title: Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism.
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(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 Ki on caspase-1(CARD) polymerization in vitro and inflammasome activation in cells. Whereas caspase-1(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.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Alvin
authors.initials: A
authors.lastname: Lu
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Florian I
authors.identifier: 0000-0002-9979-9769
authors.initials: FI
authors.lastname: Schmidt
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yin
authors.affiliation: Center for Quantitative Biology, Peking-Tsinghua Joint Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing, China.|Department of Cancer Immunology and Virology, Intel Parallel Computing Center for Structural Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Shuobing
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Tian-Min
authors.initials: TM
authors.lastname: Fu
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Tong
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
authors.affiliation: Center for Quantitative Biology, Peking-Tsinghua Joint Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing, China.|Department of Cancer Immunology and Virology, Intel Parallel Computing Center for Structural Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Youdong
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D020170:Caspase 1 / Q000737:chemistry*; D020134:Catalytic Domain; D002460:Cell Line; D017124:Conserved Sequence; D020285:Cryoelectron Microscopy; D006801:Humans; D006860:Hydrogen Bonding; D058847:Inflammasomes / Q000378:metabolism; D008958:Models, Molecular; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D058105:Polymerization; D000072756:Protein Conformation, alpha-Helical; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D020170:Caspase 1