St. Jude Children’s Research Hospital scientists advance understanding of how cells manage their vast array of proteins and how system failures can lead to cancer and other diseases
St. Jude Children’s Research Hospital scientists have discovered how an important “on” switch is attached to the machinery that cells rely on to adapt thousands of proteins to meet changing conditions. The research appears in the current issue of the journal Cell.
The switch is a small protein called NEDD8. Problems with NEDD8 have been associated with several cancers, developmental disorders and infectivity of the human immunodeficiency virus (HIV), which causes AIDS. Drugs that target NEDD8 are in anti-cancer clinical trials. The ability of HIV to evade the anti-viral immune response depends in part on the ability of the virus to hijack the NEDD8 machinery.
NEDD8 is also a key component of the machinery that cells use to adapt to changing conditions. Just as individuals adapt to changes in their environment by donning gloves, boots, hats and other accessories, cells adapt by “accessorizing” proteins to modify their function.
NEDD8 is a specialized accessory. It functions as the “on” switch for accessorizing 10 to 20 percent of the thousands of proteins that do the work of cells. Those accessories mark some proteins for elimination, others for a change in function and others for relocation to different parts of the cell. Until now, however, how NEDD8 slipped into position was unknown.
Researchers showed how part of the machinery for accessorizing proteins, a component called cullin-RING, is first modified by NEDD8. The addition of NEDD8 transforms the ability of cullin-RING to accessorize other proteins. Those proteins are involved in important biological functions such as cell division, immune response and embryonic development.
“This discovery is a major advance in understanding the machinery cells use to regulate an astonishingly vast number of proteins they depend on as well as the diseases that arise when the system malfunctions,” said corresponding author Brenda Schulman, Ph.D., a member of the St. Jude Department of Structural Biology and a Howard Hughes Medical Institute (HHMI) investigator.
Schulman and her colleagues study the machinery that manages the accessorizing process, whether the accessory is NEDD8 or a different small protein called ubiquitin. Ubiquitin accessorizes proteins though a process known as ubiquitination. Cullin-RING, which NEDD8 accessorizes, is a major command center of ubiquitination.
This study builds on an observation first author Daniel Scott, Ph.D., made shortly after joining Schulman’s laboratory in 2006. Scott, an HHMI research specialist III, showed that while ubiquitin could be coaxed into binding to and accessorizing cullin-RING, NEDD8 was the preferred partner.
Scott used a technique called X-ray crystallography to capture a crystal structure that explained why. In the process, investigators determined for the first time that different components of the ubiquitination machinery work cooperatively to align NEDD8 and cullin-RING. That alignment promotes the transfer of NEDD8 rather than ubiquitin to the proper site on cullin-RING. The transfer of NEDD8 allows other proteins to be accessorized with ubiquitin.
The mechanism outlined in this research establishes a paradigm for understanding protein regulation in cells, Schulman said. “This research sets the stage for broadly understanding this key aspect of protein regulation in cells,” Scott said.
The study’s other authors are Vladislav Sviderskiy and Shein Ei Cho, both of St. Jude; Julie Monda, formerly of St. Jude and now of the Massachusetts Institute of Technology, Cambridge, Mass.; and John Lydeard and J. Wade Harper, both of Harvard Medical School, Boston.
The research was funded in part by a Cancer Center Support Grant (CA021765) from the National Cancer Institute at the National Institutes of Health (NIH); grants (GM069530, AG011085) from the National Institute of General Medical Sciences at the NIH; the Howard Hughes Medical Institute, Damon Runyon Cancer Research Foundation and ALSAC.
St. Jude Media Relations Contacts
Carrie Strehlau | Eurek Alert!
Learning from Nature: Genomic database standard alleviates search for novel antibiotics
02.09.2015 | Max-Planck-Institut für marine Mikrobiologie
Orang-utan females prefer cheek-padded males
02.09.2015 | Max Planck Institute for Evolutionary Anthropology, Leipzig
China's Loess Plateau was formed by wind alternately depositing dust or removing dust over the last 2.6 million years, according to a new report from University of Arizona geoscientists. The study is the first to explain how the steep-fronted plateau formed.
China's Loess Plateau was formed by wind alternately depositing dust or removing dust over the last 2.6 million years, according to a new report from...
The leaves of the lotus flower, and other natural surfaces that repel water and dirt, have been the model for many types of engineered liquid-repelling surfaces. As slippery as these surfaces are, however, tiny water droplets still stick to them. Now, Penn State researchers have developed nano/micro-textured, highly slippery surfaces able to outperform these naturally inspired coatings, particularly when the water is a vapor or tiny droplets.
Enhancing the mobility of liquid droplets on rough surfaces could improve condensation heat transfer for power-plant heat exchangers, create more efficient...
Longer, more severe, and hotter droughts and a myriad of other threats, including diseases and more extensive and severe wildfires, are threatening to transform some of the world's temperate forests, a new study published in Science has found. Without informed management, some forests could convert to shrublands or grasslands within the coming decades.
"While we have been trying to manage for resilience of 20th century conditions, we realize now that we must prepare for transformations and attempt to ease...
A University of Oklahoma astrophysicist and his Chinese collaborator have found two supermassive black holes in Markarian 231, the nearest quasar to Earth, using observations from NASA's Hubble Space Telescope.
The discovery of two supermassive black holes--one larger one and a second, smaller one--are evidence of a binary black hole and suggests that supermassive...
A team of European researchers have developed a model to simulate the impact of tsunamis generated by earthquakes and applied it to the Eastern Mediterranean. The results show how tsunami waves could hit and inundate coastal areas in southern Italy and Greece. The study is published today (27 August) in Ocean Science, an open access journal of the European Geosciences Union (EGU).
Though not as frequent as in the Pacific and Indian oceans, tsunamis also occur in the Mediterranean, mainly due to earthquakes generated when the African...
20.08.2015 | Event News
20.08.2015 | Event News
19.08.2015 | Event News
02.09.2015 | Physics and Astronomy
02.09.2015 | Life Sciences
02.09.2015 | Awards Funding