A tale of the epidermal growth factor receptor: The quest for structural resolution on cells.
The challenge of determining the architecture and geometry of oligomers of the epidermal growth factor receptor (EGFR) on the cell surface has been approached using a variety of biochemical and biophysical methods. This review is intended to provide a narrative of how key concepts in the field of EGFR research have evolved over the years, from the origins of the prevalent EGFR signalling dimer hypothesis through to the development and implementation of methods that are now challenging the conventional view. The synergy between X-ray crystallography and cellular fluorescence microscopy has become particularly important, precisely because the results from these two methods diverged and highlighted the complexity of the challenge. We illustrate how developments in super-resolution microscopy are now bridging this gap. Exciting times lie ahead where knowledge of the nature of the complexes can assist with the development of a new generation of anti-cancer drugs.
Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Harwell Campus, Didcot, Oxfordshire OX11 0FA, United Kingdom.
Christopher J
CJ
Tynan
Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Harwell Campus, Didcot, Oxfordshire OX11 0FA, United Kingdom.
Valentina
V
Lo Schiavo
Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Harwell Campus, Didcot, Oxfordshire OX11 0FA, United Kingdom.
Laura
L
Zanetti-Domingues
Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Harwell Campus, Didcot, Oxfordshire OX11 0FA, United Kingdom.
Sarah R
SR
Needham
Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Harwell Campus, Didcot, Oxfordshire OX11 0FA, United Kingdom.
Selene K
SK
Roberts
Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Harwell Campus, Didcot, Oxfordshire OX11 0FA, United Kingdom.
Michael
M
Hirsch
Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Harwell Campus, Didcot, Oxfordshire OX11 0FA, United Kingdom.
Daniel J
DJ
Rolfe
Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Harwell Campus, Didcot, Oxfordshire OX11 0FA, United Kingdom.
Dimitrios
D
Korovesis
Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Harwell Campus, Didcot, Oxfordshire OX11 0FA, United Kingdom.
David T
DT
Clarke
Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Harwell Campus, Didcot, Oxfordshire OX11 0FA, United Kingdom. Electronic address: marisa.martin-fernandez@stfc.ac.uk.
Marisa L
ML
Martin-Fernandez
D000494:Allosteric Regulation; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D018360:Crystallography, X-Ray / Q000379:methods*; D004331:Drosophila melanogaster / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure*; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods*; D006801:Humans; D008856:Microscopy, Fluorescence / Q000379:methods*; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D055503:Protein Multimerization; D015398:Signal Transduction
D000970:Antineoplastic Agents; C512478:EGFR protein, human; D066246:ErbB Receptors
EGFR; FRET; Membrane protein structure; Receptor tyrosine kinase; Signal transduction; Single molecule fluorescence microscopy; Super-resolution microscopy