PDF(Pubmed)
Abstract：
The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell-cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize to the plasma membrane and, upon cell-cell contact, form extensive signaling assemblies at the contact sites. The Ephs and the ephrins are divided into A and B subclasses based on their sequence conservation and affinities for each other. The molecular details of Eph-ephrin recognition have been previously revealed and it has been documented that ephrin binding induces higher-order Eph assemblies, which are essential for full biological activity, via multiple, distinct Eph-Eph interfaces. One Eph-Eph interface type is characterized by a homotypic, head-to-tail interaction between the ligand-binding and the fibronectin domains of two adjacent Eph molecules. While the previous Eph ectodomain structural studies were focused on A class receptors, we now report the crystal structure of the full ectodomain of EphB2, revealing distinct and unique head-to-tail receptor-receptor interactions. The EphB2 structure and structure-based mutagenesis document that EphB2 uses the head-to-tail interactions as a novel autoinhibitory control mechanism for regulating downstream signaling and that these interactions can be modulated by posttranslational modifications.
摘要：
Eph受体酪氨酸激酶及其ephrin配体指导轴突寻路和神经元细胞迁移，以及调解许多其他细胞间的通信事件。它们的功能失调信号已经被证明会导致各种疾病，包括癌症.Ephs和ephrins都位于质膜，在细胞-细胞接触时，在联系点形成广泛的信号组件。Ephs和ephrins根据它们的序列保守性和彼此之间的亲和力分为A和B亚类。Eph-ephrin识别的分子细节先前已经被揭示，并且已经证明了ephrin结合诱导更高阶的Eph组装，这对完整的生物活性至关重要，通过多个，不同的Eph-Eph接口。一种Eph-Eph界面类型的特征是同型，配体结合和两个相邻Eph分子的纤连蛋白结构域之间的头对尾相互作用。虽然以前的Eph胞外域结构研究集中在A类受体上，我们现在报道了EphB2完整胞外域的晶体结构，揭示了独特的头对尾受体-受体相互作用。EphB2结构和基于结构的诱变证明了EphB2使用头对尾相互作用作为调节下游信号的新型自动抑制控制机制，并且这些相互作用可以通过翻译后修饰来调节。
