Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 17, Issue 4, Pages 398-U27Publisher
NATURE PORTFOLIO
DOI: 10.1038/nsmb.1782
Keywords
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Funding
- Cancer Research UK
- UK Medical Research Council
- Wellcome Trust [075491/Z/04]
- Cancer Research UK [10976] Funding Source: researchfish
- Medical Research Council [G0900084, G0500367, G0700232] Funding Source: researchfish
- MRC [G0500367, G0700232, G0900084] Funding Source: UKRI
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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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