静电力介导钙调素与钙调神经磷酸酶内在调控结构域的快速结合
Electrostatic Forces Mediate Fast Association of Calmodulin and the Intrinsically Disordered Regulatory Domain of Calcineurin
摘要：
内在无序蛋白（IDP）和具有内在无序区（IDR）的蛋白质控制着许多令人生畏的生理过程。对于这些蛋白质，其与信号转导通路中蛋白质相互作用的分子机制尚不清楚。使用折叠的，钙负载的钙调蛋白（CaM）与钙调磷酸酶调节IDP作为IDP介导的信号转导事件的原型的相互作用，我们发现IDP结构和静电相互作用的相互作用，在确定蛋白质-蛋白质协会的动力学。使用一系列的生物物理方法，包括停流和计算模拟，我们量化的相对贡献的静电相互作用和构象合奏的特点，在确定关联动力学的钙调蛋白（CaM）和钙调神经磷酸酶调节结构域（CaN RD）。我们的主要研究结果是，钙调素/CN RD协会率强烈依赖于离子强度和观察到的利率在很大程度上是由静电驱动的相互作用强度之间的钙调素和狭窄的CaN RD钙调素识别域。这些研究突出了控制信号转导动力学的分子机制，可用于涉及IDP的广泛的信号级联。
英文摘要：
Intrinsically disordered proteins (IDPs) and proteins with intrinsically disordered regions (IDRs) govern a daunting number of physiological processes. For such proteins, molecular mechanisms governing their interactions with proteins involved in signal transduction pathways remain unclear. Using the folded, calcium-loaded calmodulin (CaM) interaction with the calcineurin regulatory IDP as a prototype for IDP-mediated signal transduction events, we uncover the interplay of IDP structure and electrostatic interactions in determining the kinetics of protein-protein association. Using an array of biophysical approaches including stopped-flow and computational simulation, we quantify the relative contributions of electrostatic interactions and conformational ensemble characteristics in determining association kinetics of calmodulin (CaM) and the calcineurin regulatory domain (CaN RD). Our chief findings are that CaM/CN RD association rates are strongly dependent on ionic strength and that observed rates are largely determined by the electrostatically-driven interaction strength between CaM and the narrow CaN RD calmodulin recognition domain. These studies highlight a molecular mechanism of controlling signal transduction kinetics that may be utilized in wide-ranging signaling cascades that involve IDPs.
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