EGFR oligomerization organizes kinase-active dimers into competent signalling platforms

Sarah R. Needham; Selene K. Roberts; Anton Arkhipov; Venkatesh P. Mysore; Christopher J. Tynan; Laura C. Zanetti-Domingues; Eric T. Kim; Valeria Losasso; Dimitrios Korovesis; Michael Hirsch; Daniel J. Rolfe; David T. Clarke; Martyn D. Winn; Alireza Lajevardipour; Andrew H.A. Clayton; Linda J. Pike; Michela Perani; Peter J. Parker; Yibing Shan; David E. Shaw; Marisa L. Martin-Fernandez

doi:10.1038/ncomms13307

EGFR oligomerization organizes kinase-active dimers into competent signalling platforms

Sarah R. Needham, Selene K. Roberts, Anton Arkhipov, Venkatesh P. Mysore, Christopher J. Tynan, Laura C. Zanetti-Domingues, Eric T. Kim, Valeria Losasso, Dimitrios Korovesis, Michael Hirsch, Daniel J. Rolfe, David T. Clarke, Martyn D. Winn, Alireza Lajevardipour, Andrew H.A. Clayton, Linda J. Pike, Michela Perani, Peter J. Parker, Yibing Shan, David E. ShawMarisa L. Martin-Fernandez

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Abstract

Epidermal growth factor receptor (EGFR) signalling is activated by ligand-induced receptor dimerization. Notably, ligand binding also induces EGFR oligomerization, but the structures and functions of the oligomers are poorly understood. Here, we use fluorophore localization imaging with photobleaching to probe the structure of EGFR oligomers. We find that at physiological epidermal growth factor (EGF) concentrations, EGFR assembles into oligomers, as indicated by pairwise distances of receptor-bound fluorophore-conjugated EGF ligands. The pairwise ligand distances correspond well with the predictions of our structural model of the oligomers constructed from molecular dynamics simulations. The model suggests that oligomerization is mediated extracellularly by unoccupied ligand-binding sites and that oligomerization organizes kinase-active dimers in ways optimal for auto-phosphorylation in trans between neighbouring dimers. We argue that ligand-induced oligomerization is essential to the regulation of EGFR signalling.

Original language	English
Article number	13307
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13307
State	Published - Oct 31 2016

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Needham, S. R., Roberts, S. K., Arkhipov, A., Mysore, V. P., Tynan, C. J., Zanetti-Domingues, L. C., Kim, E. T., Losasso, V., Korovesis, D., Hirsch, M., Rolfe, D. J., Clarke, D. T., Winn, M. D., Lajevardipour, A., Clayton, A. H. A., Pike, L. J., Perani, M., Parker, P. J., Shan, Y., ... Martin-Fernandez, M. L. (2016). EGFR oligomerization organizes kinase-active dimers into competent signalling platforms. Nature communications, 7, Article 13307. https://doi.org/10.1038/ncomms13307

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title = "EGFR oligomerization organizes kinase-active dimers into competent signalling platforms",

abstract = "Epidermal growth factor receptor (EGFR) signalling is activated by ligand-induced receptor dimerization. Notably, ligand binding also induces EGFR oligomerization, but the structures and functions of the oligomers are poorly understood. Here, we use fluorophore localization imaging with photobleaching to probe the structure of EGFR oligomers. We find that at physiological epidermal growth factor (EGF) concentrations, EGFR assembles into oligomers, as indicated by pairwise distances of receptor-bound fluorophore-conjugated EGF ligands. The pairwise ligand distances correspond well with the predictions of our structural model of the oligomers constructed from molecular dynamics simulations. The model suggests that oligomerization is mediated extracellularly by unoccupied ligand-binding sites and that oligomerization organizes kinase-active dimers in ways optimal for auto-phosphorylation in trans between neighbouring dimers. We argue that ligand-induced oligomerization is essential to the regulation of EGFR signalling.",

