Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5

Forse, Garry Jason; Uson, Maria Loressa; Nasertorabi, Fariborz; Kolatkar, Anand; Lamberto, Ilaria; Pasquale, Elena Bianca; Kuhn, Peter; Lodola, Alessio

doi:10.1371/journal.pone.0127081

Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5

Journal Article · Wed May 20 00:00:00 EDT 2015 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0127081· OSTI ID:1252780

Forse, Garry Jason ^[1]; Uson, Maria Loressa ^[1]; Nasertorabi, Fariborz ^[1]; Kolatkar, Anand ^[1]; Lamberto, Ilaria ^[2]; Pasquale, Elena Bianca ^[3]; Kuhn, Peter ^[1]; Lodola, Alessio ^[4]

Univ. of Southern California, Los Angeles, CA (United States)
Sanford-Burnham Medical Research Inst., La Jolla, CA (United States)
Sanford-Burnham Medical Research Inst., La Jolla, CA (United States); Univ. of California San Diego, La Jolla, CA (United States)
Univ. of Parma (Italy)

he Eph receptor tyrosine kinase/ephrin ligand system regulates a wide spectrum of physiological processes, while its dysregulation has been implicated in cancer progression. The human EphA3 receptor is widely upregulated in the tumor microenvironment and is highly expressed in some types of cancer cells. Furthermore, EphA3 is among the most highly mutated genes in lung cancer and it is also frequently mutated in other cancers. We report the structure of the ligand-binding domain of the EphA3 receptor in complex with its preferred ligand, ephrin-A5. The structure of the complex reveals a pronounced tilt of the ephrin-A5 ligand compared to its orientation when bound to the EphA2 and EphB2 receptors and similar to its orientation when bound to EphA4. This tilt brings an additional area of ephrin-A5 into contact with regions of EphA3 outside the ephrin-binding pocket thereby enlarging the size of the interface, which is consistent with the high binding affinity of ephrin-A5 for EphA3. This large variation in the tilt of ephrin-A5 bound to different Eph receptors has not been previously observed for other ephrins.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: NIH

OSTI ID:: 1252780

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 5 Vol. 10; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5

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