High-resolution structures of the cardiac Ryanodine Receptor: a target for arrhythmia-causing mutations

Our heart beat is a complex biochemical event. It relies on electrical signals, which can sometimes be disturbed, resulting in potentially fatal cardiac arrhythmias. One of the key parts involved in the contraction of heart muscle is a small ion known as calcium. Just prior to the contraction, calcium rushes into heart cells and triggers the contraction. Having the right amount of calcium at the right time is key for regular heart rhythms; too much or too little entry of calcium can be potentially fatal. The different compartments within the heart muscle cell are separated by membranes, which form barriers for many molecules. The calcium ions required for contraction of the heart muscle cells must pass through special gates. The sites where it all happens are formed by highly specialized protein channels that can open and close, thus determining the amount and timing of calcium release from one compartment to another. The most important of these so-called “calcium channels” is a large protein called ryanodine receptor. The gene that encodes this protein is one of the largest known genes, with literally hundreds of mutations documented to be the cause of the arrhythmia in patients.

Our laboratory collaborates with several cardiologists specializing in arrhythmias; we aim to determine how exactly the various mutations in this gene lead to the arrhythmias as a step to developing therapeutics. To do this, it is necessary to understand the overall three-dimensional structure of the calcium channel. Because they are too small to see with regular light microscopes, we will use a highly specialized technique called “X-ray crystallography”. By shooting X-rays at crystals of the channel, we can analyze the way these rays scatter off the atoms in the crystal and determine, through complex calculations, what the 3D structure looks like. By comparing 3D structures of the calcium channels of normal and diseased individuals, we can directly observe the mechanisms of the disease-causing mutations and come up with potential therapeutic strategies.