An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly.

Journal article

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays.

Authors: Seiradake, E; Harlos, K; Sutton, G; Aricescu, A; Jones, E

• Publication status: Published
• Journal: Nature structural and molecular biology
• Volume: 17
• Issue: 4
• Pages: 398-402
• Publication date: 2010-04-01
• DOI: 10.1038/nsmb.1782
• EISSN: 1545-9985
• ISSN: 1545-9993
• Language: English
• Keywords: Ligands; Models, Molecular; Protein Conformation; Humans; Ephrins; Receptor, EphA2; Signal Transduction