Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism
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Ploegh_Molecular basis.pdf
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5.08 MB
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Author(s)
Lu, Alvin
Li, Yang
Schmidt, Florian I
Yin, Qian
Chen, Shuobing
Fu, Tian-Min
Tong, Alexander B
Mao, Youdong
Wu, Hao
Ploegh, Hidde
Date Issued
April 2016
Journal
Nature Structural & Molecular Biology
Publisher
Nature Publishing Group
Citation
Lu, Alvin et al. “Molecular Basis of Caspase-1 Polymerization and Its Inhibition by a New Capping Mechanism.” Nature Structural & Molecular Biology 23.5 (2016): 416–425.
Version
Author's final manuscript
Abstract
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-1[superscript CARD]) 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 K[subscript i] on caspase-1[superscript CARD] polymerization in vitro and inflammasome activation in cells. Whereas caspase-1[superscript CARD] 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1038/nsmb.3199
