Please use this identifier to cite or link to this item: https://doi.org/10.1038/emboj.2008.18
Title: Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates
Authors: Ng, C.
Jackson, R.A.
Buschdorf, J.P.
Sun, Q.
Guy, G.R.
Sivaraman, J. 
Keywords: c-Cbl
EGFR
Met
Reverse binding
Sprouty
TKB domain
X-ray crystallography
Issue Date: 5-Mar-2008
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
URI: http://scholarbank.nus.edu.sg/handle/10635/101741
ISSN: 02614189
DOI: 10.1038/emboj.2008.18
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