Featured Research

from universities, journals, and other organizations

Details of calcium 'safety-valve' in cells explained

Date:
June 6, 2014
Source:
DOE/Brookhaven National Laboratory
Summary:
The atomic level structure of a protein that regulates the level of calcium in cells has been detailed by scientists, providing clues about a key signaling agent that can trigger programmed cell death and potentially leading to new anticancer drug targets.

Sometimes a cell has to die -- when it's done with its job or inflicted with injury that could otherwise harm an organism. Conversely, cells that refuse to die when expected can lead to cancer. So scientists interested in fighting cancer have been keenly interested in learning the details of "programmed cell death." They want to understand what happens when this process goes awry and identify new targets for anticancer drugs.

Related Articles


The details of one such target have just been identified by a group of scientists from the U.S. Department of Energy's Brookhaven National Laboratory, Columbia University, New York University, Baylor College of Medicine, Technical University of Munich, and the New York Structural Biology Center. The group, known as the New York Consortium on Membrane Protein Structure (NYCOMPS), used x-rays at Brookhaven Lab's National Synchrotron Light Source (NSLS) to decipher the atomic level structure of a protein that regulates the level of calcium in cells. The work is described as a research article published in Science June 6, 2014.

"The accumulation of calcium is a key signaling agent that can trigger programmed cell death, or apoptosis," explained Wayne Hendrickson of Columbia and Brookhaven, and the director of NYCOMPS as well as a senior author on the paper. "Our study reveals how this protein, embedded in a cellular membrane structure called the endoplasmic reticulum, serves as a molecular safety valve for keeping calcium levels steady. Designing drugs that inhibit this protein would promote cell death, which could be a promising strategy for fighting cancers in which such proteins are overexpressed."

3-D Model for Rational Drug Design

The protein that the scientists studied is a prokaryotic homolog of human "Transmembrane Bax Inhibitor Motif" (TMBIM) proteins, which come in six varieties. TMBIM6 is overexpressed in various cancers -- including prostate, breast, glioma, uterine, ovarian, and lung.

"Our work using the prokaryotic version of this protein has enabled us to construct a three-dimensional model that can be used as a basis for the rational design of possible inhibitor molecules," said Qun Liu, a scientist at NSLS and NYCOMPS and the lead author on the paper.

The atomic-level structures were determined using x-ray crystallography at NSLS beamlines X4A and X4C. Interactions of x-rays with the 3-D lattices of the protein molecules produce diffraction patterns from which the 3-D molecular images were derived. The images reveal a novel structure consisting of a centralized helix wrapped by two novel triple-helix sandwiches that traverse the membrane. The central portion can take on an open or closed conformation dependent on the acidity level, or pH. At physiological pH, open and closed conformations exist in equilibrium, maintaining a steady of state of calcium in the cell by allowing gradual leakage of calcium across the membrane through a transient transmembrane pore.

"This leak is intrinsic to all kinds of cells and is cytoprotective for life, similar to a pressure safety value used in a standard steam boiler for safety assurance," said Liu.

The studies reveal in detail how the TMBIM protein senses and responds to changes in acidity to precisely regulate the mechanism.

"The next step will be to solve crystal structures of the human TMBIM proteins to refine the design of possible inhibitor drugs," said Liu.

That work will take place at a new light source nearing completion at Brookhaven known as NSLS-II. That facility, set to start early experiments later this year, will be 10,000 times brighter than NSLS, making it particularly suitable for studies of membrane proteins, which are difficult to crystallize.


Story Source:

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


Journal Reference:

  1. Y. Chang, R. Bruni, B. Kloss, Z. Assur, E. Kloppmann, B. Rost, W. A. Hendrickson, Q. Liu. Structural basis for a pH-sensitive calcium leak across membranes. Science, 2014; 344 (6188): 1131 DOI: 10.1126/science.1252043

Cite This Page:

DOE/Brookhaven National Laboratory. "Details of calcium 'safety-valve' in cells explained." ScienceDaily. ScienceDaily, 6 June 2014. <www.sciencedaily.com/releases/2014/06/140606185430.htm>.
DOE/Brookhaven National Laboratory. (2014, June 6). Details of calcium 'safety-valve' in cells explained. ScienceDaily. Retrieved November 28, 2014 from www.sciencedaily.com/releases/2014/06/140606185430.htm
DOE/Brookhaven National Laboratory. "Details of calcium 'safety-valve' in cells explained." ScienceDaily. www.sciencedaily.com/releases/2014/06/140606185430.htm (accessed November 28, 2014).

Share This


More From ScienceDaily



More Plants & Animals News

Friday, November 28, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

New Dinosaur Species Found in Museum Collection

New Dinosaur Species Found in Museum Collection

Reuters - Innovations Video Online (Nov. 27, 2014) A British palaeontologist has discovered a new species of dinosaur while studying fossils in a Canadian museum. Pentaceratops aquilonius was related to Triceratops and lived at the end of the Cretaceous Period, around 75 million years ago. Jim Drury has more. Video provided by Reuters
Powered by NewsLook.com
Classic Hollywood Memorabilia Goes Under the Hammer

Classic Hollywood Memorabilia Goes Under the Hammer

Reuters - Entertainment Video Online (Nov. 26, 2014) The iconic piano from "Casablanca" and the Cowardly Lion suit from "The Wizard of Oz" fetch millions at auction. Sara Hemrajani reports. Video provided by Reuters
Powered by NewsLook.com
Pet Dogs to Be Used in Anti-Ageing Trial

Pet Dogs to Be Used in Anti-Ageing Trial

Reuters - Innovations Video Online (Nov. 26, 2014) Researchers in the United States are preparing to discover whether a drug commonly used in human organ transplants can extend the lifespan and health quality of pet dogs. Video provided by Reuters
Powered by NewsLook.com
From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

Newsy (Nov. 25, 2014) The US FDA is announcing new calorie rules on Tuesday that will require everywhere from theaters to vending machines to include calorie counts. Video provided by Newsy
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:

Strange & Offbeat Stories


Plants & Animals

Earth & Climate

Fossils & Ruins

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