Crystal structure of NLRC4 reveals its autoinhibition mechanism

Zehan Hu, Chuangye Yan, Peiyuan Liu, Zhiwei Huang, Rui Ma, Chenlu Zhang, Ruiyong Wang, Yueteng Zhang, Fabio Martinon, Di Miao, Haiteng Deng, Jiawei Wang, Junbiao Chang, Jijie Chai

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188 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)172-175
Number of pages4
JournalScience
Volume341
Issue number6142
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

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    Hu, Z., Yan, C., Liu, P., Huang, Z., Ma, R., Zhang, C., Wang, R., Zhang, Y., Martinon, F., Miao, D., Deng, H., Wang, J., Chang, J., & Chai, J. (2013). Crystal structure of NLRC4 reveals its autoinhibition mechanism. Science, 341(6142), 172-175. https://doi.org/10.1126/science.1236381