Crystal Structure of NLRC4 Reveals Its Autoinhibition Mechanism

被引：330

作者：

Hu, Zehan ^{[1
,2
,3
,4
]}

Yan, Chuangye ^{[1
,2
]}

Liu, Peiyuan ^{[1
,2
]}

Huang, Zhiwei ^{[5
]}

Ma, Rui ^{[1
,2
]}

Zhang, Chenlu ^{[1
,2
]}

Wang, Ruiyong ^{[6
]}

Zhang, Yueteng ^{[6
]}

Martinon, Fabio ^{[7
]}

Miao, Di ^{[1
,2
]}

Deng, Haiteng ^{[1
,2
]}

Wang, Jiawei ^{[1
,2
]}

Chang, Junbiao ^{[6
]}

Chai, Jijie ^{[1
,2
]}

机构：

[1] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China

[2] Tsinghua Peking Ctr Life Sci, Beijing 100084, Peoples R China

[3] Natl Inst Biol Sci, Beijing 102206, Peoples R China

[4] Beijing Normal Univ, Coll Life Sci, Beijing 100875, Peoples R China

[5] Harbin Inst Technol, Sch Life Sci & Biotechnol, Harbin 150080, Peoples R China

[6] Zhengzhou Univ, Coll Chem & Mol Engn, Zhengzhou 450001, Peoples R China

[7] Univ Lausanne, Dept Biochem, CH-1066 Lausanne, Switzerland

来源：

SCIENCE | 2013年 / 341卷 / 6142期

关键词：

III SECRETION APPARATUS; CAENORHABDITIS-ELEGANS; INFLAMMASOME RECEPTORS; FLAGELLIN; ACTIVATION; APOPTOSOME; CASPASE-1; APAF-1; DEATH; IPAF;

D O I：

10.1126/science.1236381

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 alpha-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.

引用

页码：172 / 175

页数：5

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