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

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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.