Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New Regulatory Mechanism Discovered in Cell System for Eliminating Unneeded Proteins

14.08.2012
Work led by St. Jude Children’s Research Hospital scientists offers clues into molecular malfunction at the heart of a rare blood vessel disorder, revealing an important new regulator of cellular proteins

A faulty gene linked to a rare blood vessel disorder has led investigators to discover a mechanism involved in determining the fate of possibly thousands of proteins working inside cells.

St. Jude Children’s Research Hospital scientists directed the study, which provides insight into one of the body’s most important regulatory systems, the ubiquitin system. Cells use it to get rid of unneeded proteins. Problems in this system have been tied to cancers, infections and other diseases. The work appears in today’s print edition of the journal Molecular Cell.

Researchers demonstrated how a protein named Glomulin binds to a key component of the regulatory system. Investigators showed not only where Glomulin binds but also how binding shuts down a biochemical cascade that tags unnecessary proteins for dismantling.

The findings highlight a potential new approach for future studies aimed at developing treatments for glomuvenous malformations, which are associated with mutations in the gene for making the Glomulin protein. The malformations, which are often present at birth, result in veins that cause discolored raised skin lumps that are sometimes painful and disfiguring.

“The findings suggest it might someday be possible to treat disorders resulting from defects in proteins that shut off the ubiquitin system by finding an alternative mechanism for turning the pathway off. The way Glomulin works represents a new way of controlling one of the most important regulatory systems at work in cells. We believe Glomulin may represent the tip of the iceberg. There could be many proteins that work in this fashion,” said Brenda Schulman, Ph.D., a member of the St. Jude Department of Structural Biology and a Howard Hughes Medical Institute investigator. She is the study’s senior and corresponding author.

Cells rely on this ubiquitin system to keep proteins in balance. As part of the ubiquitination process, a small protein is passed from one enzyme to the next like a baton in a relay race until it reaches a protein complex known as the cullin RING ligase. There, the small protein is transferred to a waiting target protein, marking it for destruction.

In this study, researchers showed that Glomulin disrupts ubiquitination by “glomming” onto and masking the spot on the cullin RING ligase where the tagging process is completed. The binding site is on the RBX1 protein, a component of the cullin RING ligase. While Glomulin derives its name from the disease, researchers showed the name also aptly describes Glomulin’s molecular function.

The study builds on earlier work from the laboratory of James DeCaprio, M.D., of the Dana-Farber Cancer Institute, Boston. DeCaprio, a coauthor of this study, and his colleagues reported that Glomulin regulates cullin RING ligases by binding to the RBX1 protein. They also reported that Glomulin does not bind to the related RBX2 protein.

In this latest study, St. Jude scientists used X-ray crystallography to determine the structures involved in Glomulin’s interaction with RBX1 and another component of the cullin RING ligase. “This was one of those ‘ah-ha’ moments,” Schulman said. “Seeing the structure told us almost immediately how Glomulin disrupts the ubiquitination process.”

Additional tests showed that Glomulin binds tightly to the surface of the RBX1 protein. The binding prevents the enzyme carrying the kiss-of-death protein tag from delivering its cargo. The structure also suggests how Glomulin mutations associated with glomuvenous malformations prevent the protein from binding to RBX1.

Researchers showed that Glomulin disrupts ubiquitination by binding to the same spot on the cullin RING ligase where the enzyme carrying the ubiquitin protein must bind to complete the process. The location is on the RBX1 protein, which is part of the larger protein complex.

“RBX1 regulates potentially thousands of different proteins within the cell. Glomulin represents a new way of regulating this entire class of RBX1 associated proteins,” said David Duda, Ph.D., a scientist in Schulman’s laboratory and the study’s first author. Glomulin is the first protein made by a cell shown to block a site like the one on RBX1.

The other study authors are Jennifer Olszewski, Lester Lambert, M. Brett Waddell and Tanja Mittag, all of St. Jude; Adriana Tron, formerly of Dana-Farber, now of Beth Israel Deaconess Medical Center, Boston; and Michal Hammel, Lawrence Berkeley National Laboratory, Berkeley, Calif.

The research was funded in part by the Howard Hughes Medical Institute; grants (CA021765, CA93804, CA63113, CA050661 and GM069530) from the National Cancer Institute (NCI) and the National Institute of General Medical Sciences (NIGMS), both at the National Institutes of Health (NIH); and ALSAC.

St. Jude Children’s Research Hospital
Since opening 50 years ago, St. Jude Children’s Research Hospital has changed the way the world treats childhood cancer and other life-threatening diseases. No family ever pays St. Jude for the care their child receives and, for every child treated here, thousands more have been saved worldwide through St. Jude discoveries. The hospital has played a pivotal role in pushing U.S. pediatric cancer survival rates from 20 to 80 percent overall, and is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. It is also a leader in the research and treatment of blood disorders and infectious diseases in children. St. Jude was founded by the late entertainer Danny Thomas, who believed that no child should die in the dawn of life. To learn more, visit www.stjude.org. Follow us on Twitter @StJudeResearch.
St. Jude Media Relations Contacts
Summer Freeman
(desk) 901-595-3061
(cell) 901-297-9861
summer.freeman@stjude.org
Carrie Strehlau
(desk) 901-595-2295
(cell) 901-297-9875
carrie.strehlau@stjude.org

Summer Freeman | Newswise Science News
Further information:
http://www.stjude.org

Further reports about: Cancer Glomulin Glomulin’s Medical Wellness Protein RBX1 cell death eliminating mechanism regulatory

More articles from Life Sciences:

nachricht New application for acoustics helps estimate marine life populations
16.01.2018 | University of California - San Diego

nachricht Unexpected environmental source of methane discovered
16.01.2018 | University of Washington Health Sciences/UW Medicine

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

Im Focus: A thermometer for the oceans

Measurement of noble gases in Antarctic ice cores

The oceans are the largest global heat reservoir. As a result of man-made global warming, the temperature in the global climate system increases; around 90% of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Gran Chaco: Biodiversity at High Risk

17.01.2018 | Ecology, The Environment and Conservation

Only an atom thick: Physicists succeed in measuring mechanical properties of 2D monolayer materials

17.01.2018 | Physics and Astronomy

Fraunhofer HHI receives AIS Technology Innovation Award 2018 for 3D Human Body Reconstruction

17.01.2018 | Awards Funding

VideoLinks
B2B-VideoLinks
More VideoLinks >>>