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O-GlcNAcylation inhibits the oligomerization of alpha-synuclein by declining intermolecular hydrogen bonds through a steric effect.

Authors
  • Wu, Kai1
  • Li, Dechang
  • Xiu, Peng
  • Ji, Baohua
  • Diao, Jiajie
  • 1 Department of Engineering Mechanics, Zhejiang University, Hangzhou 310027, People's Republic of China. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States of America. , (China)
Type
Published Article
Journal
Physical Biology
Publisher
IOP Publishing
Publication Date
Dec 01, 2020
Volume
18
Issue
1
Pages
16002–16002
Identifiers
DOI: 10.1088/1478-3975/abb6dc
PMID: 32906104
Source
Medline
Language
English
License
Unknown

Abstract

Toxic abnormal aggregation of α-synuclein (α-Syn) is a feature of Parkinson's disease. Several biochemical and biophysical studies have demonstrated that many post-translational modifications (PTM) of α-Syn could distinctly alleviate its oligomerization-mediated toxicity. Recently, a compelling link is emerging between the PTM O-GlcNAcylation (O-GlcNAc) and protein aggregation, yet the underlying molecular mechanism remains unclear. Based on the all-atom molecular dynamics simulations, we found that O-GlcNAc modifications can suppress the process of oligomerization of α-Syn aggregates via a steric effect-the additional O-linked glycosyl group disrupts the formation of hydrogen bonds (H-bonds) between α-Syn monomers. Besides, we proposed a theoretical model to further capture the physical mechanism of α-Syn aggregation/disaggregation in the absence/presence of O-GlcNAc-modified α-Syn. Our findings unveil the molecular mechanism of the O-GlcNAc-induced inhibition of α-Syn oligomerization, which may help to understand how O-GlcNAc prevents the oligomerization of other proteins and provides the guideline for the development of O-GlcNAc-based therapeutic strategies in neurodegenerative diseases.

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