GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:22579287

From GONUTS
Jump to: navigation, search
Citation

Shan, Y, Eastwood, MP, Zhang, X, Kim, ET, Arkhipov, A, Dror, RO, Jumper, J, Kuriyan, J and Shaw, DE (2012) Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization. Cell 149:860-70

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.

Links

PubMed Online version:10.1016/j.cell.2012.02.063

Keywords

Amino Acid Sequence; Crystallography, X-Ray; Humans; Molecular Dynamics Simulation; Molecular Sequence Data; Neoplasms/metabolism; Point Mutation; Protein Folding; Protein Kinase Inhibitors/pharmacology; Protein Multimerization; Protein Structure, Tertiary; Quinazolines/pharmacology; Receptor, Epidermal Growth Factor/antagonists & inhibitors; Receptor, Epidermal Growth Factor/chemistry; Receptor, Epidermal Growth Factor/genetics; Receptor, Epidermal Growth Factor/metabolism; Sequence Alignment; Signal Transduction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:EGFR

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00533

F

Seeded From UniProt

complete

HUMAN:EGFR

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00533

F

occurs_in:(GO:0005938)

Seeded From UniProt

complete

See also

References

See Help:References for how to manage references in GONUTS.