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EGFR Dynamics Change during Activation in Native Membranes as Revealed by NMR

Kaplan, Mohammed and Narasimhan, Siddarth and de Heus, Cecilia and Mance, Deni and van Doorn, Sander and Houben, Klaartje and Popov-Čeleketić, Dušan and Damman, Reinier and Katrukha, Eugene A. and Jain, Purvi and Geerts, Willie J. C. and Heck, Albert J. R. and Folkers, Gert E. and Kapitein, Lukas C. and Lemeer, Simone and van Bergen en Henegouwen, Paul M. P. and Baldus, Marc (2016) EGFR Dynamics Change during Activation in Native Membranes as Revealed by NMR. Cell, 167 (5). pp. 1241-1251. ISSN 0092-8674. http://resolver.caltech.edu/CaltechAUTHORS:20170103-160614195

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Abstract

The epidermal growth factor receptor (EGFR) represents one of the most common target proteins in anti-cancer therapy. To directly examine the structural and dynamical properties of EGFR activation by the epidermal growth factor (EGF) in native membranes, we have developed a solid-state nuclear magnetic resonance (ssNMR)-based approach supported by dynamic nuclear polarization (DNP). In contrast to previous crystallographic results, our experiments show that the ligand-free state of the extracellular domain (ECD) is highly dynamic, while the intracellular kinase domain (KD) is rigid. Ligand binding restricts the overall and local motion of EGFR domains, including the ECD and the C-terminal region. We propose that the reduction in conformational entropy of the ECD by ligand binding favors the cooperative binding required for receptor dimerization, causing allosteric activation of the intracellular tyrosine kinase.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.cell.2016.10.038DOIArticle
http://www.sciencedirect.com/science/article/pii/S0092867416314593PublisherArticle
Additional Information:© 2016 Elsevier. Received 4 May 2016; revised 8 August 2016; accepted 20 October 2016; available online 10 November 2016. We thank Willem Kegel and Markus Weingarth for helpful discussions and Johan van der Zwan for technical support. This work was funded in part by Netherlands Organization for Scientific Research (NWO) (grants 700.26.121 and 700.10.443 to M.B, STW12152 to P.B.H. and a VIDI grant 723.013.008 to SL) and iNEXT (project number 653706), a Horizon 2020 program of the European Union. In addition, S.v.D., S.L., and A.J.R.H. are supported by the project Proteins At Work (project 184.032.201), a program of the Netherlands Proteomics Centre financed by NWO as part of the National Roadmap Largescale Research Facilities of the Netherlands. The NMR experiments were supported in part by uNMR-NL, an NWO-funded National Roadmap Large-Scale Facility of the Netherlands. We are indebted to Paul Tordo and Olivier Ouari (Marseille) for providing AMUPol.
Funders:
Funding AgencyGrant Number
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)700.26.121
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)700.10.443
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)STW12152
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)723.013.008
iNEXT653706
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)184.032.201
National Ultrahigh-field Nuclear Magnetic Resonance Facility (uNMR-NL)UNSPECIFIED
Subject Keywords:EGFR; NMR; Solid-state NMR; tyrosine kinase; receptor; activation; membrane protein; cancer
Record Number:CaltechAUTHORS:20170103-160614195
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20170103-160614195
Official Citation:Kaplan, M., Narasimhan, S., de Heus, C., Mance, D., van Doorn, S., Houben, K., Popov-Čeleketić, D., Damman, R., Katrukha, E.A., Jain, P., et al. (2016). EGFR Dynamics Change during Activation in Native Membranes as Revealed by NMR. Cell 167, 1241-1251.e1211.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73191
Collection:CaltechAUTHORS
Deposited By: Melissa Ray
Deposited On:04 Jan 2017 17:55
Last Modified:04 Jan 2017 17:55

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