炎症体
吡喃结构域
细胞生物学
蛋白质丝
胞浆
化学
半胱氨酸蛋白酶1
半胱氨酸蛋白酶
半胱氨酸蛋白酶3
生物物理学
生物
生物化学
程序性细胞死亡
细胞凋亡
受体
酶
作者
Alvin Lu,Yang Li,Florian I. Schmidt,Qian Yin,Shuobing Chen,Tian‐Min Fu,Alex Tong,Hidde L. Ploegh,Youdong Mao,Hao Wu
摘要
The CARD-only protein INCA inhibits inflammasome assembly by capping caspase-1 CARD oligomers and preventing their further polymerization. Inflammasomes are cytosolic caspase-1-activation complexes that sense intrinsic and extrinsic danger signals, and trigger inflammatory responses and pyroptotic cell death. Homotypic interactions among Pyrin domains and caspase recruitment domains (CARDs) in inflammasome-complex components mediate oligomerization into filamentous assemblies. Several cytosolic proteins consisting of only interaction domains exert inhibitory effects on inflammasome assembly. In this study, we determined the structure of the human caspase-1 CARD domain (caspase-1CARD) filament by cryo-electron microscopy and investigated the biophysical properties of two caspase-1-like CARD-only proteins: human inhibitor of CARD (INCA or CARD17) and ICEBERG (CARD18). Our results reveal that INCA caps caspase-1 filaments, thereby exerting potent inhibition with low-nanomolar Ki on caspase-1CARD polymerization in vitro and inflammasome activation in cells. Whereas caspase-1CARD uses six complementary surfaces of three types for filament assembly, INCA is defective in two of the six interfaces and thus terminates the caspase-1 filament.
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