title: Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization.
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.
authors.affiliation: D.E. Shaw Research, New York, NY 10036, USA. yibing.shan@deshawresearch.com
authors.forename: Yibing
authors.initials: Y
authors.lastname: Shan
authors.forename: Michael P
authors.initials: MP
authors.lastname: Eastwood
authors.forename: Xuewu
authors.initials: X
authors.lastname: Zhang
authors.forename: Eric T
authors.initials: ET
authors.lastname: Kim
authors.forename: Anton
authors.initials: A
authors.lastname: Arkhipov
authors.forename: Ron O
authors.initials: RO
authors.lastname: Dror
authors.forename: John
authors.initials: J
authors.lastname: Jumper
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D000077341:Lapatinib; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism*; D017354:Point Mutation; D017510:Protein Folding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000494:pharmacology; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib; D066246:ErbB Receptors; D000077156:Gefitinib