National Science Foundation (NSF)-funded scientists at the Massachusetts Institute of Technology and Northwestern University Medical School have uncovered the structural basis of an elusive replication technique that allows viruses, especially retroviruses, to commandeer cells to manufacture the proteins they need for their own survival. The results appear in a paper published for the March 1999 issue of Nature Structural Biology.
"For many years, scientists have studied a virus' ability to create an RNA structure called a pseudoknot, which allows it to control genetic material for its own purposes via a process called ribosomal frameshifting," explains Kamal Shukla, director of NSF's biophysics program, which funded the research. "Until now, the detailed three-dimensional structure of the pseudoknot - so called because the RNA is not truly knotted, but tightly bound together -- has not been known." The RNA pseudoknot formed by the beet western yellow virus has been crystallized, and the three-dimensional structure reveals many unusual features, the authors of the study report. Ribosomal frameshifting also is used by the AIDS virus.
"This research will help us uncover some of the methods that viruses use to regulate the production of components that are essential to viral replication. Knowledge of this mechanism may allow us to develop ways to modify that process and thus lead to the development of new anti-viral agents," said Alexander Rich, a biophysicist at MIT and one of the study's authors.
The work provides information that will allow researchers to understand which features of the pseudoknot formation facilitate ribosomal frameshifting by introducing mutations or changes in the pseudoknot.
Viruses have developed ingenious systems for invading cells and making more copies of themselves. One of the systems that is used in many viruses, including most retroviruses (the most famous of which is responsible for AIDS) involves inducing changes in the way the virus' genetic material is translated to produce the next generation. The virus needs to synthesize two different proteins. Typically, the first protein is involved in building the virus and the second is an enzyme, usually a polymerase, used in replicating the virus' nucleic acid, or genetic building blocks. But the virus needs many copies of the structural protein and a smaller number of the polymerase proteins, so the virus developed a novel system for regulating the production of these two proteins. It involves the use of ribosomal frameshifting.
The decision to frameshift or not to frameshift depends on whether the pseudoknot unravels when it collides with the ribosome, Rich said. If it does not unravel, the ribosome can slide back one nucleotide and then make a fusion protein, involving both the structural protein and the polymerase. If the pseudoknot does unravel, then only the structural protein is made, but not the polymerase.
This work is also supported by the National Institutes of Health, the National Foundation for Cancer Research, and the National Aeronautics and Space Administration.
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