Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c.
Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c.
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DOI：
10.1093/jb/mvs085
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发表时间：
2012-11
影响因子：
2.7
通讯作者：
K. Takeshita;T. Tezuka;Y. Isozaki;E. Yamashita;Mamoru Suzuki;Minsoo Kim;Y. Yamanashi;Tadashi Yamamoto-Tad
中科院分区：
文献类型：
--
作者：
K. Takeshita;T. Tezuka;Y. Isozaki;E. Yamashita;Mamoru Suzuki;Minsoo Kim;Y. Yamanashi;Tadashi Yamamoto-Tad
通过它们的泛素连接酶活性，Cbl家族蛋白抑制由蛋白酪氨酸激酶（PTK）介导的信号传导，但也可以作为衔接蛋白来正向调节信号传导。该家族的酪氨酸激酶结合（TKB）结构域对于与酪氨酸磷酸化的靶蛋白结合至关重要。在这里，我们分析了Cbl-c/Cbl-3（Cbl-c TKB）的TKB结构域的晶体结构，Cbl-c TKB是哺乳动物Cbl家族的不同成员。与Cbl TKB相比，Cbl-c TKB在磷酸肽结合后显示出有限的结构灵活性。Cbl-c TKB中增加这种灵活性的突变增强了其与靶磷蛋白的结合。这些结果表明，改变Cbl家族蛋白的TKB结构域的结构灵活性的蛋白质、翻译后修饰或突变可以调节它们与靶磷蛋白的结合，从而影响PTK介导的信号传导。
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.