Structural and Functional Implications of Tau Hyperphosphorylation: Information from Phosphorylation-Mimicking Mutated Tau Proteins
Abstract
Abnormal tau-immunoreactive filaments are a hallmark of tauopathies, including Alzheimer's disease (AD). A higher phosphorylation ("hyperphosphorylation") state of tau protein may represent a critical event. To determine the potential role of tau hyperphosphorylation in these disorders, mutated tau proteins were produced where serine/threonine residues known to be highly phosphorylated in tau filaments isolated from AD patients were substituted for glutamate to simulate a paired helical filament (PHF)-like tau hyperphosphorylation. We demonstrate that, like hyperphosphorylation, glutamate substitutions induce compact structure elements and SDS-resistant conformational domains in tau protein. Hyperphosphorylation-mimicking glutamate-mutated tau proteins display a complete functional loss in its ability to promote microtubule nucleation which can partially be overcome by addition of the osmolyte trimethylamine N-oxide (TMAO), which is similar to phosphorylated tau. In addition, glutamate-mutated tau proteins fail to interact with the dominant brain protein phosphatase 2A isoform ABalphaC, and exhibit a reduced ability to assemble into filaments. Interestingly, wild-type tau and phosphorylation-mimicking tau similarly bind to microtubules when added alone, but the mutated tau is almost completely displaced from the microtubule surface by equimolar concentrations of wild-type tau. The data indicate that glutamate-mutated tau proteins provide a useful model for analyzing the funct…
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In Alzheimer disease brain, abnormal hyperphosphorylation of tau in the microtubule-binding repeat and flanking domains is thought to change tau conformation and decrease its affinity for microtubules, resulting in microtubule instability and neurofibrillary tangle formation.
“In AD brain, abnormal hyperphosphorylation of tau in these regions is thought to change the conformation of tau and decrease its affinity for microtubules, resulting in microtubule instability and neurofibrillary tangle formation (7, 8).”
From An Unbiased Approach to Identifying Tau Kinases That Phosphorylate Tau at Sites Associated with Alzheimer Disease (2013) · cites this paper as [8]
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- Authors
- Eidenmüller, J., Fath, T., Hellwig, A., Reed, J., Sontag, E., & Brandt, R.
- Affiliations
- German Cancer Research Center (DE)
- Corresponding author
- Brandt, Roland
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2000-10-01
- Volume
- 39
- Issue
- 43
- Pages
- 13166-13175
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2058714994
- Cited by
- 117
- References
- 5
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 4 · 2017: 4 · 2016: 5 · 2015: 2 · 2014: 4 · 2013: 3 · 2012: 6
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG012300, AG 12300)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau hyperphosphorylation, tauopathy, Alzheimer's disease, glutamate substitution, paired helical filaments, microtubule nucleation, trimethylamine N-oxide, protein phosphatase 2A, protein conformation
- MeSH terms
- Adult, Amino Acid Sequence, Humans, Actin Cytoskeleton, Microtubules, Molecular Sequence Data, Phosphoprotein Phosphatases, Phosphorylation, Protein Conformation, Serine, Structure-Activity Relationship, Threonine, Polymerase Chain Reaction, Mutagenesis, Site-Directed, tau Proteins, Glutamic Acid, Molecular Mimicry, Amino Acid Substitution, Protein Phosphatase 2
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