Issue Date: March 12, 2012
New Sensor For Cell Metabolites
Tagging nonfluorescent molecules in live biological cells with fluorescent proteins has allowed researchers to visualize the hustle and bustle taking place in these membrane-bound metropolises and was an innovation that garnered the 2008 Nobel Prize in Chemistry.
Now, researchers led by Samie R. Jaffrey at Weill Cornell Medical College in New York City have developed a new sensor, based on RNA instead of protein, that can also use fluorescence to image small molecules and proteins in living cells (Science, DOI: 10.1126/science.1218298). The new RNA sensors can likely be modified to detect a broad range of metabolites, including some that cannot currently be visualized with protein-based fluorescent tags.
This “alternative approach to image and study small-molecule metabolites is an important piece of work and will potentially have broad applications,” comments Taekjip Ha, who develops fluorescence-based imaging methods at the University of Illinois, Urbana-Champaign.
The sensor could find application in a wide range of research, from screening metabolites in cells involved in diabetes, neurodegenerative disease, or cancer to helping drug developers evaluate how their medicines are metabolized, Jaffrey says.
The new sensor relies on an RNA-fluorophore complex that Jaffrey and his colleagues reported last summer in Science (DOI: 10.1126/science.1207339). When an engineered RNA called Spinach interacts with the fluorophore 3,5-difluoro-4-hydroxybenzylidene imidazolinone(DFHBI), the complex produces a bright green color.
To make a sensor that can report the presence of specific biological molecules, Jaffrey’s team extended Spinach by adding a second RNA component that can bind different biological molecules or metabolites of interest, such as adenosine diphosphate, guanine, or S-adenosylmethionine.
When the molecule of interest is not bound, the sensor is unfolded and therefore cannot form a fluorescing complex. When the analyte is bound, the sensor is folded, binds DFHBI, and shines green.
Geoffrey F. Strouse, a chemist at Florida State University, notes that this new sensor faces a stumbling block inherent to many fluorescence-imaging methods—that inserting the RNA into cells may alter the production of metabolites one wishes to measure, a biological version of the Heisenberg uncertainty principle that observing a system inherently changes it. Nevertheless, he says the new approach is “a truly transformative development in molecular beacon technology.”
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