Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Crouching protein, hidden enzyme

26.01.2016

TSRI and UC Berkeley team solves structure of 'flipping' cellular machine, pointing to possible Alzheimer's and Parkinson's therapies

Meet a microscopic gymnast.


New research from The Scripps Research Institute and UC Berkeley shows the workings of a crucial molecular enzyme. In this image, the green glow in the structure indicates the location of the Rpn11 enzymatic active site in its inhibited conformation at the heart of the isolated lid complex.

Credit: Lander lab, The Scripps Research Institute

A new study led by scientists at The Scripps Research Institute (TSRI) and the University of California (UC), Berkeley shows how a crucial molecular enzyme starts in a tucked-in somersault position and flips out when it encounters the right target.

The new findings, published recently in the journal eLife, give scientists a clearer picture of the process through which cells eliminate proteins that promote diseases such as cancer and Alzheimer's.

... more about:
»TSRI »cryo-EM »enzyme »proteasome »proteins

"Having an atomic-resolution structure and a better understanding of this mechanism gives us the ability to someday design therapeutics to combat cancer and neurodegeneration," said TSRI biologist Gabriel Lander, who was co-senior of author of the study with Andreas Martin of UC Berkeley.

Keeping Cells Healthy

The new study sheds light on the proteasome, a molecular machine that serves as a recycling center in cells. Proteasomes break down spent or damaged proteins and can even eliminate harmful misfolded proteins observed in many diseases.

The new research is the first study in almost 20 years to solve a large component of the proteasome at near-atomic resolution. Lander said the breakthrough was possible with recent advances in cryo-electron microscopy (EM), an imaging technique in which a sample is bombarded with an electron beam, producing hundreds of thousands of protein images that can be consolidated into a high-resolution structure.

Using cryo-EM, scientists investigated part of the proteasome that contains a deubiquitinase enzyme called Rpn11. Rpn11 performs a crucial function called deubiquitination, during which it cleaves molecular tags from proteins scheduled for recycling in the proteasome. This is a key step in proteasomal processing--without Rpn11, the protein tags would clog the proteasome and the cell would die.

From previous studies, scientists knew Rpn11 and its surrounding proteins latch onto the proteasome to form a sort of lid. "The lid complex wraps around the proteasome like a face-hugger in the movie 'Alien,'" said Lander.

The lid complex can also exist separately from the proteasome--which poses a potential problem. If Rpn11 cleaves tags from proteins that haven't gotten to the proteasome yet, those proteins could skip the recycling stage and cause disease. Scientists had wondered how nature had solved this problem.

A Guide for Future Therapies

The study provides an answer, showing the lid complex as it floats freely in cells. In this conformation, Rpn11 is carefully nestled in the crook of surrounding proteins, stabilized and inactive.

"There's a sophisticated network of interactions that pin the Rpn11 deubiquitinase against neighboring subunits to keep it inhibited in the isolated proteasome lid," explained Corey M. Dambacher, a researcher at TSRI at the time of the study and now a senior scientist at Omniome, Inc., who was first author of the study with TSRI Research Associate Mark Herzik Jr. and Evan J. Worden of UC Berkeley.

"In order for Rpn11 to perform its job, it has to flip out of this inhibited conformation," said Herzik.

The new study also shows that, to flip out of the conformation at the proteasome, the proteins surrounding deubiquitinase pivot and rotate--binding to the proteasome and releasing the deubiquitinase active site from its nook.

Lander called the system "finely tuned," but said there may be ways to manipulate it. The study collaborators at UC Berkeley made small mutations to the proteins holding Rpn11 in position, and found that any small change will release the deubiquitinase, even when the lid is floating freely.

Lander said the new understanding of the mechanism that activates Rpn11 could guide future therapies that remove damaged or misfolded proteins.

"Accumulation of these toxic proteins can lead to diseases such as Parkinson's and Alzheimer's, as well as a variety of cancers," Lander said. "If we can harness the proteasome's ability to remove specific proteins from the cell, this gives us incredible power over cellular function and improves our ability to target certain cells for destruction."

Going forward, the researchers hope to use the same cryo-EM techniques to investigate other components of the proteasome--and figure out exactly how it recognizes and destroys proteins. "There's still a lot to learn," said Lander.

###

For more information on the study, "Atomic structure of the 26S proteasome lid reveals the mechanism of deubiquitinase inhibition," see http://elifesciences.org/content/early/2016/01/08/eLife.13027

This research was supported by the Damon Runyon Cancer Research Foundation (grant DFS-#07-13), the Pew Scholars program, the National Institutes of Health (grants DP2 EB020402 and R01-GM094497), the Searle Scholars Program, the National Science Foundation CAREER Program (grant NSF-MCB-1150288), the Howard Hughes Medical Institute and a National Science Foundation Graduate Research Fellowship.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www.scripps.edu.

Media Contact

Madeline McCurry-Schmidt
madms@scripps.edu
858-784-9254

 @scrippsresearch

http://www.scripps.edu 

Madeline McCurry-Schmidt | EurekAlert!

Further reports about: TSRI cryo-EM enzyme proteasome proteins

More articles from Life Sciences:

nachricht Modern genetic sequencing tools give clearer picture of how corals are related
17.08.2017 | University of Washington

nachricht The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie

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

Gold shines through properties of nano biosensors

17.08.2017 | Physics and Astronomy

Greenland ice flow likely to speed up: New data assert glaciers move over sediment, which gets more slippery as it gets wetter

17.08.2017 | Earth Sciences

Mars 2020 mission to use smart methods to seek signs of past life

17.08.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>