Navigation Links
X-rays offer first detailed look at hotspots for calcium-related disease
Date:11/4/2010

Menlo Park, Calif.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.


'/>"/>

Contact: Melinda Lee
melinda.lee@slac.stanford.edu
650-926-8547
DOE/SLAC National Accelerator Laboratory
Source:Eurekalert  

Related biology news :

1. Lensless imaging of whole biological cells with soft X-rays
2. Helical CT scans reduce lung cancer mortality by 20 percent compared to chest X-rays
3. Stantum Offering Demo, Evaluation & Development Board Based on Its Patented Resistive Multi-Touch Technology
4. Worm genome offers clues to evolution of parasitism
5. Advance offers revolution in food safety testing
6. Commercial aquatic plants offer cost-effective method for treating wastewater
7. Ripple effect: Water snails offer new propulsion possibilities
8. Light pollution offers new global measure of coral reef health
9. New papers offer insights into process of malarial drug resistance
10. Rong Li Lab offers insight into adaptive ability of cells
11. International public-private partnership offers new paradigm for medicinal chemistry
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
X-rays offer first detailed look at hotspots for calcium-related disease
(Date:4/11/2017)... , Apr. 11, 2017 Research and ... Market 2017-2021" report to their offering. ... The global eye tracking market to grow at a ... report, Global Eye Tracking Market 2017-2021, has been prepared based on ... covers the market landscape and its growth prospects over the coming ...
(Date:4/5/2017)... YORK , April 5, 2017 Today ... is announcing that the server component of the HYPR ... known for providing the end-to-end security architecture that empowers ... HYPR has already secured over 15 million ... makers including manufacturers of connected home product suites and ...
(Date:3/30/2017)... HONG KONG , March 30, 2017 ... developed a system for three-dimensional (3D) fingerprint identification by adopting ground ... technology into a new realm of speed and accuracy for use ... applications at an affordable cost. ... ...
Breaking Biology News(10 mins):
(Date:9/20/2017)... ... ... Diversity focused business accelerator, The Refinery , announced today they are hosting ... technology-driven, women-led startups in Boston, MA, New Haven/Hamden, CT, and Newark, NJ. Fueling ... that week – in Boston, it will be part of the City of Boston's ...
(Date:9/20/2017)... ... September 20, 2017 , ... ... examining the effects of exoskeleton-assisted walking on gait parameters and neuromuscular activity ... "Neuromechanical adaptations during a robotic powered exoskeleton assisted walking session" (doi:10.1080.10790268.2017.1314900) was ...
(Date:9/20/2017)... Aurora, Ohio (PRWEB) , ... September 20, 2017 ... ... automation, systems integration, and building management solutions, announced today the opening of an ... customers in Taiwan and the Greater China region, while developing new relationships in ...
(Date:9/19/2017)... ... September 19, 2017 , ... ... group of funded early-stage tech companies. “Grit” author Angela Duckworth and her team ... the ic@3401 community is Cooley, an international law firm with decades of experience ...
Breaking Biology Technology: