8GTJ

Crystal structure of IpaH7.8-LRR and GSDMB isoform-4 complex

8GTJ の概要

• エントリーDOI: 10.2210/pdb8gtj/pdb
• 分子名称: Isoform 4 of Gasdermin-B, Probable E3 ubiquitin-protein ligase ipaH7.8 (3 entities in total)
• 機能のキーワード: complex, effector, pyroptosis, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 149938.14

構造登録者

Zhong, X.,Hou, Y.J.,Ding, J. (登録日: 2022-09-08, 公開日: 2023-04-12, 最終更新日: 2023-11-29)

主引用文献

Zhong, X.,Zeng, H.,Zhou, Z.,Su, Y.,Cheng, H.,Hou, Y.,She, Y.,Feng, N.,Wang, J.,Shao, F.,Ding, J.
Structural mechanisms for regulation of GSDMB pore-forming activity.
Nature, 616:598-605, 2023

PubMed Abstract: Cytotoxic lymphocyte-derived granzyme A (GZMA) cleaves GSDMB, a gasdermin-family pore-forming protein, to trigger target cell pyroptosis. GSDMB and the charter gasdermin family member GSDMD have been inconsistently reported to be degraded by the Shigella flexneri ubiquitin-ligase virulence factor IpaH7.8 (refs. ). Whether and how IpaH7.8 targets both gasdermins is undefined, and the pyroptosis function of GSDMB has even been questioned recently. Here we report the crystal structure of the IpaH7.8-GSDMB complex, which shows how IpaH7.8 recognizes the GSDMB pore-forming domain. We clarify that IpaH7.8 targets human (but not mouse) GSDMD through a similar mechanism. The structure of full-length GSDMB suggests stronger autoinhibition than in other gasdermins. GSDMB has multiple splicing isoforms that are equally targeted by IpaH7.8 but exhibit contrasting pyroptotic activities. Presence of exon 6 in the isoforms dictates the pore-forming, pyroptotic activity in GSDMB. We determine the cryo-electron microscopy structure of the 27-fold-symmetric GSDMB pore and depict conformational changes that drive pore formation. The structure uncovers an essential role for exon-6-derived elements in pore assembly, explaining pyroptosis deficiency in the non-canonical splicing isoform used in recent studies. Different cancer cell lines have markedly different isoform compositions, correlating with the onset and extent of pyroptosis following GZMA stimulation. Our study illustrates fine regulation of GSDMB pore-forming activity by pathogenic bacteria and mRNA splicing and defines the underlying structural mechanisms.

PubMed: 36991125
DOI: 10.1038/s41586-023-05872-5

実験手法

X-RAY DIFFRACTION (2.7 Å)