Study Title:

Phosphatidic Acid as a pH Biosensor

Study Abstract

Recognition of lipids by proteins is important for their targeting and activation in many signaling pathways, but the mechanisms that regulate such interactions are largely unknown. Here, we found that binding of proteins to the ubiquitous signaling lipid phosphatidic acid (PA) depended on intracellular pH and the protonation state of its phosphate headgroup. In yeast, a rapid decrease in intracellular pH in response to glucose starvation regulated binding of PA to a transcription factor, Opi1, that coordinately repressed phospholipid metabolic genes. This enabled coupling of membrane biogenesis to nutrient availability.

From press release:

Acidity (pH) in cells of baker's yeast, Saccharomyces cerevisiae, regulate the synthesis of cell membranes by controlling the production of enzymes that synthesize membranes. These are the findings of researchers at the University of British Columbia in Vancouver, Canada, in close collaboration with systems biologists at the University of Amsterdam (UvA). The results of this research have just been published in the journal Science. The elucidated mechanism is so simple and universal that it is highly likely that it determines many processes in the cell in all forms of life.

The UvA scientists, led by Dr. Gertien Smits, have been studying the regulation of acidity in the cell. They have developed a method to accurately and quickly measure the pH in live, growing cells. Understanding this process is important because small changes in acidity could have major consequences for the functioning of a living cell. The acidity in the cell is determined by the number of protons. These small charged particles can easily bind to many molecules in living cells, such as proteins, DNA, lipids and metabolites, or just as easily detach from the molecules. Whether or not a proton binds affects the charge properties of these molecules, and hence their properties. Given that this can occur for so many molecules in life, small changes may have big consequences. However, precisely because the process is so sensitive, until now it was very difficult to properly understand the dynamics of the acidity and the effects of their changes.

Acidity as regulator

The Vancouver researchers have focused their research on the regulation of membrane synthesis. They have studied the regulation of a central regulatory protein, Opi1, herein. This protein in the nucleus can inhibit the production of a number of membrane synthesis proteins, but is usually kept outside the nucleus because it binds to a specific lipid for membranes, phosphatidic acid. Together, the research groups from Vancouver and Amsterdam have come up with the hypothesis that the acidity in the cell can sometimes play an important role in regulating Opi1, as the physical and chemical properties of phosphatidic acid are such that the charge can be greatly determined by the proton concentration.

From signal to signal

Through the combination of measurements of pH and determination of the localization of Opi1 in living yeast cells, the correlation between the two has become increasingly apparent. Ultimately, the researchers have managed to show that the interaction between the protein and lipid is directly determined by the acidity in a very small pH range in the cell. This is precisely the range in which the acidity in living yeast cells varies depending on the presence of nutrients. In this way a signal for the presence of food can be converted into a signal to make membranes, and thereby grow. Based on the results the researchers suggest that it is highly probable that the pH determines more regulatory mechanisms and interactions in the cell.

The new findings have important implications for understanding human metabolism and disease because lipid structure and function are very similar amongst all organisms. Further work is needed to explore the implications of this discovery for other areas, such as tumor progression – because both phosphatidic acid and pH play important roles in this process – and brain research – because brain cells dynamically change their cellular pH, implying they, too, use a pH sensor.

Study Information

Barry P. Young, John J. H. Shin, Rick Orij, Jesse T. Chao, Shu Chen Li, Xue Li Guan, Anthony Khong, Eric Jan, Markus R. Wenk, William A. Prinz, Gertien J. Smits, and Christopher J. R. Loewen.
Phosphatidic Acid Is a pH Biosensor That Links Membrane Biogenesis to Metabolism
2010 August
University of British Columbia in Vancouver, Canada.

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