Crystal Structure of NLRC4 Reveals Its Autoinhibition Mechanism
Crystal Structure of NLRC4 Reveals Its Autoinhibition Mechanism
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DOI：
10.1126/science.1236381
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发表时间：
2013-07-12
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;Yan, Chuangye;Chai, Jijie
核苷酸结合和寡聚化结构域样受体(NLR)蛋白在被激活时寡聚为多蛋白复合体，称为炎性小体。它们的自身抑制机制仍未得到很好的解释。在这里，我们以封闭形式报道了小鼠NLRC4的晶体结构。二磷酸腺苷介导的中心核苷酸结合区(NBD)和翼状螺旋结构域(WHD)之间的相互作用是稳定NLRC4封闭构象的关键。螺旋结构域HD2与NBD的保守且功能重要的α螺旋相接触。C末端富含亮氨酸重复序列(LRR)结构域被定位为空间封闭NBD结构域的一侧，从而以单体状态隔离NLRC4。ADP介导的NBD-WHD或NBD-HD2/NBD-LRR相互作用的中断导致NLRC4的结构性激活。综上所述，我们的数据揭示了NBD组织的NLRC4的协同自抑制机制，并为其激活提供了洞察力。
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 alpha-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.