Eph receptor tyrosine kinases and their ephrin ligands regulate cell navigation during normal and oncogenic development
Signaling of Ephs is initiated in a multistep process leading to the assembly of higher-order signaling clusters that set off bidirectional signaling in interacting cells
However, the structural and mechanistic details of this assembly remained undefined
Here we present high-resolution structures of the complete EphA2ectodomain and complexes with ephrin-A1 and A5 as the base unit of an Eph cluster
The structures reveal an elongated architecture with novel Eph / Eph interactions, both within and outside of the Eph ligand-binding domain , that suggest the molecular mechanism underlying Eph /ephrin clustering
Structure-function analysis, by using site-directed mutagenesis and cell-based signaling assays, confirms the importance of the identified oligomerization interfaces for Eph clustering