Structural and Functional Investigation of Neuronal Calcium Channel Modulation

Cells contain highly complex protein structures that allow signals to be relayed from the outside environment using signaling receptors to proteins inside of the cell. One mechanism involves assembling protein complexes across different cell layers linked by proteins such as junctophilins (JPH). JPH proteins are found in the brain and muscles and work by interacting with receptors on the outer layer while simultaneously interacting with proteins on inner cellular structures such as the endoplasmic reticulum (ER). Thus, JPH places the outer layer of the cell and the ER in proximity allowing for a direct exchange of signals. This is essential for muscle contraction and memory and is linked to human genetic diseases. However, the interaction sites between these JPH proteins and their effect on receptors, such as voltage-receptor channels (Cav2), remain elusive. Here, we want to use X-ray crystallography and electron microscopy to solve the protein structure of JPH and find how it interacts and regulates Ca¬v receptors. This work will provide insights into JPHs’ molecular structure, cellular function and role in genetic diseases. The JPH-Cav molecular complex will serve as a resource for future mechanistic studies and drug designs.