PROTEIN PALMITOYLATION: EXPLORING THE MECHANISMS AND OUTCOMES OF AN ESSENTIAL POST-TRANSLATIONAL MODIFICATION
Palmitoylation (or S-acylation) is a dynamic post-translational modification of eukaryotic proteins. Palmitoylation has many effects on modified proteins, including regulating intracellular sorting, protein-protein interactions, membrane binding, membrane micro-localisation, and stability. A diverse array of proteins is regulated by palmitoylation, including: Ras, Src family kinases, Galpha subunits of heterotrimeric G proteins, G protein-coupled receptors, ion channels, AMPA and NMDA glutamate receptors, and membrane fusion proteins.
Recent work identified a family of 24 'DHHC' palmitoyltransferases that regulate cellular palmitoylation dynamics, and mutations in the genes encoding these proteins have been linked with cancer, schizophrenia, and mental retardation.
To understand how DHHC proteins and palmitoylation contribute to physiology and pathophysiological states, the major research questions being addressed by members of the group are aimed at delineating: (1) How DHHC proteins are regulated. (2) The general principles of DHHC-substrate specificity. (3) How palmitoylation affects the trafficking and function of substrate proteins. (4) New molecules that modulate DHHC protein activity.
We employ a range of techniques to explore the regulation and outcomes of protein palmitoylation, including live-cell imaging (FRAP, iFRAP), image deconvolution and quantitative analyses of fluorescence covariance, yeast-based protein interaction platforms (split-ubiquitin system), and protein palmitoylation assays (radiolabelling, acyl RAC, and click chemistry).