TY - JOUR
T1 - Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization
AU - Shan, Yibing
AU - Eastwood, Michael P.
AU - Zhang, Xuewu
AU - Kim, Eric T.
AU - Arkhipov, Anton
AU - Dror, Ron O.
AU - Jumper, John
AU - Kuriyan, John
AU - Shaw, David E.
N1 - Funding Information:
We thank Natalia Jura, Kate Engel, and Markus Seeliger for generously providing samples of EGFR and Src kinases, Stevan R. Hubbard and Kresten Lindorff-Larsen for helpful discussions, and Rebecca Kastleman and Mollie Kirk for editorial assistance. Author contributions: Y.S., M.P.E, and D.E.S. designed research; Y.S., E.T.K., A.A., and J.J. performed simulations; X.Z. and J.K. designed, and X.Z. performed, native gel and light scattering experiments; Y.S. analyzed data; Y.S., M.P.E., R.O.D., and D.E.S. wrote the article. J.K. and X.Z. were supported by the National Cancer Institute (R01 CA96504).
PY - 2012/5/11
Y1 - 2012/5/11
N2 - The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder. Corroborating these findings, our biophysical experiments and kinase enzymatic assays indicate that the L834R mutation causes abnormally high activity primarily by promoting EGFR dimerization rather than by allowing activation without dimerization. We also find that phosphorylation of EGFR kinase domain at Tyr845 may suppress the intrinsic disorder, suggesting a molecular mechanism for autonomous EGFR signaling.
AB - The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder. Corroborating these findings, our biophysical experiments and kinase enzymatic assays indicate that the L834R mutation causes abnormally high activity primarily by promoting EGFR dimerization rather than by allowing activation without dimerization. We also find that phosphorylation of EGFR kinase domain at Tyr845 may suppress the intrinsic disorder, suggesting a molecular mechanism for autonomous EGFR signaling.
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U2 - 10.1016/j.cell.2012.02.063
DO - 10.1016/j.cell.2012.02.063
M3 - Article
C2 - 22579287
AN - SCOPUS:84860870716
SN - 0092-8674
VL - 149
SP - 860
EP - 870
JO - Cell
JF - Cell
IS - 4
ER -