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

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The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers. / Zanetti-Domingues, Laura C.; Korovesis, Dimitrios; Needham, Sarah R.; Tynan, Christopher J.; Sagawa, Shiori; Roberts, Selene K.; Kuzmanic, Antonija; Ortiz-Zapater, Elena; Jain, Purvi; Roovers, Rob C.; Lajevardipour, Alireza; van Bergen en Henegouwen, Paul M.P.; Santis, George; Clayton, Andrew H.A.; Clarke, David T.; Gervasio, Francesco L.; Shan, Yibing; Shaw, David E.; Rolfe, Daniel J.; Parker, Peter J.; Martin-Fernandez, Marisa L.

In: Nature Communications, Vol. 9, No. 1, 4325, 01.12.2018.

Research output: Contribution to journalArticle

Harvard

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

APA

Zanetti-Domingues, L. C., Korovesis, D., Needham, S. R., Tynan, C. J., Sagawa, S., Roberts, S. K., ... Martin-Fernandez, M. L. (2018). The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers. Nature Communications, 9(1), [4325]. https://doi.org/10.1038/s41467-018-06632-0

Vancouver

Zanetti-Domingues LC, Korovesis D, Needham SR, Tynan CJ, Sagawa S, Roberts SK et al. The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers. Nature Communications. 2018 Dec 1;9(1). 4325. https://doi.org/10.1038/s41467-018-06632-0

Author

Zanetti-Domingues, Laura C. ; Korovesis, Dimitrios ; Needham, Sarah R. ; Tynan, Christopher J. ; Sagawa, Shiori ; Roberts, Selene K. ; Kuzmanic, Antonija ; Ortiz-Zapater, Elena ; Jain, Purvi ; Roovers, Rob C. ; Lajevardipour, Alireza ; van Bergen en Henegouwen, Paul M.P. ; Santis, George ; Clayton, Andrew H.A. ; Clarke, David T. ; Gervasio, Francesco L. ; Shan, Yibing ; Shaw, David E. ; Rolfe, Daniel J. ; Parker, Peter J. ; Martin-Fernandez, Marisa L. / The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers. In: Nature Communications. 2018 ; Vol. 9, No. 1.

Bibtex Download

@article{c8ce2dd4f72246a994ae78476d6b0ca9,
title = "The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers",
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.}",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-06632-0",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers

AU - Zanetti-Domingues, Laura C.

AU - Korovesis, Dimitrios

AU - Needham, Sarah R.

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

Y1 - 2018/12/1

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85055079700&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-06632-0

DO - 10.1038/s41467-018-06632-0

M3 - Article

C2 - 30337523

AN - SCOPUS:85055079700

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4325

ER -

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