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bioRxiv · 10.1101/869909

O-GlcNAcylation of small heat shock proteins enhances their anti-amyloid chaperone activity

Balana, A. T.·Levine, P. M.·Mukherjee, S.·Pedowitz, N. J.·Moon, S. P.·Takahashi, T. T.·Becker, C. F. W.·Pratt, M. R.
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Abstract

A major role for the intracellular posttranslational modification O-GlcNAc appears to be the inhibition of protein aggregation. Most of the previous studies in this area have focused on O-GlcNAcylation of the amyloid-forming proteins themselves. Here, we use synthetic protein chemistry to discover that O-GlcNAc also activates the anti-amyloid activity of certain small heat shock proteins (sHSPs), a potentially more important modification event that can act broadly and substoichiometrically. More specifically, we find that O-GlcNAcylation increases the ability of sHSPs to block the amyloid formation of both -synuclein and A{beta}. Mechanistically, we show that O-GlcNAc near the sHSP IXI-domain prevents its ability to intramolecularly compete with substrate binding. Our results have important implications for neurodegenerative diseases associated with amyloid formation and potentially other areas of sHSP biology.

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Balana, A. T., Levine, P. M., Mukherjee, S., Pedowitz, N. J., Moon, S. P., Takahashi, T. T., Becker, C. F. W., Pratt, M. R.. 2019-12-10. O-GlcNAcylation of small heat shock proteins enhances their anti-amyloid chaperone activity. https://doi.org/10.1101/869909

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