title: Structural and biochemical basis for induced self-propagation of NLRC4.
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.
authors.affiliation: 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.
authors.forename: Zehan
authors.initials: Z
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Chenlu
authors.initials: C
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Shilong
authors.initials: S
authors.lastname: Fan
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Shao
authors.affiliation: 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.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Sen-Fang
authors.initials: SF
authors.lastname: Sui
authors.affiliation: 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.
authors.forename: Jijie
authors.initials: J
authors.lastname: Chai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry; D002135:Calcium-Binding Proteins / Q000737:chemistry*; D002384:Catalysis; D020285:Cryoelectron Microscopy; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000737:chemistry*; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; C512299:Ipaf protein, mouse; C496802:Naip2 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein