The microtubule-associated tau protein has intrinsic acetyltransferase activity
Open accessAbstract
Tau proteins are the building blocks of neurofibrillary tangles (NFTs) found in a range of neurodegenerative tauopathies, including Alzheimer's disease. Recently, we demonstrated that tau is extensively post-translationally modified by lysine acetylation, which impairs normal tau function and promotes pathological aggregation. Identifying the enzymes that mediate tau acetylation could provide targets for future therapies aimed at reducing the burden of acetylated tau. Here, we report that mammalian tau proteins possess intrinsic enzymatic activity capable of catalyzing self-acetylation. Functional mapping of tau acetyltransferase activity followed by biochemical analysis revealed that tau uses catalytic cysteine residues in the microtubule-binding domain to facilitate tau lysine acetylation, thus suggesting a mechanism similar to that employed by MYST-family acetyltransferases. The identification of tau as an acetyltransferase provides a framework to further understand tau pathogenesis and highlights tau enzymatic activity as a potential therapeutic target.
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Tau proteins have intrinsic enzymatic activity that catalyzes self-acetylation, mediated by a pair of catalytic cysteine residues in the MT-binding domain.
“Tau proteins possess intrinsic enzymatic activity capable of catalyzing self-acetylation mediated by a pair of catalytic cysteine residues residing within the microtubulin (MT)-binding domain.373”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [373]
The two cysteine-containing regions of K18 are highly similar to catalytic regions in MYST-family acetyltransferases Esa1 and Tip60.
“These two regions are highly similar to the catalytic regions in MYST-family acetyltransferase Esa1 and Tip60.379”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [379]
Close lysine-cysteine contacts in K18 may facilitate tau's self-acetylation activity mediated by cysteine residues.
“The close lysine-cysteine contacts in K18 may facilitate tau’s self-acetylation activity mediated by cysteine residues as reported recently.379”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [379]
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- Authors
- Cohen, T. J., Friedmann, D., Hwang, A. W., Marmorstein, R., & Lee, V. M. Y.
- Affiliations
- University of Pennsylvania (US)
- The Wistar Institute (US)
- Corresponding author
- Cohen, Todd J
- Venue
- Nature Structural & Molecular Biology
- Published
- 2013-04-28
- Volume
- 20
- Issue
- 6
- Pages
- 756-762
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC3827724
- OpenAlex
- W1998344552
- Cited by
- 149
- References
- 33
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 7 · 2023: 9 · 2022: 12 · 2021: 16 · 2020: 19 · 2019: 9 · 2018: 17 · 2017: 11 · 2016: 9 · 2015: 7 · 2014: 11 · 2013: 5 · 2012: 1
- FWCI
- 7.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Institute on Aging (P01AG017586, AG17586)
- National Cancer Institute (T32CA009171)
- National Institute of General Medical Sciences (R01GM060293, GM060293)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- tau protein, lysine acetylation, acetyltransferase activity, microtubule-binding domain, catalytic cysteine residue, neurofibrillary tangles, tauopathy, Alzheimer's disease, protein aggregation, post-translational modification
- MeSH terms
- Acetylation, Acetyltransferases, Cysteine, DNA Mutational Analysis, Kinetics, Lysine, Microtubules, Protein Binding, tau Proteins
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