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bioRxiv · 10.1101/187211

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

Anton, L.·Sborgi, L.·Hiller, S.·Broz, P.·Maier, T.
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Abstract

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.

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Anton, L., Sborgi, L., Hiller, S., Broz, P., Maier, T.. 2017-09-11. Insights into Gasdermin D activation from the crystal structure of its C-terminal domain. https://doi.org/10.1101/187211

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