Insights into Eph Receptor Tyrosine Kinase Activation from Crystal Structures of the EphA4 Ectodomain and Its Complex with Ephrin-A5

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 Aug 21

PMID 23959867

Citations 47

Authors

Kai Xu

Dorothea Tzvetkova-Robev

Yan Xu

Yehuda Goldgur

Yee-Peng Chan

Juha P Himanen

Dimitar B Nikolov

Affiliations

Soon will be listed here.

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.

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