title: A highly efficient peptide substrate for EGFR activates the kinase by inducing aggregation.
abstract: Formation of an asymmetric dimer by the EGFR (epidermal growth factor receptor) kinase domains results in allosteric activation. Since this dimer does not readily form in solution, the EGFR kinase domain phosphorylates most peptide substrates with a relatively low catalytic efficiency. Peptide C is a synthetic peptide substrate of EGFR developed by others that is phosphorylated with a significantly higher catalytic efficiency, and we sought to understand the basis for this. Peptide C was found to increase EGFR kinase activity by promoting formation of the EGFR kinase domain asymmetric dimer. Activation of the kinase domain by Peptide C also enhances phosphorylation of other substrates. Aggregation of the EGFR kinase domain by Peptide C probably underlies activation, and Peptide C precipitates several other proteins. Peptide C was found to form fibrils independent of the presence of EGFR, and these fibrils may facilitate aggregation and activation of the kinase domain. These results establish that a peptide substrate of EGFR may increase catalytic activity by promoting kinase domain dimerization by an aggregation-mediated mechanism.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Engel
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
mesh_terms: D002851:Chromatography, High Pressure Liquid; D019281:Dimerization; D066246:ErbB Receptors / Q000378:metabolism* / Q000648:ultrastructure; D015151:Immunoblotting; D046529:Microscopy, Electron, Transmission; D010455:Peptides / Q000378:metabolism*; D010766:Phosphorylation; D013379:Substrate Specificity
chemical_list: D010455:Peptides; C050632:polypeptide C; D066246:ErbB Receptors