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J. Biol. Chem., Vol. 280, Issue 28, 26526-26532, July 15, 2005

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Three Distinct Molecular Surfaces in Ephrin-A5 Are Essential for a Functional Interaction with EphA3^*

Bryan Day, Catherine To¶, Juha-Pekka Himanen||, Fiona M. Smith, Dimitar B. Nikolov||, Andrew W. Boyd**, and Martin Lackmann¶

From the Queensland Institute of Medical Research, P. O. Royal Brisbane Hospital 4029, Queensland, Australia, ^¶Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Victoria 3168, Australia, ^||Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and ^**Department of Medicine, University of Queensland, P. O. Royal Brisbane Hospital 4029, Queensland, Australia

Eph receptor tyrosine kinases (Ephs) function as molecular relays that interact with cell surface-bound ephrin ligands to direct the position of migrating cells. Structural studies revealed that, through two distinct contact surfaces on opposite sites of each protein, Eph and ephrin binding domains assemble into symmetric, circular heterotetramers. However, Eph signal initiation requires the assembly of higher order oligomers, suggesting additional points of contact. By screening a random library of EphA3 binding-compromised ephrin-A5 mutants, we have now determined ephrin-A5 residues that are essential for the assembly of high affinity EphA3 signaling complexes. In addition to the two interfaces predicted from the crystal structure of the homologous EphB2·ephrin-B2 complex, we identified a cluster of 10 residues on the ephrin-A5 E -helix, the E-F loop, the underlying H -strand, as well as the nearby B-C loop, which define a distinct third surface required for oligomerization and activation of EphA3 signaling. Together with a corresponding third surface region identified recently outside of the minimal ephrin binding domain of EphA3, our findings provide experimental evidence for the essential contribution of three distinct protein-interaction interfaces to assemble functional EphA3 signaling complexes.

Received for publication, May 5, 2005

The atomic coordinates and structure factors (code 1SHX) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by grants from the National Health and Medical Research Council of Australia (284428, 234707) (to M. L. and A. W. B.) and National Institutes of Health Grant RO1-NS38486 (to D. B. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

These authors made equal contributions to this work and are thus regarded as joint first authors.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, P.O. Box 13D, Monash University, Victoria 3800, Australia. Tel.: 613-9905-3738; Fax: 613-9905-3726; E-mail: martin.lackmann{at}med.monash.edu.au.

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