EMBL Grenoble, 6 Rue Jules Horowitz, Grenoble 38042, France.
Cell Rep. 2013 Mar 28;3(3):734-46. doi: 10.1016/j.celrep.2013.01.034. Epub 2013 Feb 28.
Tank-binding kinase I (TBK1) plays a key role in the innate immune system by integrating signals from pattern-recognition receptors. Here, we report the X-ray crystal structures of inhibitor-bound inactive and active TBK1 determined to 2.6 Å and 4.0 Å resolution, respectively. The structures reveal a compact dimer made up of trimodular subunits containing an N-terminal kinase domain (KD), a ubiquitin-like domain (ULD), and an α-helical scaffold dimerization domain (SDD). Activation rearranges the KD into an active conformation while maintaining the overall dimer conformation. Low-resolution SAXS studies reveal that the missing C-terminal domain (CTD) extends away from the main body of the kinase dimer. Mutants that interfere with TBK1 dimerization show significantly reduced trans-autophosphorylation but retain the ability to bind adaptor proteins through the CTD. Our results provide detailed insights into the architecture of TBK1 and the molecular mechanism of activation.
Tank-binding kinase I (TBK1) 在先天免疫系统中发挥关键作用，通过整合模式识别受体的信号。在这里，我们报告了抑制剂结合的非活性和活性 TBK1 的 X 射线晶体结构，分别解析至 2.6 Å 和 4.0 Å 的分辨率。这些结构揭示了一个由三模块亚基组成的紧凑二聚体，包含一个 N 端激酶结构域（KD）、一个泛素样结构域（ULD）和一个α-螺旋支架二聚化结构域（SDD）。激活将 KD 构象重排成活性构象，同时保持整体二聚体构象。低分辨率 SAXS 研究表明，缺失的 C 端结构域（CTD）从激酶二聚体的主体延伸出来。干扰 TBK1 二聚化的突变体显示出明显降低的转磷酸化，但仍能通过 CTD 结合衔接蛋白。我们的结果提供了 TBK1 结构和激活分子机制的详细见解。
