EGFR oligomerization organizes kinase-active dimers into competent signalling platforms
Open Access
- 31 October 2016
- journal article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 7 (1), 13307
- https://doi.org/10.1038/ncomms13307
Abstract
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.Keywords
This publication has 73 references indexed in Scilit:
- Measuring EGFR Separations on Cells with ∼10 nm Resolution via Fluorophore Localization Imaging with PhotobleachingPLOS ONE, 2013
- Conformational Coupling across the Plasma Membrane in Activation of the EGF ReceptorCell, 2013
- Architecture and Membrane Interactions of the EGF ReceptorCell, 2013
- Cholesterol Induces Uneven Curvature of Asymmetric Lipid BilayersThe Scientific World Journal, 2013
- Minimal Model of Plasma Membrane Heterogeneity Requires Coupling Cortical Actin to CriticalityBiophysical Journal, 2011
- Cell Signaling by Receptor Tyrosine KinasesCell, 2010
- Improved side‐chain torsion potentials for the Amber ff99SB protein force fieldProteins-Structure Function and Bioinformatics, 2010
- An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor ReceptorCell, 2006
- Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular DomainsCell, 2002
- Crystal Structure of a Truncated Epidermal Growth Factor Receptor Extracellular Domain Bound to Transforming Growth Factor αCell, 2002