Insights into Gasdermin D activation from the crystal structure of its C-terminal domain

Gasdermin D (GSDMD) is the central executioner of pyroptosis, a proinflammatory type of cell death. GSDMD is activated by the proinflammatory caspase-1 and caspase-11 via proteolytic cleavage in the linker connecting its N-terminal and C-terminal domain (GSDMDNterm, Cterm). The released N-terminal domain is sufficient to form pores in the plasma membrane, resulting in swelling and subsequent rupture of the cell. Here, we report the crystal structure of the autoinhibitory C-terminal domain of GSDMD at 2.04 [A] resolution to further analyse determinants of GSDMD activation. GSDMDCterm adopts a compact helical fold unique to gasdermin proteins. Structural analysis and comparison to other gasdermin proteins reveals a conserved key interface for interactions between GSDMDNterm and GSDMDCterm. Variations in two additional surface patches involved in interdomain interactions in full-length gasdermins suggest a role of these regions in modulating activation pathways, in agreement with biochemical characterization of different gasdermins.