Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization

Yibing Shan, Michael P. Eastwood, Xuewu Zhang, Eric T. Kim, Anton Arkhipov, Ron O. Dror, John Jumper, John Kuriyan, David E. Shaw

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183 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)860-870
Number of pages11
JournalCell
Volume149
Issue number4
DOIs
Publication statusPublished - May 11 2012

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Shan, Y., Eastwood, M. P., Zhang, X., Kim, E. T., Arkhipov, A., Dror, R. O., ... Shaw, D. E. (2012). Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization. Cell, 149(4), 860-870. https://doi.org/10.1016/j.cell.2012.02.063