spacer Crystal structure of c-Cbl-TKB domain complexed with its binding motif in Sprouty4
Primary citation
Title Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates
Authors Ng, C.search; Jackson, R.A.search; Buschdorf, J.P.search; Sun, Q.search; Guy, G.R.search; Sivaraman, J.search
Journal EMBO J.search vol:27, pag:804-816 (2008), Identifiers: PubMed ID (18273061)search DOI (10.1038/emboj.2008.18)
Abstract The c-Cbl tyrosine kinase binding domain (Cbl-TKB), essentially an 'embedded' SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate-binding affinity, we compared crystal structures of the Cbl-TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c-Met receptors and validated the binding with point-mutational analyses using full-length proteins. An obligatory, intrapeptidyl H-bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orients the peptide into a positively charged pocket on c-Cbl. Surprisingly, c-Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H-bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c-Cbl; this may enable the selective sequestration of c-Cbl from other target proteins.
MeSH terms Binding Sitessearch, Cell Linesearch, Humanssearch, Intracellular Signaling Peptides and Proteinssearch, Phosphopeptidessearch, Protein Bindingsearch, Protein Structuresearch, Tertiarysearch, Proto-Oncogene Proteinssearch, Proto-Oncogene Proteins c-cblsearch, Proto-Oncogene Proteins c-metsearch, Receptorssearch, Growth Factorsearch, src Homology Domainssearch
Other entries described in this publication 3bum, 3buo, 3bux, 3buw
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