Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Glutathione transferases (GSTs) are a superfamily of proteins best known for detoxifying harmful electrophilic compounds by catalyzing their conjugation with glutathione. GSTP1 is one member of this superfamily. In addition to an important role in detoxification, GSTP1 is involved in the regulation of cell signalling. The location of a protein such as GSTP1 within a cell can have a significant effect on how the protein functions. Cells are organized into different compartments suspended in a cellular fluid, all of which are contained within the outer skin known as the plasma membrane. Studies previously suggested that GSTP1 is located in the cellular fluid, but we have discovered that GSTP1 is also located in cellular membranes. We have recently discovered that GSTP1 can be modified with a fatty molecule called palmitate. Palmitate modification is likely responsible for moving the location of GSTP1 from the cellular fluid to cell membranes and might have additional functions. We are trying to determine precisely where palmitoylation is occurring on GSTP1 so that we can generate a nonpalmitate modified GSTP1 mutant. We are trying to understand the influence the palmitate modification has on the structure of GSTP1 and we are using multiple biochemical approaches to investigate this. In addition, the influence of palmitate on the catalytic and non-catalytic functions of GSTP1 will be investigated. This will include the investigation of how GSTP1 tagged with palmitate interacts differently with other proteins. We will also compare how the palmitate modified GSTP1 interacts with pure lipids and membranes isolated from cell lines versus the nonmodified GSTP1. Lastly, we will determine how palmitate tagging influences where GSTP1 is located in the cell. Knowledge gained from this research will lead to novel insights into the fundamental biology of GSTP1 and how palmitate modification influences its structure, function, membrane association, and cellular localization. The GSTP1 form found in cellular fluid is well characterized, however, virtually nothing is known about the palmitate-modified form. This research will provide novel information for the diverse functions of GSTP1 in cellular detoxification and signalling. In addition, results from these studies will have far reaching implications for understanding the influence of palmitate modification on the structure, function, and membrane association of other proteins.