An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly
Clicks: 169
ID: 273050
2010
Eph receptors are cell surface protein tyrosine kinases that mediate cell-cell communication. The crystal structure of the full ectodomain of unliganded human EphA2 (eEphA2) reveals that it forms linear arrays of staggered, parallel receptors, whereas that of eEphA2 in complex with ephrinA5 forms a more elaborate assembly with interfaces that are crucial for localization at cell-cell contacts and for activation-dependent degradation. 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.
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| Authors | Elena Seiradake,Karl Harlos,Geoff Sutton,A Radu Aricescu,E Yvonne Jones;Elena Seiradake;Karl Harlos;Geoff Sutton;A Radu Aricescu;E Yvonne Jones; |
| Journal | Nature structural & molecular biology |
| Year | 2010 |
| DOI | 10.1038/nsmb.1782 |
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