The findings were published online today in the journal Nature.
“The ryanodine receptor is a complex molecular machine within muscle cells,” says Filip Van Petegem, an assistant professor in UBC’s Department of Biochemistry and Molecular Biology and lead author of the study.
“We’ve known that it plays an important role in certain congenital heart conditions but due to its size and complexity, there has never been a good, detailed model of its structure or where many of the mutations that can lead to diseases are located.”
Muscle cells contract in response to the release of calcium through ryanodine receptors, which are made up of interlocking parts, or domains. Mutations of ryanodine receptors result in ill-fitted domains and cause calcium leakage.
“It’s like having gears in a clock with missing or broken teeth – the domains slip,” explains Van Petegem. “The leaking calcium causes muscle cells to ‘misfire’ and result in premature and jerky contractions.”
In heart muscle, this can lead to fatal rapid or irregular heartbeats in response to cardiovascular stress. The same kind of irregular, rapid contractions in skeletal muscles can lead to dangerous spikes in body temperature – called malignant hyperthermia – that can be brought on by certain forms of general anaesthetics in people with a genetic mutation that causes leaky receptors.
The researchers shone super bright beams of X-rays generated at both synchrotrons onto crystallized receptor proteins and measured how the X-rays diffracted as they passed through the crystal. The resulting patterns were then used to build a high-resolution model of specific regions of the receptors prone to disease-causing mutations, or “hot spots.”
“Now that we understand how these mutations affect how the channel works, we can come up with a strategy for developing new drug treatments to help prevent calcium leakage,” says Van Petegem.
The Canadian Light Source is Canada’s national centre for synchrotron research. Located at the University of Saskatchewan in Saskatoon, the CLS is a powerful tool for academic and industrial research in a wide variety of areas including environmental science, natural resources and energy, health and life sciences, and information and communications technology. CLS operations are funded by the Government of Canada, Natural Science and Engineering Research Council, National Research Council of Canada, Canadian Institutes of Health Research, the Government of Saskatchewan and the University of Saskatchewan. For more information: www.lightsource.ca/media/quickfacts.php.
The Stanford Synchrotron Radiation Lightsource’s Structural Molecular Biology program is supported by the US Department of Energy’s Office of Biological and Environmental Research, the National Institutes of Health, National Center for Research Resources’ Biomedical Technology Program and the NIH National Institute of General Medical Sciences. SLAC National Accelerator Laboratory is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the U.S. Department of Energy Office of Science. The Stanford Synchrotron Radiation Lightsource at SLAC is a DOE Office of Science national user facility, which provides synchrotron radiation for research in chemistry, biology, physics and materials science to more than a thousand users each year.