Electrostatic control of calcineurin's intrinsically-disordered regulatory domain binding to calmodulin.
Electrostatic control of calcineurin's intrinsically-disordered regulatory domain binding to calmodulin.
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DOI：
10.1016/j.bbagen.2018.07.027
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Kekenes-Huskey PM
中科院分区：
文献类型：
--
作者：
Sun B;Cook EC;Creamer TP;Kekenes-Huskey PM
钙调磷酸酶（calcalineurin, CaN）是一种丝氨酸/苏氨酸磷酸酶，在哺乳动物组织中调节多种生理和病理生理过程。钙调神经磷酸酶（calcalineurin, CaN）调节结构域（RD）负责调节酶的磷酸酶活性，在抑制CaN时被认为是高度无序的，但在与调节蛋白钙调蛋白（calmodulin, CaM）的扩散限制结合时经历了无序到有序的转变。调节结构域（RD）中极性和带电氨基酸的普遍存在表明静电相互作用参与了钙调蛋白（CaM）结合的介导，但缺乏结合复合物的原子分辨率数据阻碍了探索RD序列如何控制其构象集合和远程吸引有助于靶蛋白结合的努力。在本研究中，我们通过计算模型研究了静电和结构紊乱共同促进或阻碍CaM/CaN结合动力学的程度。具体来说，我们通过微秒级分子动力学（MD）和布朗动力学（BD）模拟，研究了几种含有CaM结合区（CAMBR）的RD构建体，以表征静电与构象多样性在控制扩散限制缔合率方面的作用。我们的研究结果表明，RD氨基酸组成和序列长度既影响适合CaM结合的构象的动态可用性，也影响引导结合的远程静电相互作用。这些发现为构象多样性和涉及CaN的静电驱动蛋白-蛋白结合之间的相互作用提供了有趣的见解，这可能扩展到广泛的由内在无序蛋白调节的扩散限制过程。
Calcineurin (CaN) is a serine/threonine phosphatase that regulates a variety of physiological and pathophysiological processes in mammalian tissue. The calcineurin (CaN) regulatory domain (RD) is responsible for regulating the enzyme’s phosphatase activity, and is believed to be highly-disordered when inhibiting CaN, but undergoes a disorder-to-order transition upon diffusion-limited binding with the regulatory protein calmodulin (CaM). The prevalence of polar and charged amino acids in the regulatory domain (RD) suggests electrostatic interactions are involved in mediating calmodulin (CaM) binding, yet the lack of atomistic-resolution data for the bound complex has stymied efforts to probe how the RD sequence controls its conformational ensemble and long-range attractions contribute to target protein binding. In the present study, we investigated via computational modeling the extent to which electrostatics and structural disorder co-facilitate or hinder CaM/CaN association kinetics. Specifically, we examined several RD constructs that contain the CaM binding region (CAMBR) to characterize the roles of electrostatics versus conformational diversity in controlling diffusion-limited association rates, via microsecond-scale molecular dynamics (MD) and Brownian dynamic (BD) simulations. Our results indicate that the RD amino acid composition and sequence length influence both the dynamic availability of conformations amenable to CaM binding, as well as long-range electrostatic interactions to steer association. These findings provide intriguing insight into the interplay between conformational diversity and electrostatically-driven protein-protein association involving CaN, which are likely to extend to wide-ranging diffusion-limited processes regulated by intrinsically-disordered proteins.
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