UCLA scientists have created a mechanism at the nanoscale to externally control the function and action ofa protein.
"We can switch a protein on and off, and while we havecontrolled a specific protein, we believe our approach will work with virtuallyany protein," said Giovanni Zocchi, assistantprofessor of physics at UCLA, member of the California NanoSystemsInstitute and leader of the research effort. "This research has the potentialto start a new approach to protein engineering."
The research, published in the journal Physical ReviewLetters, potentially could lead to a new generation of targeted "smart"pharmaceutical drugs that are active only in cells where a certain gene isexpressed, or a certain DNA sequence is present, Zocchisaid. Such drugs would have reduced side effects. The research, federallyfunded by the National Science Foundation, also may lead to a deeperunderstanding of proteins' molecular architecture.
Proteins are switched on and off in living cells by amechanism called allosteric control; proteins areregulated by other molecules that bind to their surface, inducing a change ofconformation, or distortion in the shape, of the protein, making the proteineither active or inactive, Zocchi explained.
"We have made an artificial mechanism of allostericcontrol based on mechanical tension — the first time this has ever been done," Zocchi said. "Potentially, the applications could be veryfar-reaching and beneficial if the research continues to progress well.
"We insert a molecular spring on the protein, and we cancontrol the stiffness of the spring externally," he said. "We chemically stringa short piece of DNA around the protein. We can switch the protein on and offby changing the stiffness of the DNA. We have made a new molecule, which we cancontrol. By gluing together two disparate pieces of the cell's molecularmachinery, a protein and a piece of DNA, we have created a spring-loadedprotein which can be turned on and off."
Zocchi's graduate student, Brian Choi, worked with a transport protein called MBP (maltosebinding protein), expressed in a bacterium. The MBP protein binds andtransports a sugar.
The first applications Zocchiforesees for the new molecules are as amplified molecular probes. Currently itis difficult for scientists to study a single live cell and find what gene itis expressing, but with an amplified molecular probe, in principle one couldinject the probe into a single cell and detect that the cell is expressing aparticular gene, Zocchi said.
An amplified molecular probe would make it possible to studythe individuality of cells, with applications in stem cell research and theearly detection of disease, said Zocchi, whoselaboratory was established in part through start-up funding from UCLA'sDivision of Physical Sciences.
"I'm interested in conformational changes of macromolecules,and in understanding the physical basis of this allostericmechanism, which is central to the regulation in the cell," Zocchisaid.
Zocchi's co-authors, in addition to Choi, are L.Jeanne Perry, director of UCLA's Protein Expression Technology Center in theInstitute for Genomics and Proteomicsand adjunct associate professor of molecular, cell and developmental biology;former UCLA undergraduate Stephen Canale; and staff researchersYim Wu and Sum Chan.
The research was published in the Jan.28 issue of Physical Review Letters.