Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex

Juha P. Himanen, Yehuda Goldgur, Hui Miao, Eugene Myshkin, Hong Guo, Matthias Buck, My Nguyen, Kanagalaghatta R. Rajashankar, Bingcheng Wang, Dimitar B. Nikolov

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84 Scopus citations

Abstract

Ephrin (Eph) receptor tyrosine kinases fall into two subclasses (A and B) according to preferences for their ephrin ligands. All published structural studies of Eph receptor/ephrin complexes involve B-class receptors. Here, we present the crystal structures of an A-class complex between EphA2 and ephrin-A1 and of unbound EphA2. Although these structures are similar overall to their B-class counterparts, they reveal important differences that define subclass specificity. The structures suggest that the A-class Eph receptor/ephrin interactions involve smaller rearrangements in the interacting partners, better described by a 'lock-and-key'-type binding mechanism, in contrast to the 'induced fit' mechanism defining the B-class molecules. This model is supported by structure-based mutagenesis and by differential requirements for ligand oligomerization by the two subclasses in cell-based Eph receptor activation assays. Finally, the structure of the unligated receptor reveals a homodimer assembly that might represent EphA2-specific homotypic cell adhesion interactions.

Original languageEnglish
Pages (from-to)722-728
Number of pages7
JournalEMBO Reports
Volume10
Issue number7
DOIs
StatePublished - 16 Jun 2009
Externally publishedYes

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