000255077 001__ 255077
000255077 005__ 20190324152258.0
000255077 0247_ $$a10.1021/jacs.8b02668$$2doi
000255077 02470 $$2PMID$$a29684271
000255077 02470 $$a10.1021/jacs.8b02668$$2DOI
000255077 037__ $$aARTICLE
000255077 245__ $$aProtein Semisynthesis Provides Access to Tau Disease-Associated Post-translational Modifications (PTMs) and Paves the Way to Deciphering the Tau PTM Code in Health and Diseased States
000255077 260__ $$c2018-04-24
000255077 269__ $$a2018-04-24
000255077 336__ $$aJournal Articles
000255077 520__ $$aThe microtubule-associated protein Tau plays a central role in neurodegeneration and is a leading therapeutic target for the treatment of Alzheimer’s disease (AD). Several lines of evidence suggest that post-translational modifications (PTMs) regulate the function(s) of Tau, including its subcellular localization, clearance, aggregation, toxicity, and pathology spreading. However, the lack of tools and methodologies that allow site-specific introduction of PTMs in Tau have limited our ability to dissect the role of PTMs in regulating Tau functions in health and disease. To facilitate deciphering the Tau PTM code, we have developed, for the first time, semisynthetic strategies that allow for the site-specific introduction of single or multiple physiological or disease-associated PTMs that occur within residues 246-441 of Tau, which includes the microtubule-binding domain (MTBD). As a proof of concept, we produced unmodified Tau and three Tau variants with single or multiple disease-associated PTMs that were not previously accessible as homogeneously modified proteins; AcK280, pY310, and pS396/pS404. We then focused on investigating the effect of acetylation at lysine280 (AcK280) on the structure, aggregation, and microtubule binding properties of Tau. Our results show that site-specific acetylation at K280 significantly enhances the aggregation rate of Tau and impairs microtubule assembly. Surprisingly, compared with unmodified Tau, which forms long and flexible filaments, AcK280 Tau forms predominantly globular oligomers and short fibrils (< 200 nm) that exhibit a reduced propensity to assemble into long filaments. These findings are consistent with the increased aggregation propensity and pathogenicity of this mutant in animal models of AD and suggest that acetylation at this residue might enhance the seeding capacity or formation of toxic Tau species in vivo. Beyond acetylation and phosphorylation, the development of this semisynthetic strategy provides new opportunities to investigate other types of Tau PTMs and to study the cross-talk between PTMs that occurs within residues 246-441, which were previously inaccessible, thereby paving the way to deciphering the Tau PTM code in health and disease.
000255077 6531_ $$aTau, protein semisynthesis, native chemical ligation, phosphorylation, acetylation, post-translational modifications, PTMs.
000255077 700__ $$aHaj-Yahya, Mahmood
000255077 700__ $$aLashuel, Hilal A.
000255077 773__ $$k21$$j140$$tJournal of the American Chemical Society$$q6611-6621
000255077 8560_ $$falain.borel@epfl.ch
000255077 909C0 $$mhilal.lashuel@epfl.ch$$pLMNN$$0252159$$xU11104
000255077 909CO $$pSV$$particle$$ooai:infoscience.epfl.ch:255077
000255077 960__ $$aanass.chiki@epfl.ch
000255077 961__ $$alaurence.gauvin@epfl.ch
000255077 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000255077 980__ $$aARTICLE
000255077 981__ $$aoverwrite