CAREER: Structural dynamics of post-translationally modified Calmodulin and its role in target recognition

细胞通过产生、发送和接收化学信号进行通信。钙调蛋白存在于所有高等生物体中，它感知细胞中的钙水平，并调节心脏跳动、肌肉收缩、学习和记忆等重要功能。该项目旨在确定允许该蛋白质调节这些关键功能的基本原理。有趣的是，钙调蛋白可以激活或去激活这些功能，但钙调素选择这一作用的过程尚不清楚。该项目将研究对蛋白质的修改，这些修改可能会改变蛋白质的灵活性和三维结构。所获得的知识将有助于解释某些修饰如何调节钙调蛋白与其靶标相互作用的方式。该项目的更广泛影响包括纳入全面的教育和培训计划，以培养一批跨不同学科的高素质本科生、研究生和博士后研究人员。特别是，该计划将创建丰富的课程计划，提供使用最先进的仪器体验实践的新机会，并通过创造新的留学机会培养一支全球胜任的劳动力队伍。为了提高普通人群的科学素养，克莱姆森大学将播放一个新的视频库。该项目的目标是了解钙调蛋白的结构、动力学和磷酸化状态如何通过提供所需的靶标特异性和选择性来调节靶标识别。PI将使用结合荧光光谱工具、生物物理方法和分子动力学模拟的综合方法来表征不同磷酸化状态下钙调蛋白的三维结构和动力学。为了实现这一目标，该计划将被分成三个不同的任务。第一项任务将包括生成野生型钙调蛋白的结构模型，并使用基于Förster共振能量转移实验的混合结构动力学工具比较野生型和各种磷酸化状态。第二项任务是确定野生型钙调蛋白中央螺旋在不同磷酸化状态下的动力学差异。第三项也是最后一项任务是确定钙调蛋白磷酸化状态对靶标识别的不同影响。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Cells communicate by generating, transmitting and receiving chemical signals. The protein Calmodulin, present in all higher organisms, senses calcium levels in the cell and regulates vital functions such as heart beating, muscle contraction, learning and memory. This project is geared towards identifying the fundamental principles that allow this protein to regulate these critical functions. Interestingly, Calmodulin can activate or deactivate these functions, but the process by which Calmodulin selects this action is not understood. The project will study modifications to the protein that are likely to alter the protein's flexibility and its three-dimensional structure. The obtained knowledge would help explain how certain modifications regulate the way Calmodulin interacts with its targets. The broader impacts of this project include the incorporation of a thorough educational and training program to prepare a pool of highly qualified undergraduate, graduate, and postdoctoral researchers across various disciplines. In particular, the program will create enriched curricular programs that provide new opportunities for hands-on experience using state-of-the-art instrumentation and train a globally competent workforce by creating new study abroad opportunities. To improve scientific literacy among the general population, a new video library is to be broadcasted from Clemson University.The goal of the project is to understand how the structure, dynamics and phosphorylation state of Calmodulin modulate target recognition by providing the required target specificity and selectivity. The PI will use an integrative approach combining fluorescence spectroscopic tools, biophysical methods, and molecular dynamic simulations to characterize the three-dimensional structure and the dynamics of Calmodulin at different phosphorylated states. To accomplish this goal, the program will be split into three distinct tasks. The first task will involve the generation of structural models of wild-type Calmodulin and the comparison of the wild-type to various phosphorylated states using a hybrid structural dynamic tool based on Förster resonance energy transfer experiments. The second task is to determine the difference in the dynamics of the central helix of the wild-type Calmodulin against various phosphorylated states. The third and final task is to determine the differential impact of the phosphorylation state of Calmodulin on target recognition.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.