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 Repairing damaged hearts with self-healing heart cells
22.08.2017 | National University Health System

nachricht Biochemical 'fingerprints' reveal diabetes progression
22.08.2017 | Umea University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Cholesterol-lowering drugs may fight infectious disease

22.08.2017 | Health and Medicine

Meter-sized single-crystal graphene growth becomes possible

22.08.2017 | Materials Sciences

Repairing damaged hearts with self-healing heart cells

22.08.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>