title: 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.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Sun
authors.forename: Cherlyn
authors.initials: C
authors.lastname: Ng
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Guy
authors.forename: J
authors.initials: J
authors.lastname: Sivaraman
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001120:Arginine; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D013058:Mass Spectrometry; D019000:Phosphotyrosine; D011485:Protein Binding; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000737:chemistry / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D017978:Receptors, Growth Factor; D019000:Phosphotyrosine; D001120:Arginine; D050721:Proto-Oncogene Proteins c-cbl; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met