Department of Biochemistry, Weill Cornell Medical College, New York, New York 10021, USA.
Nature. 2010 Jun 17;465(7300):885-90. doi: 10.1038/nature09121. Epub 2010 May 19.
MyD88, IRAK4 and IRAK2 are critical signalling mediators of the TLR/IL1-R superfamily. Here we report the crystal structure of the MyD88-IRAK4-IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs. Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. Composite binding sites are required for recruitment of the individual DDs in the complex, which are confirmed by mutagenesis and previously identified signalling mutations. Specificities in Myddosome formation are dictated by both molecular complementarity and correspondence of surface electrostatics. The MyD88-IRAK4-IRAK2 complex provides a template for Toll signalling in Drosophila and an elegant mechanism for versatile assembly and regulation of DD complexes in signal transduction.
MyD88、IRAK4 和 IRAK2 是 TLR/IL1-R 超家族的关键信号转导介质。在这里，我们报告了 MyD88-IRAK4-IRAK2 死亡结构域 (DD) 复合物的晶体结构，令人惊讶的是，它揭示了一个左手螺旋寡聚体，由 6 个 MyD88、4 个 IRAK4 和 4 个 IRAK2 DD 组成。这种螺旋信号塔的组装是分层次的，其中 MyD88 招募 IRAK4，而 MyD88-IRAK4 复合物招募 IRAK4 底物 IRAK2 或相关的 IRAK1。这些 Myddosome 复合物的形成使 IRAKs 的激酶结构域靠近进行磷酸化和激活。复合结合位点是复合物中单个 DD 招募所必需的，这一点通过突变和先前确定的信号转导突变得到了证实。Myddosome 形成的特异性由分子互补性和表面静电的对应性决定。MyD88-IRAK4-IRAK2 复合物为果蝇中的 Toll 信号提供了一个模板，并为信号转导中 DD 复合物的多功能组装和调节提供了一个优雅的机制。
