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 Professor(University of Sherbrooke) CIHR Scholar AHFMR Scholar Department of Cell Biology Role of Dynamic Protein Palmitoylation in Cellular Signaling and Metabolic Regulation Protein fatty acylation is the modification of proteins by fatty acids. Protein fatty acylation greatly alters the physical and functional properties of the modified protein. Roles for protein fatty acylation range from increasing affinity for membranes and the stabilization of protein-protein interactions to the inhibition of enzymatic activity. Recently, a number of proteins involved in intracellular signaling have been shown to be palmitoylated, namely the G protein-linked receptors, the a subunits of heterotrimeric G proteins, the nitric oxide synthase and the src-related protein tyrosine kinases. Due to its reversible nature, protein palmitoylation represents a novel and exciting addition to the repertoire of cellular control mechanisms. However, further understanding of palmitoylation reactions in signal transduction has been hampered by our lack of knowledge about the specific palmitoyl acyl transferases (PATs) and palmitoyl thioesterases (PTEs) involved. In addition to playing an important role in signal transduction, dynamic protein fatty acylation was also shown to play a role in metabolic regulation. The main goal of my research is to characterize the roles of dynamic protein palmitoylation in cellular signaling and metabolic regulation. In order to investigate the role of protein palmitoylation in cellular signaling, my laboratory is interested in: 1) purifying, identifying and characterizing the PAT and PTE enzymes involved in signal transduction. Once PAT and PTE are purified, their cDNAs will be cloned and a mutagenesis approach will be utilized to probe their catalytic mechanisms and regulation, 2) characterizing the role of protein palmitoylation in subcellular targeting and cellular transformation and 3) identifying new palmitoylated proteins involved in cell cycle regulation, cellular proliferation and differentiation. I recently discovered that a mitochondrial protein, methylmalonyl semialdehyde dehydrogenase, is fatty acylated on its active site cysteine residue and that this reversible fatty acylation regulates its enzymatic activity. Moreover, I have also shown that there are at least ten other fatty acylated proteins in mitochondria. The identity of these proteins is unknown and they will be characterized. Another project in my laboratory aims at characterizing the role of dynamic protein fatty acylation in the regulation of metabolism in mitochondria. Currently, mitochondrial fatty acylated proteins are in the process of being purified. These proteins will be identify by cloning their cDNA and will be further characterized. Selected Publications Everett, H., Barry, M., Sun X., Lee, S.F., Frantz, C., Berthiaume L.G., McFadden G. Bleackley, R. C. (2002) "The myxoma poxvirus protein M11L prevents apoptosis by direct interaction with the mitochondrial protein permeability transition pore" J. Exp. Med. (In press).
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