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Science. 2013 Jul 12;341(6142):172-5. doi: 10.1126/science.1236381. Epub 2013 Jun 13.

Crystal structure of NLRC4 reveals its autoinhibition mechanism.

Author information

1
School of Life Sciences, Tsinghua University, and Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.

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.

PMID:
23765277
DOI:
10.1126/science.1236381
[Indexed for MEDLINE]
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