Oncogenic Mutations Counteract Intrinsic Disorder in the EGFR Kinase and Promote Receptor Dimerization

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. [Display omitted] ► EGFR kinase is intrinsically disordered in the dimerization interface ► Cancer mutations stabilize the interface, promoting EGFR dimerization ► High activity of EGFR cancer mutants is due primarily to enhanced dimerization ► Phosphorylation similarly promotes dimerization and allows autonomous signaling A prevalent EGFR mutation linked to lung cancer was previously thought to promote activation of the monomeric form of the receptor. A combination of biochemical and long-timescale molecular dynamics experiments now provides evidence that this mutation promotes ligand-independent dimerization by stabilizing receptors' dimerization interface.