2. Academic Validation
  3. Caspase-1 Engages Full-Length Gasdermin D through Two Distinct Interfaces That Mediate Caspase Recruitment and Substrate Cleavage

Caspase-1 Engages Full-Length Gasdermin D through Two Distinct Interfaces That Mediate Caspase Recruitment and Substrate Cleavage

  • Immunity. 2020 Jul 14;53(1):106-114.e5. doi: 10.1016/j.immuni.2020.06.007.
Zhonghua Liu 1,  Chuanping Wang 1,  Jie Yang 2,  Yinghua Chen 3,  Bowen Zhou 1,  Derek W Abbott 1,  Tsan Sam Xiao 4
Affiliations

Affiliations

  • 1 Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
  • 2 Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd, TRY-21, La Jolla, CA 92037, USA.
  • 3 Protein Expression Purification Crystallization and Molecular Biophysics Core, Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
  • 4 Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: tsx@case.edu.
PMID: 32553275 DOI: 10.1016/j.immuni.2020.06.007
Abstract

The recognition and cleavage of gasdermin D (GSDMD) by inflammatory caspases-1, 4, 5, and 11 are essential steps in initiating Pyroptosis after inflammasome activation. Previous work has identified cleavage site signatures in substrates such as GSDMD, but it is unclear whether these are the sole determinants for Caspase engagement. Here we report the crystal structure of a complex between human Caspase-1 and the full-length murine GSDMD. In addition to engagement of the GSDMD N- and C-domain linker by the Caspase-1 active site, an anti-parallel β sheet at the Caspase-1 L2 and L2' loops bound a hydrophobic pocket within the GSDMD C-terminal domain distal to its N-terminal domain. This "exosite" interface endows an additional function for the GSDMD C-terminal domain as a caspase-recruitment module besides its role in autoinhibition. Our study thus reveals dual-interface engagement of GSDMD by Caspase-1, which may be applicable to Other physiological substrates of caspases.

Keywords

active site; crystal structure; dual site engagement; exosite; gasdermin D; inflammasome; inflammatory caspases; pyroptosis.

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