Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery.
Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery.
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DOI：
10.1016/j.molcel.2017.01.014
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发表时间：
2017-02-16
期刊：
影响因子：
16
通讯作者：
Peti W
中科院分区：
文献类型：
--
作者：
Choy MS;Li Y;Machado LESF;Kunze MBA;Connors CR;Wei X;Lindorff-Larsen K;Page R;Peti W
蛋白质的功能起源于结构刚性、不同时间尺度的动力学和变构性的协同作用。然而，蛋白质功能的这三个支柱是如何整合的仍然知之甚少。在这里，我们展示了这些支柱如何连接在蛋白酪氨酸磷酸酶1B（PTP 1B）中，PTP 1B是糖尿病和癌症的药物靶点，催化重要信号通路中许多底物的去磷酸化。通过结合wt-PTP 1B和≥10个PTP 1B变体在多个状态下的新实验和计算数据，我们发现了一个基本的和进化上保守的CH/π开关，这对于定位催化重要的WPD环至关重要。此外，我们的数据表明，PTP 1B使用构象和动态变构来调节其活性。这表明构象刚性和动力学对于控制蛋白质活性是必不可少的。在不同的时间尺度上，刚性和动力学之间的这种联系可能是所有酶功能的标志。
Protein function originates from a cooperation of structural rigidity, dynamics at different timescales and allostery. However, how these three pillars of protein function are integrated is still only poorly understood. Here we show how these pillars are connected in Protein Tyrosine Phosphatase 1B (PTP1B), a drug target for diabetes and cancer that catalyzes the dephosphorylation of numerous substrates in essential signaling pathways. By combining new experimental and computational data on wt-PTP1B and ≥10 PTP1B variants in multiple states, we discovered a fundamental and evolutionarily conserved CH/π switch that is critical for positioning the catalytically important WPD loop. Furthermore, our data show that PTP1B uses conformational and dynamic allostery to regulate its activity. This shows that both conformational rigidity and dynamics are essential for controlling protein activity. This connection between rigidity and dynamics at different timescales is likely a hallmark of all enzyme function.