Tau interconverts between diffusive and stable populations on the microtubule surface in an isoform and lattice specific manner
Open accessAbstract
It has been demonstrated that Tau exists on the microtubule lattice in both diffusing and static populations, but how this may relate to Tau function is currently unclear. Tau isoforms are developmentally regulated and have been shown to have disparate effects on microtubule polymerization, the ability to bind microtubules, and the ability to inhibit kinesin. It has also been shown that Tau is sensitive to microtubule stabilizing agents and the ability to affect the persistence length of microtubules and to inhibit kinesin can be altered by stabilizing microtubules with various nucleotide analogs. Given these observations, it is likely the behavior of Tau is dictated by both the isoform of Tau and by structural changes in the microtubule lattice. In the present study, we use single molecule imaging to examine the behavior of the three‐repeat short (3RS) isoform and the four‐repeat long (4RL) isoform on different microtubule tracks stabilized with either paclitaxel or guanylyl‐(α,β)‐methylene‐diphosphate (GMPCPP). On paclitaxel‐stabilized microtubules, we find 3RS‐Tau favors the static conformation and forms complexes consisting of 2–3 molecules, while 4RL‐Tau predominantly exists as a single molecule equally distributed between the static and diffusing populations. However, on GMPCPP‐stabilized microtubules both isoforms favor the diffusing conformation and do not form static complexes composed of more than one Tau molecule. We find both isoforms of Tau interconvert between static and diffusing populations on the microtubule surface, and the equilibrium between these two states depends on both the isoform of Tau and the structure of the underlying microtubule lattice. © 2014 Wiley Periodicals, Inc.
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Tau binds to microtubules in two distinct kinetic phases: cooperative binding that results in the formation of cohesive envelopes and diffusive binding along microtubules.
“Our initial observations, consistent with previous studies, showed that tau binds to microtubules in two distinct kinetic phases: cooperative binding that results in the formation of cohesive envelopes and diffusive binding along microtubules”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as McVicker et al., 2014
The Discussion (page unavailable) reports that tau transitions between diffusing and static states and can form complexes of 2–3 molecules on the microtubule lattice. It does not characterize these as two kinetic phases or establish that cooperative binding produces cohesive envelopes; the Results also show that complex formation depends on how the microtubules are stabilized. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCooperativity leads to cohesive envelope-like structures.
“Cooperativity leads to cohesive envelope-like structures (Dixit et al., 2008; Hinrichs et al., 2012; McVicker et al., 2014; Siahaan et al., 2019; Tan et al., 2019; Siahaan et al., 2022).”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as McVicker et al., 2014
The Results report that tau forms multi-molecule complexes on paclitaxel-stabilized microtubules, and the Discussion describes patches of tau. These findings support the idea of cohesive groupings, but the paper does not show that cooperativity causes them or describe them as envelope-like structures; on GMPCPP-stabilized microtubules, tau instead binds as single molecules. The supplied copy gives no page numbers for these passages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTau exhibits both diffusive and cooperative interactions with microtubules.
“Tau exhibits both diffusive and cooperative interactions with microtubules.”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as McVicker et al., 2014
The Results report diffusing Tau and show that Tau forms multi-molecule complexes on paclitaxel-stabilized microtubules. They do not establish that Tau binds cooperatively; the Discussion uses “cooperative” to describe doublecortin, not Tau. Thus the diffusive interaction is supported, but the cooperative interaction is not established by this paper. (LLM, conf=0.84)
Experimental — accuracy not yet measured3R tau has a lower affinity for microtubules but more strongly inhibits kinesin and dynein motors compared to 4R tau.
“3R tau has a lower affinity for microtubules but more strongly inhibits kinesin and dynein motors compared to 4R tau”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as McVicker et al., 2014
The Discussion (page not available) says 3RS-Tau is a more potent inhibitor of kinesin than 4RL-Tau. The Introduction says the isoforms differ in microtubule affinity but does not specify which has lower affinity; the passages found do not address comparative inhibition of dynein. Thus only the kinesin part is supported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTau's function and microtubule affinity are modulated by alternative splicing and phosphorylation.
“Tau’s function and microtubule affinity are modulated by alternative splicing (Kellogg et al., 2018; McVicker et al., 2014) and phosphorylation, both of which play key roles in normal development and pathology”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as McVicker et al., 2014
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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
Beaudet, D., Berger, C. L., & Hendricks, A. G. (2026) · eLife · doi:10.7554/elife.110011
Self-citation
- Authors
- McVicker, D. P., Hoeprich, G. J., Thompson, A. R., & Berger, C. L.
- Affiliations
- University of Vermont (US)
- Corresponding author
- Berger, Christopher L.
- Venue
- Cytoskeleton
- Publisher
- Wiley
- Published
- 2014-02-24
- Volume
- 71
- Issue
- 3
- Pages
- 184-194
- ISSN
- 1949-3584 (ISSN-L)
- 1949-3592
- PMC
- PMC4154625
- OpenAlex
- W1829764368
- Cited by
- 40
- References
- 2
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 1 · 2023: 5 · 2022: 4 · 2021: 1 · 2020: 1 · 2019: 5 · 2018: 2 · 2017: 5 · 2016: 2 · 2015: 3 · 2014: 3
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cytoskeleton (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Centre for the Replacement Refinement and Reduction of Animals in Research
- National Institute of General Medical Sciences (R01GM101066)
- 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 › Oncology › Cancer Treatment and Pharmacology
- Keywords
- tau protein, tau isoforms, microtubule lattice, microtubule stabilization, paclitaxel, GMPCPP, single-molecule imaging
- MeSH terms
- Animals, Cattle, Diffusion, Guanosine Triphosphate, Humans, Kymography, Microtubules, Time Factors, tau Proteins, Paclitaxel, Protein Isoforms
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