Structural insights into the functions of TBK1 in innate antimicrobial immunity.
Structural insights into the functions of TBK1 in innate antimicrobial immunity.
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DOI：
10.1016/j.str.2013.04.025
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发表时间：
2013-07-02
期刊：
影响因子：
5.7
通讯作者：
Li, Pingwei
中科院分区：
文献类型：
--
作者：
Shu, Chang;Sankaran, Banumathi;Chaton, Catherine T.;Herr, Andrew B.;Mishra, Ashutosh;Peng, Junmin;Li, Pingwei
Tank-binding kinase 1（TBK 1）是一种丝氨酸/苏氨酸蛋白激酶，介导先天性抗微生物免疫。TBK 1参与TLR、RLR的信号传导和细胞溶质DNA的STING介导的传感。这些受体的刺激导致TBK 1的活化，TBK 1使干扰素调节因子IRF-3磷酸化。磷酸化IRF-3易位到细胞核中以启动IFN-β基因的转录。在这里，我们表明，TBK 1被激活的自磷酸化残基Ser 172。TBK 1与两种抑制剂结合的结构表明，TBK 1具有IκB激酶折叠，具有三个不同的结构域：激酶结构域、泛素样结构域和支架和二聚化结构域。然而，TBK 1单体及其二聚体的整体结构在三个结构域的排列和二聚体的形成方面与IKKβ不同。TBK 1在体外磷酸化IRF-3导致其寡聚化，并且残基Ser 386的磷酸化在IRF-3活化中起关键作用。
Tank-binding kinase 1 (TBK1) is a serine/threonine protein kinase mediating innate antimicrobial immunity. TBK1 is involved in the signaling of TLRs, RLRs, and STING-mediated sensing of cytosolic DNA. Stimulation of these receptors results in the activation of TBK1, which phosphorylates interferon regulatory factor IRF-3. Phosphorylated IRF-3 translocates into the nucleus to initiate the transcription of the IFN-β gene. Here we show that TBK1 is activated by autophosphorylation at residue Ser172. Structures of TBK1 bound to two inhibitors showed that TBK1 has the IκB kinase fold with three distinct domains: the kinase domain, the ubiquitin like domain, and the scaffold and dimerization domain. However, the overall structures of TBK1 monomer and its dimer are different from IKKβ in the arrangements of the three domains and in dimer formation. Phosphorylation of IRF-3 by TBK1 in vitro results in its oligomerization, and phosphorylation of residue Ser386 plays a key role in IRF-3 activation.
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