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!
Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University
How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung
Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.
Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
26.05.2017 | Life Sciences
26.05.2017 | Life Sciences
26.05.2017 | Physics and Astronomy