Architecture of Eph receptor clusters

Juha-Pekka Himanen, Laila Yermekbayeva, Peter Warwick Janes, John R Walker, Kai Xu, Lakmal SK Atapattu Mudiyanselage, Kanagalaghatta R Rajashankar, Anneloes Mensinga, Martin Lackmann, Dimitar B Nikolov, Sirano Dhe-Paganon

Research output: Contribution to journalArticleResearchpeer-review

165 Citations (Scopus)

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. Here we 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.
Original languageEnglish
Pages (from-to)10860 - 10865
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number24
DOIs
Publication statusPublished - 2010

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