Liquid–liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau
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The protein Tau aggregates into tangles in the brain of patients with Alzheimer’s disease. In solution, however, Tau is intrinsically disordered, highly soluble, and binds to microtubules. It is still unclear what initiates the conversion from an innocuous phase of high solubility and functionality to solid-like neurotoxic deposits. Here, we show that the microtubule-binding repeats of Tau, which are lysine-rich, undergo liquid–liquid phase separation in solution. Liquid–liquid demixing causes molecular crowding of amyloid-promoting elements of Tau and drives electrostatic coacervation. Furthermore, we demonstrate that three-repeat and four-repeat isoforms of Tau differ in their ability for demixing. Alternative splicing of Tau can thus regulate the formation of Tau-containing membrane-less compartments. In addition, phosphorylation of Tau repeats promotes liquid–liquid phase separation at cellular protein conditions. The combined data propose a mechanism in which liquid droplets formed by the positively charged microtubule-binding domain of Tau undergo coacervation with negatively charged molecules to promote amyloid formation.
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Peptides containing 2N4R tau microtubule binding repeats or full-length tau undergo LLPS in solution and cells, respectively.
“Peptides containing 2N4R tau microtubule binding repeats or and full-length tau undergo LLPS in solution and cells, respectively [225, 226].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [225]
LLPS may initiate tau aggregation, and this process is enhanced by tau phosphorylation, and impaired by acetylation.
“LLPS may initiate tau aggregation, and this process is enhanced by tau phosphorylation, and impaired by acetylation [225–227].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [225]
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“It is also important to note that, similarly to other disease-associated low complexity proteins [208–210], tau can undergo liquid–liquid phase separation, where tau separates into liquid-like droplets similarly as in a water–oil demixing event [58, 211].”
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Tau liquid–liquid phase separation: At the crossroads of tau physiology and tauopathy
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- Authors
- Ambadipudi, S., Biernat, J., Riedel, D., Mandelkow, E., & Zweckstetter, M.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Max Planck Institute for Biophysical Chemistry (DE)
- Max Planck Society (DE)
- Corresponding author
- Zweckstetter, Markus
- Venue
- Nature Communications
- Published
- 2017-08-17
- Volume
- 8
- Issue
- 1
- Pages
- 275-275
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5561136
- OpenAlex
- W2743471889
- Cited by
- 782
- References
- 91
- Citations by year
- 2026: 57 · 2025: 90 · 2024: 100 · 2023: 104 · 2022: 103 · 2021: 103 · 2020: 100 · 2019: 78 · 2018: 42 · 2017: 3 · 2015: 1 · 2014: 1
- FWCI
- 45.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Max Planck Digital Library (submittedVersion, other-oa)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- DZNE Pub (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- tau protein, liquid-liquid phase separation, microtubule-binding repeats, Alzheimer's disease, coacervation, macromolecular crowding, tau isoforms, alternative splicing, tau phosphorylation, amyloid fibril formation, intrinsically disordered proteins, membrane-less compartments, neurofibrillary tangles
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Brain, Humans, Lysine, Microtubules, Magnetic Resonance Spectroscopy, Phosphorylation, Protein Binding, tau Proteins, Alternative Splicing, Microscopy, Confocal, Protein Isoforms, Protein Aggregation, Pathological
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