The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers

Laura C. Zanetti-Domingues, Dimitrios Korovesis, Sarah R. Needham, Christopher J. Tynan, Shiori Sagawa, Selene K. Roberts, Antonija Kuzmanic, Elena Ortiz-Zapater, Purvi Jain, Rob C. Roovers, Alireza Lajevardipour, Paul M. P. Bergen en Henegouwen, George Santis, Andrew H. A. Clayton, David T. Clarke, Francesco L. Gervasio, Yibing Shan, David E. Shaw, Daniel J. Rolfe, Peter J. Parker and Marisa L. Martin-Fernandez ()
Additional contact information
Laura C. Zanetti-Domingues: STFC Rutherford Appleton Laboratory, Harwell Oxford
Dimitrios Korovesis: STFC Rutherford Appleton Laboratory, Harwell Oxford
Sarah R. Needham: STFC Rutherford Appleton Laboratory, Harwell Oxford
Christopher J. Tynan: STFC Rutherford Appleton Laboratory, Harwell Oxford
Shiori Sagawa: D. E. Shaw Research
Selene K. Roberts: STFC Rutherford Appleton Laboratory, Harwell Oxford
Antonija Kuzmanic: University College London
Elena Ortiz-Zapater: Kings College London
Purvi Jain: Utrecht University
Rob C. Roovers: Merus, LSI
Alireza Lajevardipour: Swinburne University of Technology
Paul M. P. Bergen en Henegouwen: Utrecht University
George Santis: Kings College London
Andrew H. A. Clayton: Swinburne University of Technology
David T. Clarke: STFC Rutherford Appleton Laboratory, Harwell Oxford
Francesco L. Gervasio: University College London
Yibing Shan: D. E. Shaw Research
David E. Shaw: D. E. Shaw Research
Daniel J. Rolfe: STFC Rutherford Appleton Laboratory, Harwell Oxford
Peter J. Parker: The Francis Crick Institute
Marisa L. Martin-Fernandez: STFC Rutherford Appleton Laboratory, Harwell Oxford

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data of monomer and dimer receptor fragments and does not explain how mutations achieve ligand-independent phosphorylation. Using a repertoire of imaging technologies and simulations we reveal an extracellular head-to-head interaction through which ligand-free receptor polymer chains of various lengths assemble. The architecture of the head-to-head interaction prevents kinase-mediated dimerisation. The latter, afforded by mutation or intracellular treatments, splits the autoinhibited head-to-head polymers to form stalk-to-stalk flexible non-extended dimers structurally coupled across the plasma membrane to active asymmetric tyrosine kinase dimers, and extended dimers coupled to inactive symmetric kinase dimers. Contrary to the previously proposed main autoinhibitory function of the inactive symmetric kinase dimer, our data suggest that only dysregulated species bear populations of symmetric and asymmetric kinase dimers that coexist in equilibrium at the plasma membrane under the modulation of the C-terminal domain.

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-018-06632-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06632-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-06632-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().