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 A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

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

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>