Structure of the Nuclear Factor κB-inducing Kinase (NIK) Kinase Domain Reveals a Constitutively Active Conformation
Structure of the Nuclear Factor κB-inducing Kinase (NIK) Kinase Domain Reveals a Constitutively Active Conformation
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DOI：
10.1074/jbc.m112.366658
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发表时间：
2012-08-10
影响因子：
4.8
通讯作者：
Wang, Zhulun
中科院分区：
文献类型：
--
作者：
Liu, Jinsong;Sudom, Athena;Wang, Zhulun
NF-kappa B 诱导激酶 (NIK) 是非经典 NF-kappa B 信号通路的核心成分。过度的 NIK 活性与多种疾病有关，例如自身免疫性疾病和癌症。在这里，我们报告了截短的人 NIK 与腺苷 5'-O-（硫代三磷酸）复合物的第一个晶体结构，分辨率为 2.5 埃。这种截短的蛋白质是一种催化活性构建体，包括激酶结构域之前的 60 个残基、激酶结构域和之后的 20 个残基的 N 端延伸。该结构表明，NIK 激酶结构域在没有任何磷酸化的情况下呈现活性构象。结构分析揭示了 N 端延伸序列的独特作用，它可以稳定螺旋 α C 的活性方向，并使激酶结构域保持催化活性构象。我们的研究结果揭示了关于 NIK 是否是一种组成型活性激酶的长期争论。它们还为最近观察到的 NIK N 末端缺失突变体 (Delta N324) 的功能获得活性提供了分子基础，该突变体导致组成型非规范 NF-κ B 信号传导，增强 B 细胞粘附和抗凋亡能力。
NF-kappa B-inducing kinase (NIK) is a central component in the non-canonical NF-kappa B signaling pathway. Excessive NIK activity is implicated in various disorders, such as autoimmune conditions and cancers. Here, we report the first crystal structure of truncated human NIK in complex with adenosine 5'-O-(thiotriphosphate) at a resolution of 2.5 angstrom. This truncated protein is a catalytically active construct, including an N-terminal extension of 60 residues prior to the kinase domain, the kinase domain, and 20 residues afterward. The structure reveals that the NIK kinase domain assumes an active conformation in the absence of any phosphorylation. Analysis of the structure uncovers a unique role for the N-terminal extension sequence, which stabilizes helix alpha C in the active orientation and keeps the kinase domain in the catalytically competent conformation. Our findings shed light on the long-standing debate over whether NIK is a constitutively active kinase. They also provide a molecular basis for the recent observation of gain-of-function activity for an N-terminal deletion mutant (Delta N324) of NIK, leading to constitutive non-canonical NF-kappa B signaling with enhanced B-cell adhesion and apoptosis resistance.