Vesicle movement along axonal microtubules in neurons requires the ATP-dependent molecular motors dynein and kinesin. Fast axonal transport is fueled by ATP, provided by vesicle-associated glycolytic enzymes, but how these predicted soluble enzymes attach to vesicles in unclear. One potential mechanism is the protein lipid modification S-acylation, which involves the addition of long chain fatty acids to protein cysteine residues mediated by the ZDHHC (Asp-His-His-Cys) family of protein S-acyltransferases. Among the many effects this lipid modification imparts is an increase in protein localization to membranes. We found that eight of the ten glycolytic enzymes are S-acylated in the brain. Of the 10 glycolytic enzymes, we focused on glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as it is the first enzyme of the payoff phase of glycolysis. GAPDH is S-acylated on cysteine 247 by ZDHHC5 and ZDHHC17. Importantly, C247 point mutation impairs GAPDH association with vesicles in hippocampal neurons. Investigating the role of S-acylation in glycolytic enzyme localization will lead to novel insights into neuronal transport mechanisms and may also shed light on neurodegenerative disease pathology and potential drug targets.
Herath, N. N., Kogut, J. A., Petropavlovskiy, A. A., Doerksen, A. H., Townsend Bennie, C. A., Dang, A., Thomas, G. M., Martin, D. D., Sanders, S. S.
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