Proline cis-trans isomerization controls autoinhibition of a signaling protein
Proline cis-trans isomerization controls autoinhibition of a signaling protein
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DOI：
10.1016/j.molcel.2007.01.004
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发表时间：
2007-02-09
期刊：
影响因子：
16
通讯作者：
Kalodimos, Charalampos G.
中科院分区：
文献类型：
--
作者：
Sarkar, Paramita;Reichman, Charles;Kalodimos, Charalampos G.
自抑制在自然界中被广泛用于抑制其他组成性蛋白质活性，并且通常受外在因素调节。在这里，我们表明，自抑制可以控制由脯氨酰顺反异构化提供的内在分子内开关。我们发现，脯氨酸的链接拴两个SH3结构域的Crk衔接蛋白之间的顺式和反式构象相互转换。在顺式构象中，两个SH3结构域在分子内相互作用，从而形成自抑制机制的基础。相反，在反式构象中，Crk以延伸的、未受抑制的构象存在，该构象是边缘填充的，但用于在配体结合时激活蛋白质。肽基脯氨酰异构酶的作用加速了顺式和反式之间的相互转化，从而加速了自抑制和激活构象之间的相互转化。脯氨酸异构化似乎是一个理想的开关，可以调节激活的动力学，从而调节信号响应的动力学。
Autoinhibition is being widely used in nature to repress otherwise constitutive protein activities and is typically regulated by extrinsic factors. Here we show that autoinhibition can be controlled by an intrinsic intramolecular switch afforded by prolyl cis-trans isomerization. We find that a proline on the linker tethering the two SH3 domains of the Crk adaptor protein interconverts between the cis and trans conformation. In the cis conformation, the two SH3 domains interact intramolecularly, thereby forming the basis of an autoinhibitory mechanism. Conversely, in the trans conformation Crk exists in an extended, uninhibited conformation that is marginally populated but serves to activate the protein upon ligand binding. Interconversion between the cis and trans, and, hence, of the autoinhibited and activated conformations, is accelerated by the action of peptidyl-prolyl isomerases. Proline isomerization appears to make an ideal switch that can regulate the kinetics of activation, thereby modulating the dynamics of signal response.