Project 460019

The cells in our cardiac and skeletal muscle are highly specialized, displaying distinct shapes. These shapes are absolutely required for normal function, and are determined by the various proteins that are expressed in these cells. Cells are surrounded by membranes that keep the content inside separate from the outside. But inside the cells are different compartments that are also surrounded by their own membrane. A very peculiar property of muscle cells is that there are 'contact' sites where different membranes meet. These contacts are critical: without them, the muscle cells would not be to process the signals that lead to contraction. This proposal focuses on Junctophilin, a very peculiar protein that has the capacity to bring different membranes together. In the heart, mutations that affect the gene encoding for Junctophilin can lead to serious problems. In particular, they cause hypertrophic cardiomyopathy, a condition that leads to a weakened heart and the potential for life-threatening disturbances in heart rhythm. We will figure out how Junctophilin works by studying its 3D structure, and how it binds the different proteins in muscle cells. We will also study the effect of mutations that cause cardiomyopathy: by comparing the 3D structure of 'normal', healthy Junctophilin with the structure of 'diseased' Junctophilin, we expect to gain fundamental insights into the disease mechanisms. We expect this research to give clues for new therapeutic approaches.