EGFR oligomerization organizes kinase-active dimers into competent signalling platformsMore about Open Access at the Crick
Authors listSarah R Needham Selene K Roberts Anton Arkhipov Venkatesh P Mysore Christopher J Tynan Laura C Zanetti-Domingues Eric T Kim Valeria Losasso Dimitrios Korovesis Michael Hirsch Daniel J Rolfe David T Clarke Martyn D Winn Alireza Lajevardipour Andrew HA Clayton Linda J Pike Michela Perani Peter Parker Yibing Shan David E Shaw Marisa L Martin-Fernandez
Epidermal growth factor receptor (EGFR) signalling is activated by ligand-induced receptor dimerization. Notably, ligand binding also induces EGFR oligomerization, but the structures and functions of the oligomers are poorly understood. Here, we use fluorophore localization imaging with photobleaching to probe the structure of EGFR oligomers. We find that at physiological epidermal growth factor (EGF) concentrations, EGFR assembles into oligomers, as indicated by pairwise distances of receptor-bound fluorophore-conjugated EGF ligands. The pairwise ligand distances correspond well with the predictions of our structural model of the oligomers constructed from molecular dynamics simulations. The model suggests that oligomerization is mediated extracellularly by unoccupied ligand-binding sites and that oligomerization organizes kinase-active dimers in ways optimal for auto-phosphorylation in trans between neighbouring dimers. We argue that ligand-induced oligomerization is essential to the regulation of EGFR signalling.
Journal Nature Communications