Project 459092

Muscle contraction underlies our every heartbeat, breath, and movement. For muscles to contract, an electrical signal from the brain must be converted to a chemical signal (calcium) in muscle cells, much like translating instructions into a different language. Translating this signal is tasked to calcium-selective ion channels - 'gates' which decide what can enter the cell. Communication between two ion channels, called Cav and RyR, is fundamental to this process. Cav receives the initial electrical signal and relays this message directly to RyR, which floods the cell with calcium and initiates muscle contraction. Disruptions to this process caused by mutations in either protein cause devasting muscle disorders, many of which currently have no cure. However, we do not understand how Cav and RyR communicate with each other, making it hard to develop therapeutics. Recent evidence suggests a small protein known as STAC3 may act as the translator between them. Our goal is to understand how STAC3 may bridge the gap between these proteins, allowing for signals to be efficiently relayed. We will use single particle cryo-electron microscopy, a Nobel-prize winning technique for visualizing the atomic structure of proteins in three-dimensions. By seeing the interactions between STAC3 and Cav/RyR on a detailed level, we can understand why mutations cause disease and rationally design pharmaceuticals to treat them.