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Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin

Ruoyu Zhou1,2,3,4, Liuqing He2,3,4,5, Jiahao Zhang2,3,4

  • 1College of Life Sciences, Fudan University, Shanghai, 200433, China.

Nature Communications
|March 4, 2024
PubMed

Insights

Paeniclostridium sordellii hemorrhagic toxin (TcsH) binds to Transmembrane Serine Protease 2 (TMPRSS2) via its serine protease domain. Disrupting this interaction reduces TcsH toxicity, offering therapeutic targets.

Area of Science:

  • Microbiology
  • Structural Biology
  • Toxicology

Background:

  • Paeniclostridium sordellii hemorrhagic toxin (TcsH) is a key virulence factor.
  • Transmembrane Serine Protease 2 (TMPRSS2) is identified as a host receptor for TcsH.

Purpose of the Study:

  • To elucidate the structural basis of TcsH-TMPRSS2 interaction using cryo-electron microscopy (cryo-EM).
  • To investigate the functional consequences of this interaction and its role in TcsH toxicity.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine the structure of the TcsH-TMPRSS2 complex.
  • Site-directed mutagenesis to disrupt TcsH-TMPRSS2 binding.
  • In vivo toxicity assays in a mouse model.

Main Results:

  • The cryo-EM structure reveals TcsH binds to the serine protease domain (SPD) of TMPRSS2 via CROP unit-VI, a unique binding mode.
  • TcsH binding inhibits the proteolytic activity of TMPRSS2.
  • Mutations disrupting TMPRSS2 binding significantly reduce TcsH toxicity in the mouse intestinal epithelium.

Conclusions:

  • The study reveals a distinct molecular mechanism for TcsH-TMPRSS2 interaction.
  • This interaction is crucial for TcsH-mediated toxicity.
  • The findings provide potential therapeutic targets for P. sordellii infections.

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