Sublytic gasdermin-D pores captured in atomistic molecular simulations.

ABSTRACT: Gasdermin-D (GSDMD) is the ultimate effector of pyroptosis, a form of programmed cell death associated with pathogen invasion and inflammation. After proteolytic cleavage by caspases, the GSDMD N-terminal domain (GSDMD^NT) assembles on the inner leaflet of the plasma membrane and induces the formation of membrane pores. We use atomistic molecular dynamics simulations to study GSDMD^NT monomers, oligomers, and rings in an asymmetric plasma membrane mimetic. We identify distinct interaction motifs of GSDMD^NT with phosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂) and phosphatidylserine (PS) headgroups and describe their conformational dependence. Oligomers are stabilized by shared lipid binding sites between neighboring monomers acting akin to double-

SUBMITTER: Schaefer SL 

PROVIDER: S-EPMC9699695 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature