Key difference in how TB bacteria degrade doomed proteins

Oct 17, 2010
Top view

(PhysOrg.com) -- 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 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."

Side view. These computer-generated images show how the “kiss of death” protein marker sequence (red) is recognized by and binds to one of three long tentacle-like structures of an enzyme (green) that sits at the entrance to the TB bacterium’s protein-degradation chamber, or proteasome — shown to the right of the green region in the side view. The enzyme will unfold the marked protein and feed it into the proteasome for degradation.

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 into the degradation chamber.

Importantly, this interaction between the bacterial proteasome and the marker sequence is unique to bacteria. Human 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.

Explore further: Herpes virus hijackers

Related Stories

Researchers discover new antituberculosis compounds

Sep 16, 2009

Attempts to eradicate tuberculosis (TB) are stymied by the fact that the disease-causing bacteria have a sophisticated mechanism for surviving dormant in infected cells. Now, a team of scientists led by researchers from Weill ...

Team finds most complex protein knot ever seen

Sep 20, 2006

An MIT team has discovered the most complicated knot ever seen in a protein, and they believe it may be linked to the protein's function as a rescue agent for proteins marked for destruction.

Recommended for you

Herpes virus hijackers

May 22, 2015

The virus responsible for the common cold sore hijacks the machinery within our cells, causing them to break down and help shield the virus from our immune system, researchers from the University of Cambridge ...

Bacteria cooperate to repair damaged siblings

May 21, 2015

A University of Wyoming faculty member led a research team that discovered a certain type of soil bacteria can use their social behavior of outer membrane exchange (OME) to repair damaged cells and improve ...

New antibody insecticide targets malaria mosquito

May 20, 2015

Malaria is a cruel and disabling disease that targets victims of all ages. Even now, it is estimated to kill one child every minute. Recent progress in halting the spread of the disease has hinged on the ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.