Structural and biochemical basis for induced self-propagation of NLRC4
Structural and biochemical basis for induced self-propagation of NLRC4
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NLRC4诱导自我繁殖的结构和生化基础
DOI：
10.1126/science.aac5489
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发表时间：
2015-10-23
期刊：
影响因子：
56.9
通讯作者：
Chai, Jijie
中科院分区：
文献类型：
--
作者：
Hu, Zehan;Zhou, Qiang;Chai, Jijie
细胞需要微生物配体结合来感知病原体（参见Liu和Xiao的观点）。与nod样受体家族的结合会触发称为炎症小体的大型蛋白质信号复合物的组装，导致感染细胞死亡并产生炎症介质。Hu等人和Zhang等人利用低温电子显微镜揭示了两种这样的受体的结构和生化基础：直接结合微生物配体的NAIP2和直接作用于下游的蛋白质NLRC4。下游炎性小体信号的自传播激活机制始于一个NAIP4分子直接与其微生物配体结合。然后，NAIP4催化10到12个NLRC4分子的活化，形成一个轮状结构。《科学》，本期399、404页；一种自催化自传播机制驱动NLRC4炎性小体的激活。[参见Liu and Xiao的观点]对刺激作出反应，核苷酸结合结构域和富含亮氨酸的重复序列蛋白（NLRs）寡聚成多蛋白复合物，称为炎症小体，介导先天免疫。NLR凋亡抑制蛋白（NAIPs）对细菌病原体的识别诱导NLR家族CARD结构域蛋白4 （NLRC4）的激活和NAIP-NLRC4炎症小体的形成。在6.6埃低温电镜下观察到的PrgJ-NAIP2-NLRC4络合物的轮状结构表明，NLRC4的活化涉及大量的结构重组，产生一个寡聚化表面（催化表面）。一旦被激活，NLRC4利用该表面催化非活性NLRC4的激活，自我传播其活性构象，形成轮状结构。NAIP蛋白具有与NLRC4的其他寡聚化表面（受体表面）匹配的催化表面，而不是它们自己的表面，确保一个NAIP足以启动NLRC4寡聚化。
Inflammasomes take the wheel Cells require microbial ligand binding to sense pathogens (see the Perspective by Liu and Xiao). Binding to the family of NOD-like receptors triggers the assembly of large protein signaling complexes called inflammasomes, leading infected cells to die and produce inflammatory mediators. Hu et al. and Zhang et al. use cryo–electron microscopy to uncover the structural and biochemical basis of two such receptors: NAIP2, which directly binds microbial ligands, and NLRC4, a protein functioning directly downstream. A self-propagating activation mechanism of downstream inflammasome signaling starts with one molecule of NAIP4 directly binding its microbial ligand. NAIP4 then catalyzes the activation of 10 to 12 NLRC4 molecules to form a wheel-like structure. Science, this issue p. 399, 404; see also p. 376 An autocatalytic self-propagating mechanism drives activation of the NLRC4 inflammasome. [Also see Perspective by Liu and Xiao] 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.