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:6/21/2016)... , June 21, 2016 NuData ... the new role of principal product architect and ... the director of customer development. Both will report ... technical officer. The moves reflect NuData,s strategic growth ... response to high customer demand and customer focus ...
(Date:6/9/2016)... 2016  Perkotek an innovation leader in attendance control systems is proud to announce ... for employers to make sure the right employees are actually signing in, and to ... ... ... ...
(Date:6/2/2016)... 2, 2016 The Department of Transport ... the 44 million US Dollar project, for the , ... including Personalization, Enrolment, and IT Infrastructure , to ... production and implementation of Identity Management Solutions. Numerous renowned international ... Decatur was selected for the most compliant ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... YORK , June 23, 2016 ... trading session at 4,833.32, down 0.22%; the Dow Jones Industrial ... S&P 500 closed at 2,085.45, down 0.17%. Stock-Callers.com has initiated ... INFI ), Nektar Therapeutics (NASDAQ: NKTR ), ... Therapeutics Inc. (NASDAQ: BIND ). Learn more about ...
(Date:6/23/2016)... ... June 23, 2016 , ... Regulatory ... technical consulting, provides a free webinar on Performing Quality Investigations: Getting ... at 12pm CT at no charge. , Incomplete investigations are still a major ...
(Date:6/23/2016)... , June 22, 2016  Amgen (NASDAQ: ... the QB3@953 life sciences incubator to accelerate ... The shared laboratory space at QB3@953 was created to ... key obstacle for many early stage organizations - access ... the sponsorship, Amgen launched two "Amgen Golden Ticket" awards, ...
(Date:6/22/2016)... , June 22, 2016 Cell ... will allow them to produce up to one ... one lot within one week. These high-quality, consistent ... laboriously preparing cells and spend more time doing ... through a proprietary, high-volume manufacturing process that produces ...
Breaking Biology Technology: