title: Crystal structure of NLRC4 reveals its autoinhibition mechanism.
abstract: Nucleotide-binding and oligomerization domain-like receptor (NLR) proteins oligomerize into multiprotein complexes termed inflammasomes when activated. Their autoinhibition mechanism remains poorly defined. Here, we report the crystal structure of mouse NLRC4 in a closed form. The adenosine diphosphate-mediated interaction between the central nucleotide-binding domain (NBD) and the winged-helix domain (WHD) was critical for stabilizing the closed conformation of NLRC4. The helical domain HD2 repressively contacted a conserved and functionally important α-helix of the NBD. The C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. Disruption of ADP-mediated NBD-WHD or NBD-HD2/NBD-LRR interactions resulted in constitutive activation of NLRC4. Together, our data reveal the NBD-organized cooperative autoinhibition mechanism of NLRC4 and provide insight into its activation.
authors.affiliation: School of Life Sciences, Tsinghua University, and Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
authors.forename: Zehan
authors.initials: Z
authors.lastname: Hu
authors.forename: Chuangye
authors.initials: C
authors.lastname: Yan
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Liu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Huang
authors.forename: Rui
authors.initials: R
authors.lastname: Ma
authors.forename: Chenlu
authors.initials: C
authors.lastname: Zhang
authors.forename: Ruiyong
authors.initials: R
authors.lastname: Wang
authors.forename: Yueteng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fabio
authors.initials: F
authors.lastname: Martinon
authors.forename: Di
authors.initials: D
authors.lastname: Miao
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wang
authors.forename: Junbiao
authors.initials: J
authors.lastname: Chang
authors.forename: Jijie
authors.initials: J
authors.lastname: Chai
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D051379:Mice; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; C512299:Ipaf protein, mouse; D000244:Adenosine Diphosphate