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

TLDR

Gasdermin D is a caspase substrate that mediates pyroptosis by binding lipids and forming pores, yet its detailed structure has not been resolved. The crystal structure of human GSDMD’s C‑terminal domain shows a loop inserting into the N‑terminal domain to stabilize the full protein, and a short segment capable of killing bacteria, providing insight into its role in innate immunity.

Abstract

Significance The protein gasdermin D (GSDMD) is the physiological substrate of inflammatory caspases and plays key roles in cell pyroptosis upon microbial infection and associated danger signals. GSDMD, as well as other gasdermin members, can bind lipid and form pore structures to induce pyroptosis. However, detailed structural information for GSDMD remains unknown. We have determined the crystal structure of the C-terminal domain of human GSDMD. The structure reveals that the first loop inserts into the N-terminal domain to help stabilize the full-length GSDMD conformation. Furthermore, we identify that one short segment is sufficient to kill bacteria and can act as a potential antimicrobial peptide. Thus, these findings offer a perspective for understanding the mechanism of GSDMD in innate immune defense.