Proline-directed and non-proline-directed phosphorylation of PHF-tau
Open accessAbstract
To gain insight into the abnormal phosphorylation of PHF-tau, we have determined the phosphorylation sites by identifying phosphopeptides by means of ion spray mass spectrometry followed by sequencing of ethane-thiol-modified peptides. Nineteen sites have been identified; all but Ser-262 are localized to the amino- and carboxyl-terminal flanking regions of the microtubule-binding domain. Eleven sites correspond to fetal type sites. Unexpectedly, 10 are non-proline-directed, whereas the others are proline-directed. Thus, the abnormal phosphorylation of PHF-tau can be considered to consist of fetal type phosphorylation and additional proline-directed and non-proline-directed phosphorylation. This non-fetal type phosphorylation may provide PHF-tau with the unusual characteristics.
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More than 45 tau residues were found phosphorylated at higher frequencies in post-mortem brain tissue from Alzheimer's disease patients.
“Of which >45 residues were found to be phosphorylated at higher frequencies in post-mortem brain tissue from Alzheimer’s disease patients (Morishima-Kawashima et al., 1995; Hanger et al., 2007; Hanger et al., 2009; Wesseling et al., 2020).”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Morishima-Kawashima et al., 1995
In the section on peptide maps (page unavailable), the paper reports phosphorylated PHF-tau from Alzheimer’s disease brains and identifies 19 sites in its analysis. It does not establish that more than 45 residues were phosphorylated at higher frequencies in patients’ post-mortem brain tissue. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHyperphosphorylation of Tau is linked to neurodegeneration, with phosphorylation of more than 20 sites shown in degenerated brains of Alzheimer's patients.
“However, hyperphosphorylation is linked to neurodegeneration with phosphorylation of more than 20 sites shown in the degenerated brains of Alzheimer's patients (Watanabe et al., 1993;Morishima-Kawashima et al., 1995;Stoothoff and Johnson, 2005).”
From Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease (2012) · cites this paper as Morishima-Kawashima et al., 1995
The opening section reports abnormal phosphorylation of PHF-tau in Alzheimer’s disease and identifies 19 sites, not more than 20. It also describes neurofibrillary tangles as closely related to neuronal loss, while the Discussion presents a link between abnormal tau phosphorylation and neuronal degeneration as a possibility rather than an established finding. (LLM, conf=0.90)
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- Authors
- Morishima-Kawashima, M., Hasegawa, M., Takio, K., Suzuki, M., Yoshida, H., Titani, K., & Ihara, Y.
- Affiliations
- The University of Tokyo (JP)
- RIKEN (JP)
- Fujita Health University (JP)
- Corresponding author
- Ihara, Yasuo
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-01
- Volume
- 270
- Issue
- 2
- Pages
- 823-829
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1978668412
- Cited by
- 557
- References
- 6
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 9 · 2023: 8 · 2022: 14 · 2021: 11 · 2020: 13 · 2019: 9 · 2018: 14 · 2017: 5 · 2016: 22 · 2015: 8 · 2014: 16 · 2013: 14 · 2012: 13
- FWCI
- 20.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (03102008)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Keywords
- PHF-tau, tau phosphorylation, proline-directed phosphorylation, phosphorylation sites, microtubule-binding domain, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Animals, Molecular Sequence Data, Neurofibrils, Peptide Mapping, Phosphopeptides, Phosphorylation, Proline, tau Proteins, Rats
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