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. 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; Marisa L. Martin-Fernandez

doi:10.1038/s41467-018-06632-0

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. 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. ParkerMarisa L. Martin-Fernandez^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

66 Citations (Scopus)

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.

Original language	English
Article number	4325
Journal	Nature Communications
Volume	9
Issue number	1
Early online date	18 Oct 2018
DOIs	https://doi.org/10.1038/s41467-018-06632-0
Publication status	Published - 1 Dec 2018

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Zanetti-Domingues, L. C., Korovesis, D., Needham, S. R., Tynan, C. J., Sagawa, S., Roberts, S. K., Kuzmanic, A., Ortiz-Zapater, E., Jain, P., Roovers, R. C., Lajevardipour, A., van Bergen en Henegouwen, P. M. P., Santis, G., Clayton, A. H. A., Clarke, D. T., Gervasio, F. L., Shan, Y., Shaw, D. E., Rolfe, D. J., ... Martin-Fernandez, M. L. (2018). The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers. Nature Communications, 9(1), Article 4325. https://doi.org/10.1038/s41467-018-06632-0

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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.",

author = "Zanetti-Domingues, {Laura C.} and Dimitrios Korovesis and Needham, {Sarah R.} and Tynan, {Christopher J.} and Shiori Sagawa and Roberts, {Selene K.} and Antonija Kuzmanic and Elena Ortiz-Zapater and Purvi Jain and Roovers, {Rob C.} and Alireza Lajevardipour and {van Bergen en Henegouwen}, {Paul M.P.} and George Santis and Clayton, {Andrew H.A.} and Clarke, {David T.} and Gervasio, {Francesco L.} and Yibing Shan and Shaw, {David E.} and Rolfe, {Daniel J.} and Parker, {Peter J.} and Martin-Fernandez, {Marisa L.}",

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Zanetti-Domingues, LC, Korovesis, D, Needham, SR, Tynan, CJ, Sagawa, S, Roberts, SK, Kuzmanic, A, Ortiz-Zapater, E, Jain, P, Roovers, RC, Lajevardipour, A, van Bergen en Henegouwen, PMP, Santis, G, Clayton, AHA, Clarke, DT, Gervasio, FL, Shan, Y, Shaw, DE, Rolfe, DJ, Parker, PJ & Martin-Fernandez, ML 2018, 'The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers', Nature Communications, vol. 9, no. 1, 4325. https://doi.org/10.1038/s41467-018-06632-0

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AU - Zanetti-Domingues, Laura C.

AU - Korovesis, Dimitrios

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AU - Tynan, Christopher J.

AU - Sagawa, Shiori

AU - Roberts, Selene K.

AU - Kuzmanic, Antonija

AU - Ortiz-Zapater, Elena

AU - Jain, Purvi

AU - Roovers, Rob C.

AU - Lajevardipour, Alireza

AU - van Bergen en Henegouwen, Paul M.P.

AU - Santis, George

AU - Clayton, Andrew H.A.

AU - Clarke, David T.

AU - Gervasio, Francesco L.

AU - Shan, Yibing

AU - Shaw, David E.

AU - Rolfe, Daniel J.

AU - Parker, Peter J.

AU - Martin-Fernandez, Marisa L.

PY - 2018/12/1

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

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