Cryo-EM structure of the gasdermin A3 membrane pore

Article

关键词: PYROPTOTIC CELL-DEATH;    PLASMA-MEMBRANE;    CRYSTAL-STRUCTURE;    REVEALS;    GSDMD;    CASPASE-11;    MECHANISM;    PROTEINS;    CLEAVAGE;    PERFORIN;   

DOI  :  10.1038/s41586-018-0058-6

来源: SCIE

【 摘 要 】

Gasdermins mediate inflammatory cell death after cleavage by caspases or other, unknown enzymes. The cleaved N-terminal fragments bind to acidic membrane lipids to form pores, but the mechanism of pore formation remains unresolved. Here we present the cryo-electron microscopy structures of the 27-fold and 28-fold single-ring pores formed by the N-terminal fragment of mouse GSDMA3 (GSDMA3-NT) at 3.8 and 4.2 angstrom resolutions, and of a double-ring pore at 4.6 angstrom resolution. In the 27-fold pore, a 108-stranded anti-parallel beta-barrel is formed by two beta-hairpins from each subunit capped by a globular domain. We identify a positively charged helix that interacts with the acidic lipid cardiolipin. GSDMA3-NT undergoes radical conformational changes upon membrane insertion to form long, membrane-spanning beta-strands. We also observe an unexpected additional symmetric ring of GSDMA3-NT subunits that does not insert into the membrane in the double-ring pore, which may represent a pre-pore state of GSDMA3-NT. These structures provide a basis that explains the activities of several mutant gasdermins, including defective mutants that are associated with cancer.

【 授权许可】

Free