nat Commun. 2024 Mar 4;15(1):1976. doi: 10.1038/s41467-024-46394-6. PMID:38438396[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhou R, He L, Zhang J, Zhang X, Li Y, Zhan X, Tao L. Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin. Nat Commun. 2024 Mar 4;15(1):1976. PMID:38438396 doi:10.1038/s41467-024-46394-6
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