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

Research output: Contribution to journalArticle

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. van 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 & 1 more Marisa L. Martin-Fernandez

Original languageEnglish
Article number4325
JournalNature Communications
Issue number1
Publication statusPublished - 1 Dec 2018

King's Authors


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.

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