Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes
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Abstract
Tau is an intrinsically disordered protein, which diffuses on microtubules 1. In neurodegenerative diseases, collectively termed tauopathies, malfunction of tau and its detachment from axonal microtubules are correlated with axonal degeneration 2. Tau can protect microtubules from microtubule-degrading enzymes such as katanin 3. However, how tau carries out this regulatory function is still unclear. Here, using in vitro reconstitution, we show that tau molecules on microtubules cooperatively form cohesive islands that are kinetically distinct from tau molecules that individually diffuse on microtubules. Dependent on the tau concentration in solution, the islands reversibly grow or shrink by addition or release of tau molecules at their boundaries. Shielding microtubules from kinesin-1 motors and katanin, the islands exhibit regulatory qualities distinct from a comparably dense layer of diffusible tau. Superprocessive kinesin-8 motors penetrate the islands and cause their disassembly. Our results reveal a microtubule-dependent phase of tau that constitutes an adaptable protective layer on the microtubule surface. We anticipate that other intrinsically disordered axonal proteins display a similar cooperative behaviour and potentially compete with tau in regulating access to the microtubule surface.
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The proline-rich region and C-terminal pseudo-repeat domain of tau regulate its cooperative interactions with microtubules.
“the proline-rich region and C-terminal pseudo-repeat domain of tau regulate its cooperative interactions with microtubules”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Siahaan et al., 2019
The section “Tau on microtubules separates into two kinetically distinct phases” reports cooperative tau-island formation and finds that a construct lacking the N-terminus did not form islands. It does not isolate the proline-rich region or establish a regulatory role for the C-terminal pseudo-repeat domain, so the claim’s domain-specific attribution is not supported. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAt high levels of tau, when the lattice is fully decorated, bending of the lattice leads to local decrease in tau densities, which could be explained by disruption of the tau envelope on stretched lattice on the outer side of the bend.
“By contrast, at high levels of tau, when the lattice is fully decorated by tau, bending of the lattice leads to local decrease in tau densities28, which could be explained by the disruption of the tau envelope on stretched lattice on the outer side of the bend.”
From Microtubule lattice spacing governs cohesive envelope formation of tau family proteins (2022) · cites this paper as [28]
The Additional information figure caption (p. unavailable) reports significantly lower tau density on highly curved microtubule regions than in islands on straight regions. The paper also reports saturation at high tau concentrations, but the cited passages do not establish that bending itself causes the density decrease under those conditions. The proposed disruption of a tau envelope appears after the citation as the citing authors’ explanation, not a finding attributed to this source. (LLM, conf=0.80)
Experimental — accuracy not yet measuredTau envelopes can be detected by their occlusion of kinesin-1.
“However, tau envelopes can be detected by their effect on kinesin-1, which is occluded from the envelopes28.”
From Microtubule lattice spacing governs cohesive envelope formation of tau family proteins (2022) · cites this paper as [28]
Tau molecules inside envelopes do not diffuse but remain stationary.
“since tau molecules inside envelopes do not diffuse, but remain stationary9,28.”
From Microtubule lattice spacing governs cohesive envelope formation of tau family proteins (2022) · cites this paper as [28]
During taxol-driven extension of the native compacted microtubule lattice, tau signal disappeared from microtubules in patterns resembling disassembly of tau envelopes in vitro.
“we found that the tau signal disappeared from the microtubules in patterns that resembled the disassembly of tau envelopes in vitro9,28.”
From Microtubule lattice spacing governs cohesive envelope formation of tau family proteins (2022) · cites this paper as [28]
If tau were bound non-cooperatively, tau would unbind uniformly along the microtubule length, as observed for non-cooperatively bound tau in vitro.
“If tau would have been bound non-cooperatively, we would expect tau to unbind from the microtubules uniformly along the microtubule length, as observed for non-cooperatively bound tau in vitro28.”
From Microtubule lattice spacing governs cohesive envelope formation of tau family proteins (2022) · cites this paper as [28]
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Cites
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Flagged first, then by citations
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Cited by
Sorted by citations
Microtubule lattice spacing governs cohesive envelope formation of tau family proteins
Siahaan, V., Tan, R., Humhalova, T., Libusova, L., Lacey, S. E., Tan, T., Dacy, M., Ori-McKenney, K. M., McKenney, R. J., Braun, M., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01096-2 · Cited by 94 · see citing works
Self-citationModeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming
Sun, Z., Kwon, J.-S., Ren, Y., Chen, S., Walker, C. K., Lu, X., Cates, K., Karahan, H., Sviben, S., Fitzpatrick, J. A. J., et al. (2024) · Science · doi:10.1126/science.adl2992 · Cited by 77 · see citing works
“Both ADAD and HC neurites displayed p-tau signals, mirroring the tau island patterns observed in primary neurons (20, 38, 39) (Fig.”
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Liquid − liquid phase separation of tau: Driving forces, regulation, and biological implications
Li, P., Chen, J., Wang, X., Su, Z., Gao, M., & Huang, Y. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106167 · Cited by 30 · see citing works
Beaudet, D., Berger, C. L., & Hendricks, A. G. (2026) · eLife · doi:10.7554/elife.110011
- Authors
- Siahaan, V., Krattenmacher, J., Hyman, A. A., Diez, S., Hernández-Vega, A., Lansky, Z., & Braun, M.
- Affiliations
- Czech Academy of Sciences, Institute of Biotechnology (CZ)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Czech Academy of Sciences (CZ)
- Corresponding author
- Braun, Marcus
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2019-09
- Volume
- 21
- Issue
- 9
- Pages
- 1086-1092
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2971448217
- Cited by
- 169
- References
- 5
- Citations by year
- 2026: 28 · 2025: 18 · 2024: 21 · 2023: 26 · 2022: 21 · 2021: 26 · 2020: 21 · 2019: 8
- FWCI
- 12.73
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Cell Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Grantová Agentura České Republiky (18-08304S, 17-12496Y)
- 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 › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- tau protein, microtubules, tauopathy, intrinsically disordered proteins, phase separation, kinesin-1, kinesin-8, katanin, microtubule severing, axonal degeneration, protein diffusion, axonal proteins
- MeSH terms
- Katanin, Adenosine Triphosphatases, Animals, Axons, Cells, Cultured, Kinetics, Microtubules, Neurons, Kinesins, tau Proteins, Neurodegenerative Diseases
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