Water-directed pinning is key to tau prion formation
Edited by Byron Caughey, National Institute of Allergy and Infectious Diseases (NIH), Hamilton, MT; received October 24, 2024; accepted March 10, 2025 by Editorial Board Member Lila M. Gierasch
Significance
This study presents a step toward designing a tauopathy-specific aggregation pathway by engineering a minimal tau prion building block, jR2R3, that can template and propagate distinct disease folds. We present the finding that P301L—among the widest used mutations in cell and animal models of Alzheimer’s disease—destabilizes an aggregation-prohibiting internal hairpin and enhances the surface water structure at a hyperlocalized site that serves as a pinning site to promote templated aggregation. Our study suggests that P301L may be a more suitable mutation to include in modeling 4R tauopathies, besides frontotemporal dementia, than Alzheimer’s disease, and that mutations are powerful tools for the purpose of designing tau prion models as therapeutic tools.
Abstract
Tau forms fibrillar aggregates that are pathological hallmarks of a family of neurodegenerative diseases known as tauopathies. The synthetic replication of disease-specific fibril structures is a critical gap for developing diagnostic and therapeutic tools. This study debuts a strategy of identifying a critical and minimal folding motif in fibrils characteristic of tauopathies and generating seeding-competent fibrils from the isolated tau peptides. The 19-residue jR2R3 peptide (295 to 313) which spans the R2/R3 splice junction of tau, and includes the P301L mutation, is one such peptide that forms prion-competent fibrils. This tau fragment contains the hydrophobic VQIVYK hexapeptide that is part of the core of all known pathological tau fibril structures and an intramolecular counterstrand that stabilizes the strand–loop–strand (SLS) motif observed in 4R tauopathy fibrils. This study shows that P301L exhibits a duality of effects: it lowers the barrier for the peptide to adopt aggregation-prone conformations and enhances the local structuring of water around the mutation site to facilitate site-directed pinning and dewetting around sites 300-301 to achieve in-register stacking of tau to cross β-sheets. We solved a 3 Å cryo-EM structure of jR2R3-P301L fibrils in which each protofilament layer contains two jR2R3-P301L copies, of which one adopts a SLS fold found in 4R tauopathies and the other wraps around the SLS fold to stabilize it, reminiscent of the three- and fourfold structures observed in 4R tauopathies. These jR2R3-P301L fibrils are competent to template full-length 4R tau in a prion-like manner.
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Data, Materials, and Software Availability
EM map and model were deposited to the protein databank (accession #8V1N) (85). Water rings were counted using code from this repository: https://github.com/vitroid/cycless.git (86).
Acknowledgments
The study of the role of disease mutation and selecting tauopathy-specific pathways was supported by the NIH under Grant Number R01AG05605. The study of the minimal prion design and seeding of tau was supported by the Tau Consortium of the Rainwater charitable fund. The ODNP study of the role of water in protein interactions, and the cryo-EM sample preparation was supported by NIH MIRA under Grant Number R35GM136411 awarded to S.H. The ODNP study of water in protein interactions was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy (EXC-2033, project no. 390677874). The W.M. Keck Foundation (www.wmkeck.org) supported the development of experimental and computational methods and concepts for the study of tau shape propagation. Computational modeling was supported by NSF-ANR MCB/PHY 2423885 awarded to J.-E.S. Electron microscopy was conducted at the Microscopy and Microanalysis facility at UCSB, a part of the materials research lab (MRL). The MRL Shared Experimental Facilities are supported by the MRSEC Program of the NSF under Award No. DMR 1720256; a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org). The cryo-EM data collection portion of this research was supported by NIH Grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. We thank Dr. Omar Davulcu for his expert assistance with grid preparation and data collection, and the staff at PNCC for providing training. We thank Prof. Dan Southworth, Dr. Eric Tse, Dr. Gregory Merz, Prof. Dorit Hanein, Dr. Peter Van Blerkom, and Prof. Niels Volkmann for valuable input and advice on cryo-EM sample preparation, data acquisition and image reconstruction, and Bill FitzGerald for contributing to the quantification of residue backbone entropy.
