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Science. 2015 Oct 23;350(6259):399-404. doi: 10.1126/science.aac5489. Epub 2015 Oct 8.

Structural and biochemical basis for induced self-propagation of NLRC4.

Author information

1
Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China.
2
State Key Laboratory of Biomembrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
3
Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China.
4
National Institute of Biological Sciences, Beijing 102206, China.
5
State Key Laboratory of Biomembrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. chaijj@tsinghua.edu.cn suisf@mail.tsinghua.edu.cn.
6
Ministry of Education Key Laboratory of Protein Science, Center for Structural Biology, School of Life Sciences, Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China. chaijj@tsinghua.edu.cn suisf@mail.tsinghua.edu.cn.

Abstract

Responding to stimuli, nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs) oligomerize into multiprotein complexes, termed inflammasomes, mediating innate immunity. Recognition of bacterial pathogens by NLR apoptosis inhibitory proteins (NAIPs) induces NLR family CARD domain-containing protein 4 (NLRC4) activation and formation of NAIP-NLRC4 inflammasomes. The wheel-like structure of a PrgJ-NAIP2-NLRC4 complex determined by cryogenic electron microscopy at 6.6 angstrom reveals that NLRC4 activation involves substantial structural reorganization that creates one oligomerization surface (catalytic surface). Once activated, NLRC4 uses this surface to catalyze the activation of an inactive NLRC4, self-propagating its active conformation to form the wheel-like architecture. NAIP proteins possess a catalytic surface matching the other oligomerization surface (receptor surface) of NLRC4 but not those of their own, ensuring that one NAIP is sufficient to initiate NLRC4 oligomerization.

PMID:
26449475
DOI:
10.1126/science.aac5489
[Indexed for MEDLINE]
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