An adjacent arginine, and the phosphorylated tyrosine in the c-Met receptor target sequence, dictates the orientation of c-Cbl binding

Abstract

Previously, we have demonstrated that the tyrosine phosphorylated hepatocyte growth factor receptor (Met) binds to the c-Cbl phosphotyrosine- recognition, tyrosine kinase binding (TKB) domain in a reverse orientation compared to other c-Cbl binding partners. A Met peptide with the DpYR motif changed to RpYD (MetRD) retains a similar TKB binding affinity as the native Met peptide. However, the TKB: MetRD complex crystal structure reveals a complete reversal of the binding orientation. Collated data indicates that both binding and orientation is dictated by the phosphorylated tyrosine and an adjacent arginine forming intra-peptide hydrogen bonds and aligning unidirectionally with complementary charges in the phosphotyrosine binding pocket of c-Cbl. Structured summary: c-Cbl and MetRD bind: shown by x-ray crystallography (view interaction) c-Cbl and MetRD bind: shown by mass spectrometry studies of complexes (view interaction) c-Cbl bind to Met: shown by surface plasmon resonance (view interactions 1,2). © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.