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

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-GlcNAc modification of the amyloid-forming proteins themselves. Here, we use synthetic protein chemistry to disc...

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Autores principales: Balana, Aaron T., Levine, Paul M., Craven, Timothy W., Mukherjee, Somnath, Pedowitz, Nichole J., Moon, Stuart P., Takahashi, Terry T., Becker, Christian F. W., Baker, David, Pratt, Matthew R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102337/
https://www.ncbi.nlm.nih.gov/pubmed/33723378
http://dx.doi.org/10.1038/s41557-021-00648-8
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author Balana, Aaron T.
Levine, Paul M.
Craven, Timothy W.
Mukherjee, Somnath
Pedowitz, Nichole J.
Moon, Stuart P.
Takahashi, Terry T.
Becker, Christian F. W.
Baker, David
Pratt, Matthew R.
author_facet Balana, Aaron T.
Levine, Paul M.
Craven, Timothy W.
Mukherjee, Somnath
Pedowitz, Nichole J.
Moon, Stuart P.
Takahashi, Terry T.
Becker, Christian F. W.
Baker, David
Pratt, Matthew R.
author_sort Balana, Aaron T.
collection PubMed
description 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-GlcNAc modification 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-GlcNAc increases the ability of sHSPs to block the amyloid formation of both α-synuclein and Aβ(1-42). Mechanistically, we show that O-GlcNAc near the sHSP IXI-domain prevents its ability to intramolecularly compete with substrate binding. Finally, we find that although O-GlcNAc levels are globally reduced in Alzheimer’s disease brains, the modification of relevant sHSPs is either maintained or increased, suggesting a mechanism to maintain these potentially protective O-GlcNAc modifications. Our results have important implications for neurodegenerative diseases associated with amyloid formation and potentially other areas of sHSP biology.
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spelling pubmed-81023372021-09-15 O-GlcNAc modification of small heat shock proteins enhances their anti-amyloid chaperone activity Balana, Aaron T. Levine, Paul M. Craven, Timothy W. Mukherjee, Somnath Pedowitz, Nichole J. Moon, Stuart P. Takahashi, Terry T. Becker, Christian F. W. Baker, David Pratt, Matthew R. Nat Chem Article 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-GlcNAc modification 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-GlcNAc increases the ability of sHSPs to block the amyloid formation of both α-synuclein and Aβ(1-42). Mechanistically, we show that O-GlcNAc near the sHSP IXI-domain prevents its ability to intramolecularly compete with substrate binding. Finally, we find that although O-GlcNAc levels are globally reduced in Alzheimer’s disease brains, the modification of relevant sHSPs is either maintained or increased, suggesting a mechanism to maintain these potentially protective O-GlcNAc modifications. Our results have important implications for neurodegenerative diseases associated with amyloid formation and potentially other areas of sHSP biology. 2021-03-15 2021-05 /pmc/articles/PMC8102337/ /pubmed/33723378 http://dx.doi.org/10.1038/s41557-021-00648-8 Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Balana, Aaron T.
Levine, Paul M.
Craven, Timothy W.
Mukherjee, Somnath
Pedowitz, Nichole J.
Moon, Stuart P.
Takahashi, Terry T.
Becker, Christian F. W.
Baker, David
Pratt, Matthew R.
O-GlcNAc modification of small heat shock proteins enhances their anti-amyloid chaperone activity
title O-GlcNAc modification of small heat shock proteins enhances their anti-amyloid chaperone activity
title_full O-GlcNAc modification of small heat shock proteins enhances their anti-amyloid chaperone activity
title_fullStr O-GlcNAc modification of small heat shock proteins enhances their anti-amyloid chaperone activity
title_full_unstemmed O-GlcNAc modification of small heat shock proteins enhances their anti-amyloid chaperone activity
title_short O-GlcNAc modification of small heat shock proteins enhances their anti-amyloid chaperone activity
title_sort o-glcnac modification of small heat shock proteins enhances their anti-amyloid chaperone activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102337/
https://www.ncbi.nlm.nih.gov/pubmed/33723378
http://dx.doi.org/10.1038/s41557-021-00648-8
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