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Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches
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Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches

Published on: October 13, 2022

Cryo-EM structures of human caspase-4 in complex with full-length gasdermin D

Ying Luan1, Enbo Chen1, Youdong Mao2

  • 1State Key Laboratory for Artificial Microstructure and Mesoscopic Physics, School of Physics, Peking University, Beijing 100871, China; Peking-Tsinghua Joint Center for Life Sciences, Peking University, Beijing 100871, China.

Structure (London, England : 1993)
|July 13, 2026
PubMed

Insights

Caspase-4 cleaves gasdermin D (GSDMD) to trigger pyroptosis. Cryo-EM structures reveal how different caspase-4 forms bind GSDMD, clarifying inflammasome signaling mechanisms.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Immunology

Background:

  • Caspase-4 initiates non-canonical inflammasome signaling by cleaving gasdermin D (GSDMD), leading to pyroptosis.
  • Autoprocessing of caspase-4 generates distinct forms (p20/p12, p22/p10, p20/p10) that can process GSDMD.

Purpose of the Study:

  • To elucidate the structural basis of full-length human GSDMD recognition by distinct autoprocessed forms of human caspase-4.
  • To understand how different caspase-4 cleavage states influence GSDMD binding and processing.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to determine the structures of full-length human GSDMD complexed with p22/p10 and p20/p10 caspase-4 forms.
  • Structural analysis focused on protein-protein interactions, including exosite recognition and catalytic groove occupancy.

Main Results:

  • Cryo-EM structures revealed complexes of full-length human GSDMD with p22/p10 and p20/p10 caspase-4.
  • Both complexes showed exosite-mediated recognition of the GSDMD C-terminal domain.
  • Distinct catalytic groove occupancy was observed: the p22/p10 complex featured an interdomain linker (IDL) segment, while the p20/p10 complex had the GSDMD FLTD cleavage site in the groove.

Conclusions:

  • The distinct structural organizations of caspase-4/GSDMD complexes explain how different autoprocessing states mediate GSDMD cleavage.
  • These findings provide a structural framework for understanding GSDMD recognition by caspase-4, crucial for inflammasome signaling.
  • The study clarifies the molecular mechanisms underlying pyroptosis initiation via non-canonical inflammasome activation.
Keywords:
caspase-4cryo-EMgasdermin Dinterdomain linkerstepwise maturation

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