Phosphoregulation of Tau modulates inhibition of kinesin-1 motility
Open accessAbstract
Microtubule-based axonal transport is tightly regulated by numerous pathways, ensuring appropriate delivery of specific organelle cargoes to selected subcellular domains. Highlighting the importance of this process, pathological evidence has linked alterations in these pathways to the pathogenesis of several neurodegenerative diseases. An important regulator of this system, the microtubule-associated protein Tau, has been shown to participate in signaling cascades, modulate microtubule dynamics, and preferentially inhibit kinesin-1 motility. However, the cellular means of regulating Tau’s inhibition of kinesin-1 motility remains unknown. Tau is subject to various posttranslational modifications, including phosphorylation, but whether phosphorylation regulates Tau on the microtubule surface has not been addressed. It has been shown that tyrosine 18 phosphorylated Tau regulates inhibition of axonal transport in the disease state. Tyrosine 18 is both a disease- and nondisease-state modification and is therefore an attractive starting point for understanding control of Tau’s inhibition of kinesin-1 motility. We show that pseudophosphorylation of tyrosine 18 reduces 3RS-Tau’s inhibition of kinesin-1 motility. In addition, we show that introduction of negative charge at tyrosine 18 shifts Tau’s previously described static–dynamic state binding equilibrium toward the dynamic state. We also present the first evidence of Tau’s static–dynamic state equilibrium under physiological conditions.
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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 Stern et al., 2017
The Results (Figure 3; page unavailable) show that Tau can bind statically or move dynamically along the microtubule surface, and the Discussion describes concentration-dependent multiprotein patches. The paper does not describe these as two kinetic phases in which cooperative binding produces cohesive envelopes; it also says static binding at low concentration is not governed by complex formation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMutations at Y18 increase tau dynamics on microtubules, reduce tau accumulation, and impair tau-mediated regulation of intracellular transport.
“mutations at Y18, the terminal residue of PAD, increase tau dynamics on microtubules, reduce tau accumulation, and impair tau-mediated regulation of intracellular transport”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Stern et al., 2017
The Results report that the Y18E phosphomimetic shifts 3RS-Tau toward dynamic binding on microtubules and reduces its inhibition of kinesin-1 motility. The Discussion also reports less Y18E Tau bound to microtubules, which may explain “reduced accumulation” if that means reduced microtubule binding. The claim overgeneralizes these findings to Y18 mutations as a group and to intracellular transport broadly; the motility experiment measured kinesin-1 in vitro. (LLM, conf=0.85)
Experimental — accuracy not yet measured
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Synaptic dysfunction in Alzheimer's disease: Mechanisms and therapeutic strategies
Chen, Y., Fu, A. K. Y., & Ip, N. Y. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.11.006 · Cited by 258 · see citing works
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Self-citationBeaudet, D., Berger, C. L., & Hendricks, A. G. (2026) · eLife · doi:10.7554/elife.110011
Self-citation
- Authors
- Stern, J. L., Lessard, D. V., Hoeprich, G. J., Morfini, G. A., & Berger, C. L.
- Affiliations
- University of Vermont (US)
- University of Illinois Chicago (US)
- Corresponding author
- Berger, Christopher L.
- Venue
- Molecular Biology of the Cell
- Published
- 2017-04-15
- Volume
- 28
- Issue
- 8
- Pages
- 1079-1087
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC5391184
- OpenAlex
- W2594553294
- Cited by
- 69
- References
- 4
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 7 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 3 · 2019: 9 · 2018: 7 · 2017: 7
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- cc-by-nc-sa
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- University of Vermont
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM101066)
- National Institute of Neurological Disorders and Stroke (R01NS066942)
- 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 phosphorylation, axonal transport, microtubule-associated proteins, microtubule dynamics, neurodegenerative diseases
- MeSH terms
- Axonal Transport, Cell Movement, Cytoskeleton, Humans, Microtubules, Neurons, Phosphorylation, Protein Binding, Tyrosine, Kinesins, tau Proteins
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