Menlo Park, CA--Using intense X-rays from the Stanford Synchrotron Radiation Lightsource (SSRL) at the Department of Energy's SLAC National Accelerator Laboratory, researchers have determined the detailed structure of a key part of the ryanodine receptor, a protein associated with calcium-related disease. Their results, which combine data from SSRL and the Canadian Light Source, pinpoint the locations of more than 50 mutations that cluster in disease "hotspots" along the receptor. The protein understanding could play a role in developing therapies for such calcium-related problems as heart disease.
Calcium regulates many critical processes within the body, including muscle contraction, the heartbeat, and the release of hormones. But too much calcium can be a bad thing. In excess, it can lead to a host of diseases, such as severe muscle weakness, a fatal reaction to anesthesia, or sudden cardiac death.
"Until now, no one could tell where these disease mutations were located or what they were doing," said principal investigator Filip Van Petegem of the University of British Columbia in Vancouver. The ryanodine receptor controls the release of calcium ions from a storehouse within skeletal-muscle and heart-muscle cells as needed to perform critical functions. Previous studies at lower resolution indicated that mutations cluster in three regions along the receptor, but without more detailed information it remained unclear exactly how they contributed to disease.
In a study published this week in Nature, Van Petegem and his group describe the structure of one of these hotspots in extremely fine detail and predict how the mutations might cause the receptor to malfunction and release calcium too soon. "These mutations most likely cause the same disease effects, but a severe mutation leads to stronger symptoms, and doesn't require as big of a stimulus to induce disease," Van Petegem said.
A premature release of calcium produces extra electrical signals within the cells. In skeletal muscle, this can lead to fatal rises in body temperature under certain anesthetics, or the failure of major muscles. In cardiac muscle it can trigger an arrhythmia, resulting in sudden cardiac death. While it is difficult to determine the exact number of people with these mutations, it is estimated that as many as one in 10,000 may be at risk for disease.
"Thanks to the technological capabilities at SSRL, we were able to rapidly screen hundreds of crystallized samples of this receptor protein to find ones with the best quality, giving the best structure. This study is a good first step toward designing new molecules that could be used as a drug," Van Petegem said. "These mutations could be a very promising therapeutic target for treating heart disease."
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