Professor Williams' research resolves this paradox and shows that the A3G protein does not always have the rapid movement needed for chemical function. Instead, its activity changes over time. "First, A3G is a really fast protein," said Williams. "Then, gradually over time, it becomes a slow protein and remains bound to the DNA, blocking replication."
CHALLENGING POPULAR OPINION
Many researchers doubted that a protein could have both enzyme and roadblock functions. An enzyme is designed to act rapidly, so the idea of the A3G protein starting off fast, and then gradually slowing down seemed physically impossible. Professor Williams' collaborator Dr. Ioulia Rouzina from the University of Minnesota came up with the novel idea that when A3G proteins group together, they become slower over time. To test the idea, the Williams lab used an instrument called optical tweezers that allowed them to stretch single DNA molecules with A3G proteins bound. By measuring the change in DNA length over time as the proteins came on and off the DNA, they could show that the rates at which A3G bound to DNA became slower over time.
How does this happen? It was already known that A3G proteins bind to each other and form a multi-protein complex. "Once the complex is formed, the A3G proteins are no longer able to move rapidly along the DNA strand as needed for chemical modification of the DNA," said Williams. "This suggests that slow binding can also block HIV replication."
IMPACT ON HIV RESEARCH
The A3G protein has at least two mechanisms by which it can block HIV replication. We have known for over 10 years that A3G can, in principle, provide protection from HIV. However, finding a drug that can counter the anti-A3G activity of the virus has been elusive. This new work has the potential to develop alternative approaches to HIV therapy and development of drugs that can enhance the roadblock activity of A3G. This provides an alte
|Contact: Lori Lennon|
Northeastern University College of Science