Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c.
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Takeshita K, Tezuka T, Isozaki Y, Yamashita E, Suzuki M, Kim M, Yamanashi Y, Yamamoto T, Nakagawa A
Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c.
J Biochem. 2012 Nov;152(5):487-95. doi: 10.1093/jb/mvs085. Epub 2012 Aug 9.
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- 22888118 [ View in PubMed]
- Abstract
Through their ubiquitin ligase activity, Cbl-family proteins suppress signalling mediated by protein-tyrosine kinases (PTKs), but can also function as adaptor proteins to positively regulate signalling. The tyrosine kinase binding (TKB) domain of this family is critical for binding with tyrosine-phosphorylated target proteins. Here, we analysed the crystal structure of the TKB domain of Cbl-c/Cbl-3 (Cbl-c TKB), which is a distinct member of the mammalian Cbl-family. In comparison with Cbl TKB, Cbl-c TKB showed restricted structural flexibility upon phosphopeptide binding. A mutation in Cbl-c TKB augmenting this flexibility enhanced its binding to target phosphoproteins. These results suggest that proteins, post-translational modifications or mutations that alter structural flexibility of the TKB domain of Cbl-family proteins could regulate their binding to target phosphoproteins and thereby, affect PTK-mediated signalling.