Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Key difference in how TB bacteria degrade doomed proteins

18.10.2010
Interaction between 'kiss of death' marker and protein-chopping factory -- new target for anti-TB drugs

Scientists at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory and Stony Brook University have discovered a key difference in the way human cells and Mycobacterium tuberculosis bacteria, which cause TB, deliver unwanted proteins — marked with a "kiss of death" sequence — to their respective cellular recycling factories.

This critical difference, described in a paper published online October 17, 2010, in the journal Nature Structural and Molecular Biology, may help scientists design drugs to disable the bacterial system while leaving normal human protein recycling centers intact.

"With tuberculosis infecting a third of the world's population, primarily in developing countries, there is great need for new, effective TB treatments," said study co-author Huilin Li, a Brookhaven biophysicist and associate professor at SBU. "Our research seeks to understand the protein-recycling mechanism of TB bacteria, because it is one of the microbe's keys to survival in human cells.* Targeting this system with small-molecule-based drugs could inhibit the bacteria and effectively treat TB."

The catch is that human cells have a similar protein-recycling system, essential for their survival, which could also be destroyed by inhibitory drugs. "It's important to find differences between the species so we can target features unique to the bacterial system," Li said.

Li has previously looked at differences in the cellular structure known as a proteasome that chops up the unwanted proteins [see links below]. The current study examined the way proteins destined for degradation are recognized by the bacterial proteasome before entering that structure.

Using beams of high-intensity x-rays at the Lab's ["http://www.nsls.bnl.gov/">National Synchrotron Light Source (NSLS), the scientists determined atomic-level structures of the portion of the bacterial proteasome that identifies the unwanted protein's "kiss of death" marker sequence — as well as structures of the marker sequence as it binds with the proteasome.

Based on the structures, the scientists describe a detailed mechanism by which coiled, tentacle-like arms protruding from the proteasome identify the death sentence label, causing a series of protein-folding maneuvers that pull the doomed protein into the degradation chamber.

Importantly, this interaction between the bacterial proteasome and the marker sequence is unique to bacteria. Human cells use a different marker protein and a completely different mechanism for drawing doomed proteins into the proteasome. Thus the details of proteasome-substrate interaction revealed by the current study may provide highly specific targets for the development of new anti-tuberculosis therapies.

In addition to Li, Tao Wang of Brookhaven Lab and Heran Darwin of New York University's School of Medicine contributed to this research.

This work was supported by grants from the National Institutes of Health, Brookhaven's Laboratory Directed Research and Development funds, and by a Burroughs Wellcome Investigator in the Pathogenesis of Infectious Diseases award. X-ray diffraction data for this study were collected at the National Synchrotron Light Source (NSLS), supported by the DOE Office of Science (SC). Research was performed at NSLS beam lines X25 and X29, which are supported by funding from SC and the National Center for Research Resources of the National Institutes of Health.

*Sidebar: TB Survival Mechanism

Most people infected with TB remain symptom-free because the bacterium is kept in check within immune system cells. These cells produce compounds such as nitric oxide, which scientists believe damage or destroy the bacteria's proteins. If allowed to accumulate, the damaged proteins would kill the bacteria. But the TB proteasome, a protein-cleaving complex, carves up the damaged proteins, allowing Mycobacterium tuberculosis to survive, and possibly go on to cause active infections.

Related Links

New Details of Tuberculosis Protein-Cleaving Machinery Revealed:
http://www.bnl.gov/bnlweb/pubaf/pr/PR_display.asp?prID=1129
Inhibitors of Important Tuberculosis Survival Mechanism Identified:
http://www.bnl.gov/bnlweb/pubaf/pr/PR_display.asp?prID=996
Studies Suggest New Targets for Tuberculosis Treatments:
http://www.bnl.gov/bnlweb/pubaf/pr/PR_display.asp?prID=06-19
One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by the Research Foundation of State University of New York on behalf of Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.

Visit Brookhaven Lab's electronic newsroom for links, news archives, graphics, and more: http://www.bnl.gov/newsroom

Karen McNulty Walsh | EurekAlert!
Further information:
http://www.bnl.gov

More articles from Life Sciences:

nachricht More genes are active in high-performance maize
19.01.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht How plants see light
19.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Let the good tubes roll

19.01.2018 | Materials Sciences

How cancer metastasis happens: Researchers reveal a key mechanism

19.01.2018 | Health and Medicine

Meteoritic stardust unlocks timing of supernova dust formation

19.01.2018 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>