Protein
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
Version 2 2018-06-13, 08:18
Version 1 2018-05-21, 13:35
Posted on 2018-06-13 - 08:18
The
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 pathological 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 lysine 280 (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.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Haj-Yahya, Mahmood; Lashuel, Hilal A. (2018). Protein
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. ACS Publications. Collection. https://doi.org/10.1021/jacs.8b02668
or
Select your citation style and then place your mouse over the citation text to select it.