An intramolecular SH3-domain interaction regulates c-Abl activity
An intramolecular SH3-domain interaction regulates c-Abl activity
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DOI：
10.1038/ng0398-280
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发表时间：
1998-03-01
期刊：
影响因子：
30.8
通讯作者：
Superti-Furga, G
中科院分区：
文献类型：
--
作者：
Barilá, D;Superti-Furga, G
原癌基因ABL1编码一种胞质和核蛋白酪氨酸激酶(c-Abl)，参与细胞分化、细胞分裂、细胞黏附和应激反应过程(1-4)。通过染色体重排或病毒转导改变ABL1可导致恶性转化(5，6)。C-Abl蛋白的活性受其SH3结构域的负调控，机制未知，SH3结构域的缺失使ABL1成为癌基因(7-10)。我们提出了SH3结构域与催化域以及SH2与催化域之间的连接体(SH2-CD连接体)存在分子内抑制相互作用的证据。这三个元件中每一个的定点突变都激活了c-Abl。连接子的突变会导致分子的构象变化，并增加SH3结构域与多肽配体的结合。SH3和催化区的两个电荷残基的单独突变激活了c-Abl，而在双互易突变体中恢复了抑制。我们认为，c-Abl的调节剂将对其活性产生相反的影响，这取决于它们促进或破坏这些分子内相互作用的能力。
The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase (c-Abl) that has been implicated in processes of cell differentiation, cell division, cell adhesion and stress response(1-4). Alterations of ABL1 by chromosomal rearrangement or viral transduction can lead to malignant transformation(5,6). Activity of the c-Abl protein is negatively regulated by its SH3 domain through an unknown mechanism, and deletion of the SH3 domain turns ABL1 into an oncogene(7-10). We present evidence for an intramolecular inhibitory interaction of the SH3 domain with the catalytic domain and with the linker between the SH2 and catalytic domain (SH2-CD linker). Site-directed mutations in each of these three elements activate c-Abl. Mutations in the linker cause a conformational change of the molecule and increase binding of the SH3 domain to peptide ligands. Individual mutation of two charged residues in the SH3 and catalytic domain activates c-Abl, while inhibition is restored in the double reciprocal mutant. We propose that regulators of c-Abl will have opposite effects on its activity depending on their ability to favour or disrupt these intramolecular interactions.