Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mechanism discovered for attaching an “on” switch that helps cells accessorize proteins

20.06.2014

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
(desk) 901-595-2295
(cell) 901-297-9875
carrie.strehlau@stjude.org

Summer Freeman
(desk) 901-595-3061
(cell) 901-297-9861
summer.freeman@stjude.org

Carrie Strehlau | Eurek Alert!
Further information:
http://www.stjude.org/stjude/v/index.jsp?vgnextoid=437e6743230b6410VgnVCM100000290115acRCRD&cpsextcurrchannel=1

Further reports about: Cancer HIV NEDD8 NIH conditions immune proteins thousands ubiquitination

More articles from Life Sciences:

nachricht Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg

nachricht Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Attoseconds break into atomic interior

A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.

In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...

Im Focus: Good vibrations feel the force

A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.

By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...

Im Focus: Developing reliable quantum computers

International research team makes important step on the path to solving certification problems

Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Basque researchers turn light upside down

23.02.2018 | Physics and Astronomy

Finnish research group discovers a new immune system regulator

23.02.2018 | Health and Medicine

Attoseconds break into atomic interior

23.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>