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

Elena Seiradake, Karl Harlos, Geoff Sutton, Alexandru R Aricescu, E. Yvonne Jones

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)398-402
Number of pages5
JournalNature Structural & Molecular Biology
Volume17
Issue number4
DOIs
Publication statusPublished - Apr 2010

Keywords / Materials (for Non-textual outputs)

  • Ephrins
  • Humans
  • LIGANDS
  • Models, Molecular
  • Protein Conformation
  • Receptor, EphA2
  • Signal Transduction

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