The nucleotide-binding state of microtubules modulates kinesin processivity and the ability of Tau to inhibit kinesin-mediated transport
Open accessAbstract
The ability of Tau to act as a potent inhibitor of kinesin's processive run length in vitro suggests that it may actively participate in the regulation of axonal transport in vivo. However, it remains unclear how kinesin-based transport could then proceed effectively in neurons, where Tau is expressed at high levels. One potential explanation is that Tau, a conformationally dynamic protein, has multiple modes of interaction with the microtubule, not all of which inhibit kinesin's processive run length. Previous studies support the hypothesis that Tau has at least two modes of interaction with microtubules, but the mechanisms by which Tau adopts these different conformations and their functional consequences have not been investigated previously. In the present study, we have used single molecule imaging techniques to demonstrate that Tau inhibits kinesin's processive run length in an isoform-dependent manner on GDP-microtubules stabilized with either paclitaxel or glycerol/DMSO but not guanosine-5'-((α,β)-methyleno)triphosphate (GMPCPP)-stabilized microtubules. Furthermore, the order of Tau addition to microtubules before or after polymerization has no effect on the ability of Tau to modulate kinesin motility regardless of the stabilizing agent used. Finally, the processive run length of kinesin is reduced on GMPCPP-microtubules relative to GDP-microtubules, and kinesin's velocity is enhanced in the presence of 4-repeat long Tau but not the 3-repeat short isoform. These results shed new light on the potential role of Tau in the regulation of axonal transport, which is more complex than previously recognized.
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Some motors, such as kinesin-1 and kinesin-3, are strongly inhibited by tau in an isoform- and lattice-dependent manner, while kinesin-2 and dynein can more effectively navigate tau-decorated regions.
“While some motors, such as kinesin-1 and kinesin-3, are strongly inhibited by tau in an isoform- and lattice-dependent manner, others, like kinesin-2 and dynein, can more effectively navigate tau-decorated regions”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as McVicker et al., 2011
The Results report that tau shortened the runs of the kinesin motor studied, with 3RS-tau more inhibitory than 4RL-tau; the Discussion says inhibition also depends on the microtubule lattice state. Experimental Procedures identify that motor as KIF5C, a kinesin-1 motor. The paper does not establish the claimed effects on kinesin-3 or that kinesin-2 and dynein navigate tau-decorated regions more effectively. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe extent of tau's influence on motor proteins depends on the tau isoform and PTMs, the underlying microtubule lattice, and the intrinsic properties of the motors themselves.
“The extent of tau’s influence on motor proteins depends on several factors including (1) the tau isoform and PTMs, (2) the underlying microtubule lattice, and (3) the intrinsic properties of the motors themselves.”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as McVicker et al., 2011
The Discussion (page unavailable) says Tau’s effect on kinesin depends on its isoform and interaction with the underlying microtubule lattice. The paper does not establish that Tau’s post-translational modifications or differences in motors’ intrinsic properties determine Tau’s influence; its mention of post-translational modifications concerns kinesin subunits and the microtubule track. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAxonal cargoes are transported by teams of motors with differing sensitivities to tau.
“Axonal cargoes are transported by teams of motors with differing sensitivities to tau, as we observed for kinesin-1 (KIF5C) and kinesin-3 (KIF1A) (Figure 3) and as shown previously”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as McVicker et al., 2011
The introductory passage describes kinesin and dynein transporting axonal cargo, and the Discussion says Tau can modulate kinesin-mediated transport. But the paper does not establish that cargo is carried by teams of motors with differing sensitivities to Tau; its experiments compare Tau isoforms and microtubule conditions for kinesin, not sensitivities across motor types. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPrevious studies showed that tau differentially regulates motor proteins, with kinesin-1 and kinesin-3 being more sensitive to tau-mediated inhibition than kinesin-2 and dynein.
“Previous studies showed that tau differentially regulates motor proteins, with kinesin-1 and kinesin-3 being more sensitive to tau-mediated inhibition than kinesin-2 and dynein”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as McVicker et al., 2011
The Results (page unavailable) show that tau inhibits kinesin run length, with the degree of inhibition differing between tau isoforms. The cited paper does not establish the claimed comparison among kinesin-1, kinesin-3, kinesin-2, and dynein; searches for those motor classes and dynein found no such comparison. (LLM, conf=0.85)
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., 2011
The Results (page unavailable) report that 3RS-Tau inhibited kinesin run lengths more than 4RL-Tau on paclitaxel-stabilized microtubules. The paper does not report that 3R tau has lower microtubule affinity than 4R tau or that it more strongly inhibits dynein; its affinity comparison concerns different microtubule preparations, not a 3R-versus-4R difference. (LLM, conf=0.88)
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Cites
Differential Regulation of Dynein and Kinesin Motor Proteins by Tau
Dixit, R., Ross, J. L., Goldman, Y. E., & Holzbaur, E. L. F. (2008) · Science · doi:10.1126/science.1152993 · Cited by 1,012 · see citing works
Single-molecule investigation of the interference between kinesin, tau and MAP2c
Seitz, A., Kojima, H., Oiwa, K., Mandelkow, E.-M., Song, Y.-H., & Mandelkow, E. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf503 · Cited by 257 · see citing works
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Cited by
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Axonal transport deficits and neurodegenerative diseases
Millecamps, S., & Julien, J.-P. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3380 · Cited by 755 · see citing works
A combinatorial MAP code dictates polarized microtubule transport
Monroy, B. Y., Tan, T. C., Oclaman, J. M., Han, J. S., Simó, S., Niwa, S., Nowakowski, D. W., McKenney, R. J., & Ori-McKenney, K. M. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.01.029 · Cited by 157 · see citing works
Beaudet, D., Berger, C. L., & Hendricks, A. G. (2026) · eLife · doi:10.7554/elife.110011
Self-citation
- Authors
- McVicker, D. P., Chrin, L. R., & Berger, C. L.
- Affiliations
- University of Vermont (US)
- Corresponding author
- Berger, Christopher L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 286
- Issue
- 50
- Pages
- 42873-42880
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3234877
- OpenAlex
- W2037981058
- Cited by
- 85
- References
- 2
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 3 · 2017: 11 · 2016: 6 · 2015: 3 · 2014: 12 · 2013: 7 · 2012: 6
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Centre for the Replacement Refinement and Reduction of Animals in Research
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R21NS066249)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Keywords
- tau protein, kinesin, axonal transport, tau isoforms, paclitaxel, single-molecule imaging
- MeSH terms
- Biological Transport, Microtubules, Nucleotides, Kinesins, tau Proteins, Paclitaxel, Protein Isoforms, Tubulin Modulators
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