EGFR oligomerization organizes kinase-active dimers into competent signalling platforms

Sarah 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 H. A. Clayton, Linda J. Pike, Michela Perani, Peter J. Parker, Yibing Shan (), David E. Shaw () and Marisa L. Martin-Fernandez ()
Additional contact information
Sarah R. Needham: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford
Selene K. Roberts: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford
Anton Arkhipov: D.E. Shaw Research
Venkatesh P. Mysore: D.E. Shaw Research
Christopher J. Tynan: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford
Laura C. Zanetti-Domingues: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford
Eric T. Kim: D.E. Shaw Research
Valeria Losasso: Science and Technology Facilities Council, Daresbury Laboratory
Dimitrios Korovesis: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford
Michael Hirsch: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford
Daniel J. Rolfe: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford
David T. Clarke: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford
Martyn D. Winn: Science and Technology Facilities Council, Daresbury Laboratory
Alireza Lajevardipour: Centre for Micro-Photonics, Faculty of Science, Engineering and Technology, Swinburne University of Technology
Andrew H. A. Clayton: Centre for Micro-Photonics, Faculty of Science, Engineering and Technology, Swinburne University of Technology
Linda J. Pike: Washington University School of Medicine
Michela Perani: King’s College London, Guy’s Medical School Campus
Peter J. Parker: King’s College London, Guy’s Medical School Campus
Yibing Shan: D.E. Shaw Research
David E. Shaw: D.E. Shaw Research
Marisa L. Martin-Fernandez: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13307

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