author = "Needham, {Sarah R.} and Roberts, {Selene K.} and Anton Arkhipov and Mysore, {Venkatesh P.} and Tynan, {Christopher J.} and Zanetti-Domingues, {Laura C.} and Kim, {Eric T.} and Valeria Losasso and Dimitrios Korovesis and Michael Hirsch and Rolfe, {Daniel J.} and Clarke, {David T.} and Winn, {Martyn D.} and Alireza Lajevardipour and Clayton, {Andrew H.A.} and Pike, {Linda J.} and Michela Perani and Parker, {Peter J.} and Yibing Shan and Shaw, {David E.} and Martin-Fernandez, {Marisa L.}",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = oct,

day = "31",

doi = "10.1038/ncomms13307",

language = "English",

volume = "7",

journal = "Nature communications",

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Needham, SR, Roberts, SK, Arkhipov, A, Mysore, VP, Tynan, CJ, Zanetti-Domingues, LC, Kim, ET, Losasso, V, Korovesis, D, Hirsch, M, Rolfe, DJ, Clarke, DT, Winn, MD, Lajevardipour, A, Clayton, AHA, Pike, LJ, Perani, M, Parker, PJ, Shan, Y, Shaw, DE & Martin-Fernandez, ML 2016, 'EGFR oligomerization organizes kinase-active dimers into competent signalling platforms', Nature communications, vol. 7, 13307. https://doi.org/10.1038/ncomms13307

TY - JOUR

T1 - EGFR oligomerization organizes kinase-active dimers into competent signalling platforms

AU - Needham, Sarah R.

AU - Roberts, Selene K.

AU - Arkhipov, Anton

AU - Mysore, Venkatesh P.

AU - Tynan, Christopher J.

AU - Zanetti-Domingues, Laura C.

AU - Kim, Eric T.

AU - Losasso, Valeria

AU - Korovesis, Dimitrios

AU - Hirsch, Michael

AU - Rolfe, Daniel J.

AU - Clarke, David T.

AU - Winn, Martyn D.

AU - Lajevardipour, Alireza

AU - Clayton, Andrew H.A.

AU - Pike, Linda J.

AU - Perani, Michela

AU - Parker, Peter J.

AU - Shan, Yibing

AU - Shaw, David E.

AU - Martin-Fernandez, Marisa L.

PY - 2016/10/31

Y1 - 2016/10/31

N2 - Epidermal growth factor receptor (EGFR) signalling is activated by ligand-induced receptor dimerization. Notably, ligand binding also induces EGFR oligomerization, but the structures and functions of the oligomers are poorly understood. Here, we use fluorophore localization imaging with photobleaching to probe the structure of EGFR oligomers. We find that at physiological epidermal growth factor (EGF) concentrations, EGFR assembles into oligomers, as indicated by pairwise distances of receptor-bound fluorophore-conjugated EGF ligands. The pairwise ligand distances correspond well with the predictions of our structural model of the oligomers constructed from molecular dynamics simulations. The model suggests that oligomerization is mediated extracellularly by unoccupied ligand-binding sites and that oligomerization organizes kinase-active dimers in ways optimal for auto-phosphorylation in trans between neighbouring dimers. We argue that ligand-induced oligomerization is essential to the regulation of EGFR signalling.

AB - Epidermal growth factor receptor (EGFR) signalling is activated by ligand-induced receptor dimerization. Notably, ligand binding also induces EGFR oligomerization, but the structures and functions of the oligomers are poorly understood. Here, we use fluorophore localization imaging with photobleaching to probe the structure of EGFR oligomers. We find that at physiological epidermal growth factor (EGF) concentrations, EGFR assembles into oligomers, as indicated by pairwise distances of receptor-bound fluorophore-conjugated EGF ligands. The pairwise ligand distances correspond well with the predictions of our structural model of the oligomers constructed from molecular dynamics simulations. The model suggests that oligomerization is mediated extracellularly by unoccupied ligand-binding sites and that oligomerization organizes kinase-active dimers in ways optimal for auto-phosphorylation in trans between neighbouring dimers. We argue that ligand-induced oligomerization is essential to the regulation of EGFR signalling.

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DO - 10.1038/ncomms13307

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JO - Nature communications

JF - Nature communications

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ER -

EGFR oligomerization organizes kinase-active dimers into competent signalling platforms

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