6cb8 | pdb_00006cb8
Cryo-EM structure of the Gasdermin A3 membrane pore
Structural highlights
Disease[GSDA3_MOUSE] Defects in Gsdma3 are the cause of a number of alopecia phenotypes, bareskin (Bsk), defolliculated (Dfl), finnegan (Fgn) reduced coat 2 (Rco2), Rex-denuded (Re-den) and recombination induced mutation 3 (Rim3). These are dominant conditions characterized by loss of hair.[1] [2] [3] Function[GSDA3_MOUSE] Upon activation, mediates pyroptosis (PubMed:26375003). May play a role in the transition from catagen to telogen at the end of hair follicle morphogenesis (PubMed:15475261).[4] [5] Publication Abstract from PubMedGasdermins 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 A resolutions, and of a double-ring pore at 4.6 A 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. Cryo-EM structure of the gasdermin A3 membrane pore.,Ruan J, Xia S, Liu X, Lieberman J, Wu H Nature. 2018 May;557(7703):62-67. doi: 10.1038/s41586-018-0058-6. Epub 2018 Apr, 25. PMID:29695864[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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