London: 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.
"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," said Huilin Li, a Brookhaven biophysicist and associate professor at SBU.
The catch is that human cells have a similar protein-recycling system, essential for their survival, which could also be destroyed by inhibitory drugs.
Using beams of high-intensity x-rays, 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.
The paper published is online October 17, 2010, in the journal Nature Structural and Molecular Biology.