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Structure insight of GSDMD reveals the basis of GSDMD autoinhibition in cell pyroptosis

Siyun Kuang1, Jun Zheng1, Hui Yang1

  • 1State Key Laboratory of Genetic Engineering, School of Life Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200438, China.

Proceedings of the National Academy of Sciences of the United States of America
|September 21, 2017
PubMed

Insights

Gasdermin D (GSDMD) protein structures were revealed, showing how it forms pores for cell pyroptosis. This research uncovers GSDMD

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Structural Biology

Background:

  • Gasdermin D (GSDMD) is crucial for initiating programmed cell death known as pyroptosis.
  • GSDMD's role in pyroptosis involves lipid binding and pore formation, triggered by infections and danger signals.
  • Detailed structural insights into GSDMD's mechanism have been lacking.

Purpose of the Study:

  • To determine the crystal structure of the C-terminal domain of human GSDMD (GSDMD-C).
  • To elucidate the autoinhibited conformation of GSDMD in solution.
  • To investigate the functional roles of GSDMD domains in pyroptosis and antimicrobial activity.

Main Methods:

  • X-ray crystallography to resolve the GSDMD-C structure at 2.64-Å resolution.
  • Small-angle X-ray scattering (SAXS) to determine the overall GSDMD conformation in solution.
  • Site-directed mutagenesis (e.g., F283A, F283R) and in vitro assays to assess protein function and cell death induction.

Main Results:

  • The crystal structure of GSDMD-C revealed an autoinhibited conformation where GSDMD-C interacts with GSDMD-N.
  • Mutations in key residues (F283A/R) and alterations in the GSDMD-C/N interaction region affected cell death.
  • A specific GSDMD segment demonstrated potent in vitro antibacterial activity against *E. coli* and *M. Smegmatis*.

Conclusions:

  • GSDMD-C functions as an auto-inhibition regulator, maintaining GSDMD in an inactive state.
  • Upon caspase cleavage, GSDMD-N is released, exposing a charged surface that facilitates oligomerization and pore formation.
  • GSDMD possesses direct antimicrobial capabilities, highlighting its multifaceted role in host defense.
Keywords:
antibacterial activityautoinhibitioncrystal structuregasdermin D

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