Investigating Dynamic Interdomain Allostery in Pin1.
Investigating Dynamic Interdomain Allostery in Pin1.
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DOI：
10.1007/s12551-015-0171-9
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发表时间：
2015-06-01
影响因子：
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通讯作者：
Peng JW
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文献类型：
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作者：
Peng JW
信号蛋白通常将互补的功能位点隔离在不同的结构域中。不同的域如何相互通信？解决这个问题的一个有吸引力的系统是有丝分裂调节器，人类 Pin1。 Pin-1 由两个束缚结构域组成：用于底物结合的 WW 结构域和用于肽基脯氨酰异构酶 (PPIase) 活性的催化结构域。 Pin1 加速调节细胞周期和神经元发育的蛋白质内磷酸-Ser/Thr-Pro (pS/T-P) 基序的顺反异构化。 Pin1 的早期 X 射线和溶液核磁共振研究表明域间和域内运动。我们开始对使用 NMR 探索此类运动如何影响域间通信产生兴趣。我们积累的结果表明，底物与 Pin1 WW 结构域的结合改变了结构域内/结构间的迁移率，从而改变了远端 PPIase 结构域催化位点的底物活性。因此，Pin1 显示了库珀和德莱顿意义上的动态变构的证据。我们强调了支持这一结论的结果，并通过构象选择的简单推测模型对它们进行了总结。
Signaling proteins often sequester complementary functional sites in separate domains. How do the different domains communicate with one another? An attractive system to address this question is the mitotic regulator, human Pin1. Pin-1 consists of two tethered domains: a WW domain for substrate binding, and a catalytic domain for peptidyl-prolyl isomerase (PPIase) activity. Pin1 accelerates the cis-trans isomerization of phospho-Ser/Thr-Pro (pS/T-P) motifs within proteins regulating the cell cycle and neuronal development. The early x-ray and solution NMR studies of Pin1 indicated inter- and intradomain motion. We became interested in exploring how such motions might affect interdomain communication, using NMR. Our accumulated results indicate substrate binding to Pin1 WW domain changes the intra/inter domain mobility, thereby altering substrate activity in the distal PPIase domain catalytic site. Thus, Pin1 shows evidence of dynamic allostery, in the sense of Cooper and Dryden. We highlight our results supporting this conclusion, and summarize them via a simple speculative model of conformational selection.