Oncogenic mutations reduce the stability of Src kinase
Oncogenic mutations reduce the stability of Src kinase
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DOI：
10.1016/j.jmb.2004.08.091
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发表时间：
2004-11-12
影响因子：
5.6
通讯作者：
Buchner, J
中科院分区：
文献类型：
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作者：
Falsone, SF;Leptihn, S;Buchner, J
病毒酪氨酸激酶v-Src的致癌潜力是由于其组成活性。与高度同源的细胞c-Src激酶不同，调节尾的C末端缺失和许多点突变使得病毒激酶无法控制。为了确定这些差异的基础，我们在体外分析了v-Src和c-Src的结构和稳定性。我们发现，v-Src对展开和不可逆聚集的稳定性显着低于c-Src。此外，在v-Src中，疏水残基在天然状态下已经更多地暴露。因此，发现v-Src在接近生理温度时无活性。因此，我们认为，合奏的突变，转化成致癌变异的c-Src导致伴随的激酶的不稳定。(C)2004爱思唯尔有限公司保留所有权利。
The oncogenic potential of the viral tyrosine kinase v-Src is due to its constitutive activity. Unlike the highly homologous cellular c-Src kinase, a C-terminal deletion of the regulatory tail and numerous point mutations make the viral kinase uncontrollable. To determine the basis of these differences, we analysed the structure and stability of v-Src and c-Src in vitro. We show that the stability of v-Src against unfolding and irreversible aggregation is significantly lower than that of c-Src. Furthermore, in v-Src hydrophobic residues are more exposed already in the native state. In consequence, v-Src was found to be inactive close to physiological temperatures. We thus suggest that the ensemble of mutations that transform c-Src into the oncogenic variant cause a concomitant destabilisation of the kinase. (C) 2004 Elsevier Ltd. All rights reserved.