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Structurally encoded intraclass differences in EphA clusters drive distinct cell responses

DOI: 10.1038/nsmb.2617 DOI Help
PMID: 23812375 PMID Help

Authors: Elena Seiradake (Wellcome Trust Centre for Human Genetics, University of Oxford) , Andreas Schaupp (Max Planck Institute of Neurobiology) , Daniel Del Toro Ruiz (Max Planck Institute of Neurobiology) , Rainer Kaufmann (Wellcome Trust Centre for Human Genetics) , Nikolaos Mitakidis (Wellcome Trust Centre for Human Genetics, University of Oxford) , Karl Harlos (Wellcome Trust Centre for Human Genetics, University of Oxford) , A. Radu Aricescu (Wellcome Trust Centre for Human Genetics, University of Oxford) , RĂ¼diger Klein (Max Planck Institute of Neurobiology) , E. Yvonne Jones (Wellcome Trust Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 20 (8) , PAGES 958 - 964

State: Published (Approved)
Published: June 2013

Abstract: Functional outcomes of ephrin binding to Eph receptors (Ephs) range from cell repulsion to adhesion. Here we used cell collapse and stripe assays, showing contrasting effects of human ephrinA5 binding to EphA2 and EphA4. Despite equivalent ligand binding affinities, EphA4 triggered greater cell collapse, whereas EphA2-expressing cells adhered better to ephrinA5-coated surfaces. Chimeric receptors showed that the ectodomain is a major determinant of cell response. We report crystal structures of EphA4 ectodomain alone and in complexes with ephrinB3 and ephrinA5. These revealed closed clusters with a dimeric or circular arrangement in the crystal lattice, contrasting with extended arrays previously observed for EphA2 ectodomain. Localization microscopy showed that ligand-stimulated EphA4 induces smaller clusters than does EphA2. Mutant Ephs link these characteristics to interactions observed in the crystal lattices, suggesting a mechanism by which distinctive ectodomain surfaces determine clustering, and thereby signaling, properties.

Journal Keywords: COS; Cercopithecus; Crystallography; X-Ray; HEK293; HeLa; Humans; Mice; Microscopy; Fluorescence; Models; Molecular; MultiProtein; Receptors; Eph; Recombinant Fusion Proteins

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 16/08/2013 10:41

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)