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|Title:||Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates|
|Citation:||Ng, C., Jackson, R.A., Buschdorf, J.P., Sun, Q., Guy, G.R., Sivaraman, J. (2008-03-05). Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates. EMBO Journal 27 (5) : 804-816. ScholarBank@NUS Repository. https://doi.org/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 orientates 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. © 2008 European Molecular Biology Organization | All Rights Reserved.|
|Source Title:||EMBO Journal|
|Appears in Collections:||Staff Publications|
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