title: EGFR oligomerization organizes kinase-active dimers into competent signalling platforms.
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.
authors: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford OX11 0QX, UK.
authors: Sarah R
authors: SR
authors: Needham
authors: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford OX11 0QX, UK.
authors: Selene K
authors: SK
authors: Roberts
authors: D.E. Shaw Research, New York, New York 10036, USA.
authors: Anton
authors: A
authors: Arkhipov
authors: D.E. Shaw Research, New York, New York 10036, USA.
authors: Venkatesh P
authors: VP
authors: Mysore
authors: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford OX11 0QX, UK.
authors: Christopher J
authors: CJ
authors: Tynan
authors: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford OX11 0QX, UK.
authors: Laura C
authors: LC
authors: Zanetti-Domingues
authors: D.E. Shaw Research, New York, New York 10036, USA.
authors: Eric T
authors: ET
authors: Kim
authors: Computational Science and Engineering Department, Science and Technology Facilities Council, Daresbury Laboratory, Warrington WA4 4AD, UK.
authors: Valeria
authors: V
authors: Losasso
authors: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford OX11 0QX, UK.
authors: Dimitrios
authors: D
authors: Korovesis
authors: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford OX11 0QX, UK.
authors: Michael
authors: M
authors: Hirsch
authors: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford OX11 0QX, UK.
authors: Daniel J
authors: DJ
authors: Rolfe
authors: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford OX11 0QX, UK.
authors: David T
authors: DT
authors: Clarke
authors: Computational Science and Engineering Department, Science and Technology Facilities Council, Daresbury Laboratory, Warrington WA4 4AD, UK.
authors: Martyn D
authors: MD
authors: Winn
authors: Centre for Micro-Photonics, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.
authors: Alireza
authors: 0000-0003-1925-6113
authors: A
authors: Lajevardipour
authors: Centre for Micro-Photonics, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.
authors: Andrew H A
authors: AH
authors: Clayton
authors: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: Linda J
authors: LJ
authors: Pike
authors: Division of Cancer Studies, King's College London, Guy's Medical School Campus, London SE1 1UL, UK.
authors: Michela
authors: M
authors: Perani
authors: Division of Cancer Studies, King's College London, Guy's Medical School Campus, London SE1 1UL, UK.|The Francis Crick Institute, Protein Phosphorylation Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors: Peter J
authors: PJ
authors: Parker
authors: D.E. Shaw Research, New York, New York 10036, USA.
authors: Yibing
authors: Y
authors: Shan
authors: D.E. Shaw Research, New York, New York 10036, USA.|Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
authors: David E
authors: DE
authors: Shaw
authors: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford OX11 0QX, UK.
authors: Marisa L
authors: ML
authors: Martin-Fernandez
mesh_terms: D000818:Animals; D016477:Artifacts; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D008024:Ligands; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D000072417:Protein Domains; D055503:Protein Multimerization; D015398:Signal Transduction
chemical_list: D008024:Ligands; D004815:Epidermal Growth Factor; D066246:ErbB Receptors