Author contributions
M.P.V., S.L., S.N., A.D., A.P.L., S.K.B., K.S.K., M.S.S., J.-E.S., and S.H. designed research; M.P.V., S.L., S.N., A.D., K.T., P.G., A.P.L., and Y.J. performed research; M.P.V., S.L., S.N., K.T., P.G., A.P.L., Y.J., and J.-E.S. analyzed data; K.S.K., M.S.S., J.-E.S., and S.H. supervised study; and M.P.V. and S.H. wrote the paper.
Competing interests
K.S.K. consults for ADRx and Expansion Therapeutics and is a member of the Tau Consortium Board of Directors, M.P.V., S.L., A.D., A.P.L., K.T., K.S.K., and S.H. have filed for a patent based on the design of tau peptides presented in this paper. Patent information: Disc-ID-24-06-12-001.
Supporting Information
Appendix 01 (PDF)
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Movie S1.
Animation of the unclamping mode of jR2R3-P301L showing the most likely unpinching pathway of a representative conformation from cluster 1 of the free energy landscape of jR2R3-P301L. The white dot shows the position in the 2D landscape of the peptide in the left panel.
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- 11.26 MB
Movie S2.
Animation of the unpinching mode of jR2R3-P301L showing the most likely unpinching pathway of a representative conformation from cluster 1 of the free energy landscape of jR2R3-P301L. The white dot shows the position in the 2D landscape of the peptide in the left panel.
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- 15.53 MB
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Copyright © 2025 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Data, Materials, and Software Availability
EM map and model were deposited to the protein databank (accession #8V1N) (85). Water rings were counted using code from this repository: https://github.com/vitroid/cycless.git (86).
Submission history
Received: October 24, 2024
Accepted: March 10, 2025
Published online: April 28, 2025
Published in issue: May 6, 2025
Keywords
Acknowledgments
The study of the role of disease mutation and selecting tauopathy-specific pathways was supported by the NIH under Grant Number R01AG05605. The study of the minimal prion design and seeding of tau was supported by the Tau Consortium of the Rainwater charitable fund. The ODNP study of the role of water in protein interactions, and the cryo-EM sample preparation was supported by NIH MIRA under Grant Number R35GM136411 awarded to S.H. The ODNP study of water in protein interactions was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy (EXC-2033, project no. 390677874). The W.M. Keck Foundation (www.wmkeck.org) supported the development of experimental and computational methods and concepts for the study of tau shape propagation. Computational modeling was supported by NSF-ANR MCB/PHY 2423885 awarded to J.-E.S. Electron microscopy was conducted at the Microscopy and Microanalysis facility at UCSB, a part of the materials research lab (MRL). The MRL Shared Experimental Facilities are supported by the MRSEC Program of the NSF under Award No. DMR 1720256; a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org). The cryo-EM data collection portion of this research was supported by NIH Grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. We thank Dr. Omar Davulcu for his expert assistance with grid preparation and data collection, and the staff at PNCC for providing training. We thank Prof. Dan Southworth, Dr. Eric Tse, Dr. Gregory Merz, Prof. Dorit Hanein, Dr. Peter Van Blerkom, and Prof. Niels Volkmann for valuable input and advice on cryo-EM sample preparation, data acquisition and image reconstruction, and Bill FitzGerald for contributing to the quantification of residue backbone entropy.
Author contributions
M.P.V., S.L., S.N., A.D., A.P.L., S.K.B., K.S.K., M.S.S., J.-E.S., and S.H. designed research; M.P.V., S.L., S.N., A.D., K.T., P.G., A.P.L., and Y.J. performed research; M.P.V., S.L., S.N., K.T., P.G., A.P.L., Y.J., and J.-E.S. analyzed data; K.S.K., M.S.S., J.-E.S., and S.H. supervised study; and M.P.V. and S.H. wrote the paper.
Competing interests
K.S.K. consults for ADRx and Expansion Therapeutics and is a member of the Tau Consortium Board of Directors, M.P.V., S.L., A.D., A.P.L., K.T., K.S.K., and S.H. have filed for a patent based on the design of tau peptides presented in this paper. Patent information: Disc-ID-24-06-12-001.
Notes
This article is a PNAS Direct Submission. B.C. is a guest editor invited by the Editorial Board.
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Water-directed pinning is key to tau prion formation, Proc. Natl. Acad. Sci. U.S.A.
122 (18) e2421391122,
https://doi.org/10.1073/pnas.2421391122
(2025).
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