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Published on: November 30, 2018
Crystal structure of NLRC4 reveals its autoinhibition mechanism
Zehan Hu1, Chuangye Yan, Peiyuan Liu
1School 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.
Insights
Nucleotide-binding and oligomerization domain-like receptor (NLR) proteins, like NLRC4, use a novel autoinhibition mechanism. This involves interactions between domains, keeping NLRC4 inactive until specific signals trigger its activation.
Area of Science:
- Immunology
- Structural Biology
- Molecular Biology
Background:
- Nucleotide-binding and oligomerization domain-like receptor (NLR) proteins form inflammasomes upon activation.
- The precise autoinhibition mechanisms of NLR proteins are not fully understood.
Purpose of the Study:
- To elucidate the autoinhibition mechanism of mouse NLRC4.
- To determine the structural basis for NLRC4's inactive state.
Main Methods:
- X-ray crystallography to obtain the closed-form structure of mouse NLRC4.
- Biochemical analysis to investigate domain interactions and their role in autoinhibition.
Main Results:
- The crystal structure revealed NLRC4 in a closed conformation.
- Adenosine diphosphate (ADP)-mediated interactions between the nucleotide-binding domain (NBD) and winged-helix domain (WHD), and between NBD and helical domain 2 (HD2)/leucine-rich repeat (LRR) domain, stabilize the autoinhibited state.
- Disrupting these interactions led to constitutive NLRC4 activation.
Conclusions:
- NLRC4 is autoinhibited through a cooperative mechanism organized by the NBD.
- Specific inter-domain interactions, stabilized by ADP, are crucial for maintaining NLRC4 in its inactive, monomeric state.
- Understanding this mechanism provides insights into inflammasome activation pathways.
