Crystal Structure of NLRC4 Reveals Its Autoinhibition Mechanism

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 diphosph...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2013-07, Vol.341 (6142), p.172-175
Main Authors: Hu, Zehan, Yan, Chuangye, Liu, Peiyuan, Huang, Zhiwei, Ma, Rui, Zhang, Chenlu, Wang, Ruiyong, Zhang, Yueteng, Martinon, Fabio, Miao, Di, Deng, Haiteng, Wang, Jiawei, Chang, Junbiao, Chai, Jijie
Format: Article
Language:English
Subjects:
Activation
Adenosine diphosphate
Adenosine Diphosphate - chemistry
Adenosine triphosphatases
Animals
Apoptosis
Apoptosis Regulatory Proteins - antagonists & inhibitors
Apoptosis Regulatory Proteins - chemistry
Biological sciences
Calcium-Binding Proteins - antagonists & inhibitors
Calcium-Binding Proteins - chemistry
Cellular biology
Crystal structure
Crystallography, X-Ray
Dimers
Hydrogen bonds
Immune systems
Ligands
Mice
Molecules
Oligomerization
Pathogens
Protein Multimerization
Protein Structure, Secondary
Protein Structure, Tertiary
Protein subunits
Proteins
Recruitment
Secretions
Transfection
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1236381