Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism
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 ol...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2017
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| Online Access: | http://hdl.handle.net/1721.1/108705 https://orcid.org/0000-0002-1090-6071 |
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| author | Lu, Alvin Li, Yang Schmidt, Florian I Yin, Qian Chen, Shuobing Fu, Tian-Min Tong, Alexander B Mao, Youdong Wu, Hao Ploegh, Hidde |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Lu, Alvin Li, Yang Schmidt, Florian I Yin, Qian Chen, Shuobing Fu, Tian-Min Tong, Alexander B Mao, Youdong Wu, Hao Ploegh, Hidde |
| author_sort | Lu, Alvin |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:33:42Z |
| format | Article |
| id | mit-1721.1/108705 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:33:42Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1087052022-10-01T09:47:52Z Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism Lu, Alvin Li, Yang Schmidt, Florian I Yin, Qian Chen, Shuobing Fu, Tian-Min Tong, Alexander B Mao, Youdong Wu, Hao Ploegh, Hidde Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Ploegh, Hidde 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. 2017-05-05T17:52:12Z 2017-05-05T17:52:12Z 2016-04 2015-11 Article http://purl.org/eprint/type/JournalArticle 1545-9993 1545-9985 http://hdl.handle.net/1721.1/108705 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. https://orcid.org/0000-0002-1090-6071 en_US http://dx.doi.org/10.1038/nsmb.3199 Nature Structural & Molecular Biology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | Lu, Alvin Li, Yang Schmidt, Florian I Yin, Qian Chen, Shuobing Fu, Tian-Min Tong, Alexander B Mao, Youdong Wu, Hao Ploegh, Hidde Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism |
| title | Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism |
| title_full | Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism |
| title_fullStr | Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism |
| title_full_unstemmed | Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism |
| title_short | Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism |
| title_sort | molecular basis of caspase 1 polymerization and its inhibition by a new capping mechanism |
| url | http://hdl.handle.net/1721.1/108705 https://orcid.org/0000-0002-1090-6071 |
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