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Cited by 19Alzheimer's disease research and treatmentsMicrotubule and mitosis dynamicsProtein Structure and Dynamics

The pathogenic R5L mutation disrupts formation of Tau complexes on the microtubule by altering local N-terminal structure

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Cario, Alisa, Savastano, Adriana, Wood, Neil B., Liu, Zhu, Previs, Michael J., Hendricks, Adam G., Zweckstetter, Markus, Berger, Christopher L.·2022·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2114215119PMC PMC8851524

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Abstract

Significance: The microtubule-associated protein Tau is strongly linked to a number of neurological diseases. Disease onset is typically associated with weakened interaction with the microtubule, but this widely accepted model is based on hyperphosphorylation or mutations within the C-terminal microtubule-binding domain of Tau. Here, we find that an N-terminal disease-associated mutation in Tau, R5L, does not reduce Tau affinity for microtubules but instead, modifies the N-terminal structure, altering Tau’s behavior and ability to condense on the microtubule surface. Our findings challenge the current paradigms of both how mutations in Tau lead to disease and the functional role of the N-terminal region of Tau.

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  • The pathogenic R5L mutation in the phosphatase-activating domain (PAD) disrupts cooperative binding by altering the structure of the N-terminal projection domain without affecting the microtubule-binding repeats or tau's microtubule affinity.

    “the pathogenic R5L mutation in the phosphatase-activating domain (PAD) disrupts cooperative binding by altering the structure of the N-terminal projection domain without affecting the microtubule-binding repeats or tau's microtubule affinity”

    From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Cario et al., 2022

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Authors
Cario, A., Savastano, A., Wood, N. B., Liu, Z., Previs, M. J., Hendricks, A. G., Zweckstetter, M., & Berger, C. L.
Affiliations
  • University of Vermont (US)
  • German Center for Neurodegenerative Diseases (DE)
  • McGill University (CA)
Corresponding author
Berger, Christopher L.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2022-02-08
Volume
119
Issue
7
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2114215119
PMC
PMC8851524
OpenAlex
W4220720205
Cited by
19
References
2
Citations by year
2026: 6 · 2024: 5 · 2023: 5 · 2022: 3
FWCI
2.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DZNE Pub (submittedVersion, other-oa)
Funders
  • University of Vermont
  • European Commission (HORIZON2020, 787679)
  • Deutsche Forschungsgemeinschaft (TP B2), SFB 860)
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R00HL124041)
  • National Institute of General Medical Sciences (R01GM132646)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
tau protein, progressive supranuclear palsy, intrinsically disordered proteins, microtubule binding, projection domain, tau aggregation, microtubule-associated proteins
MeSH terms
Amino Acid Sequence, Humans, Microtubules, Mutation, tau Proteins, Amino Acid Substitution

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