O-GlcNAc Modification of tau Directly Inhibits Its Aggregation without Perturbing the Conformational Properties of tau Monomers |
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Authors: | Scott A. Yuzwa Adrienne H. Cheung Mark Okon Lawrence P. McIntosh David J. Vocadlo |
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Affiliation: | 1 Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6;2 Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6;3 Department of Biochemistry and Molecular Biology, Department of Chemistry, and the Michael Smith Laboratories, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3 |
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Abstract: | The aggregation of the microtubule-associated protein tau into paired helical filaments to form neurofibrillary tangles constitutes one of the pathological hallmarks of Alzheimer's disease. Tau is post-translationally modified by the addition of N-acetyl-d-glucosamine O-linked to several serine and threonine residues (O-GlcNAc). Previously, increased O-GlcNAcylation of tau has been shown to block the accumulation of tau aggregates within a tauopathy mouse model. Here we show that O-GlcNAc modification of full-length human tau impairs the rate and extent of its heparin-induced aggregation without perturbing its activity toward microtubule polymerization. O-GlcNAcylation, however, does not impact the “global-fold” of tau as measured by a Förster resonance energy transfer assay. Similarly, nuclear magnetic resonance studies demonstrated that O-GlcNAcylation only minimally perturbs the local structural and dynamic features of a tau fragment (residues 353–408) spanning the last microtubule binding repeat to the major GlcNAc-acceptor Ser400. These data indicate that the inhibitory effects of O-GlcNAc on tau aggregation may result from enhanced monomer solubility or the destabilization of fibrils or soluble aggregates, rather than by altering the conformational properties of the monomeric protein. This work further underscores the potential of targeting the O-GlcNAc pathway for potential Alzheimer's disease therapeutics. |
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Keywords: | NFT, neurofibrillary tangle AD, Alzheimer's disease OGT, O-GlcNAc transferase ESI-MS, electrospray ionization mass spectrometry FRET, Fö rster resonance energy transfer HSQC, heteronuclear single quantum correlation NOE, nuclear Overhauser effect ThS, Thioflavin-S TFA, trifluoroacetic acid NSERC, Natural Sciences and Engineering Research Council of Canada |
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