Takeshita K, Tezuka T, Isozaki Y, Yamashita E, Suzuki M, Kim M, Yamanashi Y, Yamamoto T, Nakagawa A

Through their ubiquitin ligase activity, Cbl-family proteins suppress signaling mediated by protein-tyrosine kinases (PTKs), but can also function as adaptor proteins to positively regulate signaling. The tyrosine kinase binding (TKB) domain of this family is critical for binding with tyrosine-phosphorylated target proteins. Here, we analyzed the crystal structure of the ...

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TKB domain of Cbl-c/Cbl-3 (Cbl-c TKB), which is a distinct member of the mammalian Cbl-family. In comparison to 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, posttranslational 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 signaling.

Date: Aug. 09, 2012

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