Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

X-rays offer first detailed look at hotspots for calcium-related disease

05.11.2010
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.

Now, 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.

"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.

The receptor is made up of more than 20,000 molecules called amino acids. Van Petegem's group studied a string of about 560 amino acids, where they found 57 mutations. In 56 cases, the mutations involved a change in a single amino acid, while the last one involved a deletion of 35 amino acids from the string.

"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.

In the heart, the receptor is stimulated to open about once a second when the body is at rest, sending regular pulses of calcium into the rest of the cell. In skeletal muscles, the timing of the pulses is determined by how often the muscles contract. Each time the receptor opens, certain amino acids rearrange themselves to facilitate the calcium release. Mutations can disrupt this process by causing the receptor to open either earlier or more easily than it should.

This 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.”

Future studies at SSRL and other synchrotron facilities will map out other receptor hotspots where these disease mutations cluster and use the detailed information to better understand the complex functions of the protein.

"It is very exciting to see the significant impact of our advanced structural biology technologies in helping users address difficult projects,” said SSRL staff scientist Michael Soltis.

This research was supported by the Canadian Institutes of Health Research. The Stanford Synchrotron Radiation Lightsource is supported by the U. S. Department of Energy Office of Science. 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 Canadian Light Source is Canada's national center 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.

Melinda Lee | EurekAlert!
Further information:
http://www.stanford.edu

More articles from Health and Medicine:

nachricht Discovery shows promise for treating Huntington's Disease
05.08.2020 | Ecole Polytechnique Fédérale de Lausanne

nachricht Carbon monoxide improves endurance performance
05.08.2020 | Universität Bayreuth

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: ScanCut project completed: laser cutting enables more intricate plug connector designs

Scientists at the Fraunhofer Institute for Laser Technology ILT have come up with a striking new addition to contact stamping technologies in the ERDF research project ScanCut. In collaboration with industry partners from North Rhine-Westphalia, the Aachen-based team of researchers developed a hybrid manufacturing process for the laser cutting of thin-walled metal strips. This new process makes it possible to fabricate even the tiniest details of contact parts in an eco-friendly, high-precision and efficient manner.

Plug connectors are tiny and, at first glance, unremarkable – yet modern vehicles would be unable to function without them. Several thousand plug connectors...

Im Focus: New Strategy Against Osteoporosis

An international research team has found a new approach that may be able to reduce bone loss in osteoporosis and maintain bone health.

Osteoporosis is the most common age-related bone disease which affects hundreds of millions of individuals worldwide. It is estimated that one in three women...

Im Focus: AI & single-cell genomics

New software predicts cell fate

Traditional single-cell sequencing methods help to reveal insights about cellular differences and functions - but they do this with static snapshots only...

Im Focus: TU Graz Researchers synthesize nanoparticles tailored for special applications

“Core-shell” clusters pave the way for new efficient nanomaterials that make catalysts, magnetic and laser sensors or measuring devices for detecting electromagnetic radiation more efficient.

Whether in innovative high-tech materials, more powerful computer chips, pharmaceuticals or in the field of renewable energies, nanoparticles – smallest...

Im Focus: Tailored light inspired by nature

An international research team with Prof. Cornelia Denz from the Institute of Applied Physics at the University of Münster develop for the first time light fields using caustics that do not change during propagation. With the new method, the physicists cleverly exploit light structures that can be seen in rainbows or when light is transmitted through drinking glasses.

Modern applications as high resolution microsopy or micro- or nanoscale material processing require customized laser beams that do not change during...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“Conference on Laser Polishing – LaP 2020”: The final touches for surfaces

23.07.2020 | Event News

Conference radar for cybersecurity

21.07.2020 | Event News

Contact Tracing Apps against COVID-19: German National Academy Leopoldina hosts international virtual panel discussion

07.07.2020 | Event News

 
Latest News

Rare Earth Elements in Norwegian Fjords?

06.08.2020 | Earth Sciences

Anode material for safe batteries with a long cycle life

06.08.2020 | Power and Electrical Engineering

Turning carbon dioxide into liquid fuel

06.08.2020 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>