Discovery of 'overdrive' protein could broaden drug desi...(gy Program predoctoral fellowship. D...),Health

Despite 20 years of study, G-protein signaling continues to produce surprises. The advent of the human genome project revealed that some three percent of our DNA is dedicated to these messenger molecules. However, the genomic data also drew biologists away from the research technique the UNC team used to discover the new protein, Dohlman said. People stopped looking for things that could activate G-proteins using functional criteria, he said. Instead, they searched for new receptors and activators based on common genetic patterns.

Mike Lee, a graduate student in the UNC School of Medicines department of pharmacology, identified the new protein, called Arr4, in yeast cells. Lee employed a mutant form of G-protein to search for any messengers inside the yeast cell with an affinity for G-proteins.

We went looking for things that could activate G-proteins but dont resemble known receptors, Lee said.

He identified seven proteins that werent receptors, but did bind to G-proteins, and did further tests on one of the seven proteins, Arr4, to determine its function.

In yeast, Arr4 is involved in cell fusion, a process in which two yeasts fuse together to form one cell, combining their genetic data. A G-protein coupled receptor (GPCR) controls cell fusion, while Arr4 appears to play a supporting role.

Lee said he thinks that Arr4 may allow the cell to go through several additional rounds of signal activation without needing to go back to the receptor.

Our current thinking is its not so much that this is the ignition for signaling, its more like an overdrive. Once the pathway is activated by the hormone outside, Arr4 sustains the activity inside, Lee said. What we dont know is if Arr4 is itself simulated by some signal, and of course were very interested in finding out if thats the case.

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