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Crystal Structure of NLRC4 Reveals Its Autoinhibition Mechanism

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Science  13 Jun 2013:
1236381
DOI: 10.1126/science.1236381

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Abstract

NOD-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 the mouse NLRC4 in a closed form. The ADP-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.

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