EGFR oligomerization organizes kinase-active dimers into competent signalling platforms

Nat Commun. 2016 Oct 31:7:13307. doi: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Artifacts
  • Binding Sites
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / chemistry*
  • ErbB Receptors / metabolism*
  • Fluorescence Resonance Energy Transfer
  • Ligands
  • Molecular Dynamics Simulation
  • Phosphorylation
  • Protein Domains
  • Protein Multimerization
  • Signal Transduction

Substances

  • Ligands
  • Epidermal Growth Factor
  • ErbB Receptors