School of Life Sciences, Tsinghua University, and Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
Science. 2013 Jul 12;341(6142):172-5. doi: 10.1126/science.1236381. Epub 2013 Jun 13.
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.
核苷酸结合寡聚化结构域样受体（NLR）蛋白在被激活时会寡聚形成多蛋白复合物，称为炎性体。然而，其自身抑制机制仍未被充分阐明。在此，我们报告了处于关闭构象的小鼠 NLRC4 的晶体结构。二磷酸腺苷（ADP）介导的中央核苷酸结合域（NBD）与翼状螺旋域（WHD）之间的相互作用对于稳定 NLRC4 的关闭构象至关重要。螺旋域 HD2 抑制性地与 NBD 的保守且具有重要功能的α-螺旋接触。C 端富含亮氨酸重复（LRR）结构域定位在 NBD 结构域的一侧，从而阻止 NLRC4 形成二聚体。破坏 ADP 介导的 NBD-WHD 或 NBD-HD2/NBD-LRR 相互作用会导致 NLRC4 的组成型激活。总之，我们的数据揭示了 NLRC4 的 NBD 组织的协同自身抑制机制，并为其激活提供了深入了解。
