Abstract: |
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. Herewe present high-resolution structures of the complete EphA2 ectodomain 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. |
Keywords: |
signal transduction; protein function; cell line; protein interaction; molecular mechanics; amino acid sequence; molecular sequence data; recombinant proteins; models, molecular; crystallography, x-ray; protein structure, tertiary; multiprotein complexes; binding sites; ephrin receptor a2; protein structure; site directed mutagenesis; ligand binding; protein structure, secondary; ephrin receptor a1; oligomerization; ephrin-a1; ephrin receptor a5; cell-cell attraction and repulsion; eph receptor clustering; ephrin-a5; receptor, epha1; receptor, epha2
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