IRAK4 dimerization and trans-autophosphorylation are induced by Myddosome assembly.
IRAK4 dimerization and trans-autophosphorylation are induced by Myddosome assembly.
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DOI：
10.1016/j.molcel.2014.08.006
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发表时间：
2014-09-18
期刊：
影响因子：
16
通讯作者：
Wu, Hao
中科院分区：
文献类型：
--
作者：
Ferrao, Ryan;Zhou, Hao;Shan, Yibing;Liu, Qun;Li, Qiubai;Shaw, David E.;Li, Xiaoxia;Wu, Hao
Trans -autophosphorylation is among the most prevalent means of protein kinase activation, yet its molecular basis is poorly defined. In Toll-like receptor and interleukin-1 receptor signaling pathways, the kinase IRAK4 is recruited to the membrane proximal adapter MyD88 through death domain (DD) interactions, forming the oligomeric Myddosome and mediating NF-κB activation. Here we show that unphosphorylated IRAK4 dimerizes in solution with a Kd of 2.5 μM and that Myddosome assembly greatly enhances IRAK4 kinase domain (KD) autophosphorylation at sub-Kd concentrations. The crystal structure of the unphosphorylated IRAK4KD dimer captures a conformation that appears to represent the actual trans-autophosphorylation reaction, with the activation loop phosphosite of one IRAK4 monomer precisely positioned for phosphotransfer by its partner. We show dimerization is crucial for IRAK4 autophosphorylation in vitro and ligand-dependent signaling in cells. These studies identify a mechanism for oligomerization-driven allosteric autoactivation of IRAK4 that may be general to other kinases activated by autophosphorylation.
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