Proline-directed Pseudo-phosphorylation at AT8 and PHF1 Epitopes Induces a Compaction of the Paperclip Folding of Tau and Generates a Pathological (MC-1) Conformation
Open accessAbstract
Tau, a neuronal microtubule-associated protein that aggregates in Alzheimer disease is a natively unfolded protein. In solution, Tau adopts a "paperclip" conformation, whereby the N- and C-terminal domains approach each other and the repeat domain ( Jeganathan, S., von Bergen, M., Brutlach, H., Steinhoff, H. J., and Mandelkow, E. (2006) Biochemistry 45, 2283-2293 ). In AD, Tau is in a hyperphosphorylated state. The consequences for microtubule binding or aggregation are a matter of debate. We therefore tested whether phosphorylation alters the conformation of Tau. To avoid the ambiguities of heterogeneous phosphorylation we cloned "pseudo-phosphorylation" mutants of Tau where combinations of Ser or Thr residues were converted into Glu. These mutations were combined with FRET pairs inserted in different locations to allow distance measurements. The results show that the paperclip conformation becomes tighter or looser, depending on the pseudo-phosphorylation state. In particular, pseudo-phosphorylation at the epitope of the diagnostic antibody AT8* (S199E + S202E + T205E) moves the N-terminal domain away from the C-terminal domain. Pseudo-phosphorylation at the PHF1 epitope (S396E + S404E) moves the C-terminal domain away from the repeat domain. In both cases the paperclip conformation is opened up. By contrast, the combination of AT8* and PHF1 sites leads to compaction of the paperclip, such that the N-terminus approaches the repeat domain. The compaction becomes even stronger by combining pseudo-phosphorylated AT8*, AT100, and PHF1 epitopes. This is accompanied by a strong increase in the reaction with conformation-dependent antibody MC1, suggesting the generation of a pathological conformation characteristic for Tau in AD. Furthermore, the compact paperclip conformation enhances the aggregation to paired helical filaments but has little influence on microtubule interactions. The data provide a framework for the global folding of Tau dependent on proline-directed phosphorylation in the domains flanking the repeats and the consequences for pathological properties of Tau.
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When Ser199/Ser202/Thr205 sites are phosphorylated, the N-terminal domain swings away from the C-terminal domain, resulting in a conformation that extends from the MT wall.
“When the Ser199/Ser202/Thr205 sites are phosphorylated the N-terminal domain swings away from the C-terminal domain, resulting in a conformation that extends from the MT wall (Jeganathan et al., 2008).”
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 Jeganathan et al., 2008
The Results passage on the AT8* mutant (page unavailable) reports that mimicking phosphorylation at Ser199, Ser202, and Thr205 makes the N-terminal domain swing away from the C-terminal domain. The paper used phosphomimetic mutations rather than directly phosphorylating those sites. It separately states that Tau’s N-terminal domain projects away from the microtubule surface, but does not establish that AT8* produces a conformation extending from the microtubule wall. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPhosphorylation at the AT8 sites may extend the projection domain outwards from the surface of microtubules and affect mitochondrial transport.
“Phosphorylation at these sites may extend the projection domain outwards from the surface of MTs (Jeganathan et al., 2008) and affect mitochondrial transport (Mukhopadhyay and Hoh, 2001;Jeganathan et al., 2008;Shahpasand et al., 2008).”
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 Jeganathan et al., 2008
The Results passage (Fig. 2C–D; page unavailable) reports that an AT8 phosphorylation mimic makes tau’s N-terminal domain swing away from its C-terminal domain. The introductory passage says the N-terminal domain projects away from the microtubule surface, but the study does not show that AT8 phosphorylation extends it farther from that surface. It discusses microtubule-based organelle transport generally, not an effect on mitochondrial transport. (LLM, conf=0.82)
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- Authors
- Jeganathan, S., Hascher, A., Chinnathambi, S., Biernat, J., Mandelkow, E.-M., & Mandelkow, E.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 283
- Issue
- 46
- Pages
- 32066-32076
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1968232509
- Cited by
- 278
- References
- 7
- Citations by year
- 2026: 18 · 2025: 33 · 2024: 14 · 2023: 15 · 2022: 10 · 2021: 18 · 2020: 17 · 2019: 18 · 2018: 22 · 2017: 12 · 2016: 11 · 2015: 16 · 2014: 19 · 2013: 10 · 2012: 14
- FWCI
- 6.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, proline-directed phosphorylation, Alzheimer's disease, protein folding, paired helical filaments, tau aggregation, microtubule binding, intrinsically disordered proteins, conformational change
- MeSH terms
- Alzheimer Disease, Antibodies, Epitopes, Circular Dichroism, Mutation, Phosphorylation, Proline, Protein Conformation, Protein Denaturation, tau Proteins, Protein Structure, Secondary, Protein Folding, Guanidine, Microscopy, Electron, Transmission
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