HCV's Gene Unraveling Secret Discovered
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Hepatitis-promoting protein caught in the act
By Greg Kline
Sunday, September 16, 2007 10:29 AM CDT
www.news-gazette.com
When your body, or a nasty virus invading it, cooks up a batch of genes, helicases – an enzyme, or type of catalyzing protein molecule – appear to be bigger than Betty Crocker in the kitchen.
The tasks performed by the proteins apparently include the unwinding of the tightly coiled ribbonlike DNA and RNA molecules containing the instructions for gene making.
Those chains of nucleic acids – the “N” and “A” in DNA and RNA and the basic building blocks of life – are then read by another type of protein molecule, called a polymerase.
But the genetic cookbook has to be cracked open by helicases first, and scientists have been of two minds on how that happens.
Some structural studies of helicases frozen in place seemed to suggest they work one page – or base pair, the basic unit of DNA and RNA strands – at a time.
Meanwhile, biochemical studies indicated that helicases sometimes work over three base pairs at once.
University of Illinois Professors Sua Myong and Taekjip Ha might have resolved the conflict. Their theory, backed by research using a technique developed by Ha to capture the movement of single molecules, is that it’s both.
Helicases have three domains, or legs, as Myong described it recently. Two of those legs step along the acid chains, a base pair at a time during the unwinding process. The third leg remains anchored behind and gets stretched out until enough tension builds that it snaps lose and ahead three pairs. Ha, a UI physics professor, likened its movement to a spring.
“When we saw it, it made a lot of sense,” said Myong, a professor at the UI Institute for Genomic Biology and the lead author of a paper on the study in the journal Science.
While interesting biologically, the information also has the potential to play into medical breakthroughs.
The UI researchers and collaborators at Yale University and the Maryland-based Howard Hughes Medical Institute looked at a helicase from the hepatitis C virus, which affects hundreds of millions of people worldwide – and for which there is no vaccine.
The helicase and its unwinding job are necessary for the virus to replicate, which makes the protein a potential target for new hepatitis C treatments.
That is undoubtedly a ways off and presents some challenges. For one thing, it appears that many helicases, including those of benefit in the human body, might function in a similar manner. A treatment would need to hone in on the hepatitis C helicase while leaving others alone, said Ha, a biological physicist who’s also an affiliate of the Institute for Genomic Biology and of the Hughes Institute.
Besides their role in hepatitis C propagation, helicases have been implicated in human maladies such as cancers and in premature aging diseases, Ha said.
“If they don’t function properly, then you can get into trouble,” he said.
In their study of the hepatitis C helicase, the researchers found that the protein is powered by a lot of energy – and plenty of a cellular fuel called adenosine triphosphate, or ATP, to generate it. Ha said that makes a helicase more like an SUV than an economy car in this instance.
But gas guzzling could be a good thing here, Ha and Myong said. The nucleic acid chain road is a rough one, full of bumps and twists and turns and possibly obstacles to be cleared, such as other proteins interacting with the DNA or RNA molecules. The helicases might need an SUV’s power and off-road capability, a lot more than most SUV owners do, to get their job done.
To track the tiny protein as it moves, Ha’s lab uses a method called fluorescence resonance energy transfer, FRET for short, in which the researchers attach, through a biochemical process, fluorescent dye markers at various locations.
The sample is exposed to laser light, which makes the dye glow, and glow in different colors depending on its proximity to another marker.
Those light signals can be captured and interpreted to understand how a helicase is moving, at a resolution that allows not only pictures but animations to be created from the data.
The study was funded by the National Institute of General Medical Sciences at the National Institutes of Health.
Next, the researchers need to look at other helicases in action, Ha said. Myong has a plan to contrast the hepatitis C helicase with a helicase involved in putting the body’s immune system on a battle footing in response to invaders like the hepatitis virus.
