An isozyme-specific redox switch in human brain glycogen phosphorylase modulates its allosteric activation by AMP
Résumé
Brain glycogen and its metabolism are increasingly recognized as major players in
brain functions. Moreover, alteration of glycogen metabolism in the brain
contributes to neurodegenerative processes. In the brain, both muscle and brain
glycogen phosphorylase isozymes regulate glycogen mobilization. However, given
their distinct regulatory features, these two isozymes could confer distinct
metabolic functions of glycogen in brain. Interestingly, recent proteomics
studies have identified isozyme-specific reactive cysteine residues in brain
glycogen phosphorylase (bGP). In this manuscript, we show that the activity of
human bGP is redox-regulated through the formation of a disulphide bond involving
a highly reactive cysteine unique to the bGP isozyme. We found that this
disulphide bond acts as a redox switch that precludes the allosteric activation
of the enzyme by AMP without affecting its activation by phosphorylation. This
unique regulatory feature of bGP sheds new light on the isoform-specific
regulation of glycogen phosphorylase and glycogen metabolism.