Structures of the Gasdermin D C-Terminal Domains Reveal Mechanisms of Autoinhibition.

Structure 2018 05 22;26(5):778-784.e3. Epub 2018 Mar 22.

Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address:

Pyroptosis is an inflammatory form of programmed cell death that plays important roles in immune protection against infections and in inflammatory disorders. Gasdermin D (GSDMD) is an executor of pyroptosis upon cleavage by caspases-1/4/5/11 following canonical and noncanonical inflammasome activation. GSDMD N-terminal domain assembles membrane pores to induce cytolysis, whereas its C-terminal domain inhibits cell death through intramolecular association with the N domain. The molecular mechanisms of autoinhibition for GSDMD are poorly characterized. Here we report the crystal structures of the human and murine GSDMD C-terminal domains, which differ from those of the full-length murine GSDMA3 and the human GSDMB C-terminal domain. Mutations of GSDMD C-domain residues predicted to locate at its interface with the N-domain enhanced pyroptosis. Our results suggest that GSDMDs may employ a distinct mode of intramolecular domain interaction and autoinhibition, which may be relevant to its unique role in pyroptosis downstream of inflammasome activation.

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http://dx.doi.org/10.1016/j.str.2018.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932255PMC
May 2018
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