A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms
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Abstract
Tau is a microtubule-associated protein that regulates the stability of microtubules. We use metainference cryoelectron microscopy, an integrative structural biology approach, to determine an ensemble of conformations representing the structure and dynamics of a tau-microtubule complex comprising the entire microtubule-binding region of tau (residues 202-395). We thus identify the ground state of the complex and a series of excited states of lower populations. A comparison of the interactions in these different states reveals positions along the tau sequence that are important to determine the overall stability of the tau-microtubule complex. This analysis leads to the identification of positions where phosphorylation and acetylation events have destabilizing effects, which we validate by using site-specific post-translationally modified tau variants obtained by chemical mutagenesis. Taken together, these results illustrate how the simultaneous determination of ground and excited states of macromolecular complexes reveals functional and regulatory mechanisms.
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Tau phosphorylation at specific sites overlapping AD sites diminishes tau's affinity for microtubules.
“It is well established that tau phosphorylation, especially at specific sites that overlap with the sites that are phosphorylated in AD, diminishes the affinity of tau for microtubules (4, 26–29).”
From All the Tau We Cannot See (2023) · cites this paper as [4]
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- Authors
- Brotzakis, Z. F., Lindstedt, P. R., Taylor, R. J., Rinauro, D. J., Gallagher, N. C. T., Bernardes, G. J. L., & Vendruscolo, M.
- Affiliations
- University of Cambridge (GB)
- University of Lisbon (PT)
- Corresponding author
- Vendruscolo, Michele
- ORCID
- Venue
- ACS Central Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-12-08
- Volume
- 7
- Issue
- 12
- Pages
- 1986-1995
- ISSN
- 2374-7943 (ISSN-L)
- 2374-7951
- PMC
- PMC8704032
- OpenAlex
- W4225655998
- Cited by
- 70
- References
- 42
- Citations by year
- 2026: 17 · 2025: 19 · 2024: 9 · 2023: 13 · 2022: 9 · 2021: 3
- FWCI
- 5.50
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- ACS Central Science (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Cambridge University Engineering Department Publications Database (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Zenodo (CERN European Organization for Nuclear Research) (cc-by)
- Funders
- Royal Society (URF/R/180019)
- Federation of European Biochemical Societies
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Keywords
- tau protein, microtubule-binding region, structural ensembles, excited states, ground state, tau phosphorylation, tau acetylation, post-translational modification, protein stability, chemical mutagenesis
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