Because these previously unrecognized sugar switches are so abundant and potential targets of manipulation by drugs, the discovery of their role has implications for new treatments for a number of diseases, including cancer, the scientists say.
In the January 12 edition of Science Signaling, the team reported that it focused efforts on the apparatus that enables a human cell to split into two, a complicated biochemical machine involving hundreds of proteins. Conventional wisdom was that the job of turning these proteins on and off — thus determining if, how and when a cell divides — fell to phosphates, chemical compounds containing the element phosphorus, which fasten to and unfasten from proteins in a process called phosphorylation.
Instead, the Johns Hopkins scientists say, there is another layer of regulation by a process of sugar-based protein modification called O-GlcNAcylation (pronounced O-glick-NAC-alation). "This sugar-based system seems as influential and ubiquitous a cell-division signaling pathway as its phosphate counterpart and, indeed, even plays a role in regulating phosphorylation itself," says Chad Slawson, Ph.D., an author of the paper and research associate in the Department of Biological Chemistry, Johns Hopkins University School of Medicine.
Because the sugar molecule has some novel qualities — it is small, easily altered, and without an electrical charge — it is virtually imperceptible to researchers using standard physical techniques of detection such as mass spectrometry.
Suspecting that the sugar known as O-GlcNAc might play a role in cell division, the Hopkins team devised a protein-mapping scheme using new mass spectrometric methods. Essentially, they applied a combination of chemical modification and enrichment methods, and new fragmentation technology to proteins that comprise the cell division machinery in order to figure out and analyze their molecular makeup, identifying more than 150 sites where the sugar molecule known as O-GlcNAc was attached. Phosphates were found to be attached at more than 300 sites.
They noticed that when an O-GlcNAc molecule was located near a phosphate site, or at the same site, it prevented the phosphate from attaching. The proteins involved in cell division weren't phosphorylated and activated until O-GlcNAc detached.
"I think of phosphorylation as a micro-switch that regulates the circuitry of cell division, and O-GlcNAcylation as the safety switch that regulates the microswitches," says Gerald Hart, Ph.D., the DeLamar Professor and director of biological chemistry at the Johns Hopkins School of Medicine.
Using a standard human cell line (HeLa cells), the scientists discovered abnormalities when they disrupted the cell division process by adding extra O-GlcNAc. Although the cell's chromosome-containing nuclei divided normally, the cells themselves didn't divide, resulting in too many nuclei per cell — a condition known as polyploidy that's exhibited by many cancer cells.
The researchers not only mapped O-GlcNAc and phosphorylation sites but also measured changes in the cell division machinery, because, Hart says, the chemical changes act more like "dimmer" switches, than simple on/off ones.
As important as the discovery is to a deeper understanding of cell division, Hart says, this extensive cross talk between O-GlcNAc and phosphorylation is paradigm-shifting in terms of signaling. Signaling is how a cell perceives its environment, and how it regulates its machinery in response to stimuli. The new sugar switches reveal that the cellular circuitry is much more complex than previously thought, he adds.
The research was funded by the National Institutes of Health.
Johns Hopkins authors on the paper are Zihao Wang, Chad Slawson, Kaoru Sakabe, Win D. Cheung and Gerald W. Hart. Other authors are Namrata D. Udeshi, Philip D. Compton, Jeffrey Shabanowitz and Donald F. Hunt, all of the University of Virginia.On the Web:
Maryalice Yakutchik | EurekAlert!
The birth of a new protein
20.10.2017 | University of Arizona
Building New Moss Factories
20.10.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
20.10.2017 | Information Technology
20.10.2017 | Materials Sciences
20.10.2017 | Interdisciplinary Research