Featured Research

from universities, journals, and other organizations

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

Date:
November 6, 2010
Source:
DOE/SLAC National Accelerator Laboratory
Summary:
Using intense X-rays, researchers have determined the detailed structure of a key part of the ryanodine receptor, a protein associated with calcium-related disease. Their results pinpoint the locations of more than 50 mutations that cluster in disease "hotspots" along the receptor and offer insights into how the mutations might cause the receptor to malfunction.

High-resolution images of the ryanodine receptor, a protein associated with calcium-related disease, reveal in unprecedented detail the locations of more than 50 mutations that cluster in disease "hotspots" along the receptor. The grey portion of the above image represents low-resolution information about the entire receptor. The high-resolution structure is shown in blue, where each sphere represents a single atom. Mutations identified in individual amino acids are colored red.
Credit: Image courtesy of Filip Van Petegem/University of British Columbia

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.


Story Source:

The above story is based on materials provided by DOE/SLAC National Accelerator Laboratory. Note: Materials may be edited for content and length.


Journal Reference:

  1. Ching-Chieh Tung, Paolo A. Lobo, Lynn Kimlicka, Filip Van Petegem. The amino-terminal disease hotspot of ryanodine receptors forms a cytoplasmic vestibule. Nature, November 3, 2010 DOI: 10.1038/nature09471

Cite This Page:

DOE/SLAC National Accelerator Laboratory. "X-rays offer first detailed look at hotspots for calcium-related disease." ScienceDaily. ScienceDaily, 6 November 2010. <www.sciencedaily.com/releases/2010/11/101103141537.htm>.
DOE/SLAC National Accelerator Laboratory. (2010, November 6). X-rays offer first detailed look at hotspots for calcium-related disease. ScienceDaily. Retrieved August 1, 2014 from www.sciencedaily.com/releases/2010/11/101103141537.htm
DOE/SLAC National Accelerator Laboratory. "X-rays offer first detailed look at hotspots for calcium-related disease." ScienceDaily. www.sciencedaily.com/releases/2010/11/101103141537.htm (accessed August 1, 2014).

Share This




More Health & Medicine News

Friday, August 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

House Republicans Vote to Sue Obama Over Healthcare Law

House Republicans Vote to Sue Obama Over Healthcare Law

Reuters - US Online Video (July 31, 2014) The Republican-led House of Representatives votes to sue President Obama, accusing him of overstepping his executive authority in making changes to the Affordable Care Act. Mana Rabiee reports. Video provided by Reuters
Powered by NewsLook.com
Despite Health Questions, E-Cigs Are Beneficial: Study

Despite Health Questions, E-Cigs Are Beneficial: Study

Newsy (July 31, 2014) Citing 81 previous studies, new research out of London suggests the benefits of smoking e-cigarettes instead of regular ones outweighs the risks. Video provided by Newsy
Powered by NewsLook.com
Dangerous Bacteria Kills One in Florida

Dangerous Bacteria Kills One in Florida

AP (July 31, 2014) Sarasota County, Florida health officials have issued a warning against eating raw oysters and exposing open wounds to coastal and inland waters after a dangerous bacteria killed one person and made another sick. (July 31) Video provided by AP
Powered by NewsLook.com
Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins