title: Insights into Eph receptor tyrosine kinase activation from crystal structures of the EphA4 ectodomain and its complex with ephrin-A5.
abstract: Eph receptor tyrosine kinases and their ephrin ligands mediate cell signaling during normal and oncogenic development. Eph signaling is initiated in a multistep process leading to the assembly of higher-order Eph/ephrin clusters that set off bidirectional signaling in interacting cells. Eph and ephrins are divided in two subclasses based on their abilities to bind and activate each other and on sequence conservation. EphA4 is an exception to the general rule because it can be activated by both A- and B-class ephrin ligands. Here we present high-resolution structures of the complete EphA4 ectodomain and its complexes with ephrin-A5. The structures reveal how ligand binding promotes conformational changes in the EphA4 ligand-binding domain allowing the formation of signaling clusters at the sites of cell-cell contact. In addition, the structural data, combined with structure-based mutagenesis, reveal a previously undescribed receptor-receptor interaction between the EphA4 ligand-binding and membrane-proximal fibronectin domains, which is functionally important for efficient receptor activation.
authors: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Kai
authors: K
authors: Xu
authors: Dorothea
authors: D
authors: Tzvetkova-Robev
authors: Yan
authors: Y
authors: Xu
authors: Yehuda
authors: Y
authors: Goldgur
authors: Yee-Peng
authors: YP
authors: Chan
authors: Juha P
authors: JP
authors: Himanen
authors: Dimitar B
authors: DB
authors: Nikolov
mesh_terms: D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D036386:Ephrin-A5 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D036122:Receptor, EphA4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D036386:Ephrin-A5; D036122:Receptor, EphA4
keywords: crystallography; phosphorylation; protein; transmembrane
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