A water-pinning hot spot drives templated tau aggregation.
4 affiliations
- 1Department of Chemistry, Northwestern University, Evanston, IL 60208-3113.
- 2Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510.
- 3Department of Chemical Engineering, University of California, Santa Barbara, CA 93106-5080.
- 4Department of Physics, University of California, Santa Barbara, CA 93106-9530.
Abstract
Tau assembles into fibrillar aggregates that are pathological hallmarks of a group of neurodegenerative diseases collectively called tauopathies. Templated aggregation of naïve tau to seeding-competent fibrils that proceed from cell to cell is a key driver of prion-like progression of tauopathies. This study tests the hypothesis that tau, an intrinsically disordered protein, achieves in-register stacking to form seed-competent fibrils by a pinning action of tau to each other and/or the seed surface via a single dominant hotspot to avoid mismatch in tau stacking to fibrils. Structured solvation water has been proposed to be a signature of such hot spots at both the tau fibril-end surface and soluble tau monomers. Although jR2R3-P301L tau exhibits a heterogeneous hydration landscape in its intrinsically disordered state, with enhanced water structuring near the P301L mutation site, it is unclear whether a localized hotspot exists at the fibril end surface and surface water facilitates the initial contacts in templated aggregation. Using rapid ¹H-¹⁵N SOFAST-HMQC NMR to track seed-induced aggregation of jR2R3-P301L in real time, complemented by molecular dynamics simulation of fibril surface hydration, we identify a residue-specific pinning hotspot that is prone to dewetting followed by sequential folding and incorporation of the remaining segment in a two-step dock-and-lock process. Site-specific spin labeling further demonstrates that blocking this pinning hotspot disrupts templated aggregation, leading to shorter fibrils. The identification of a dominant pinning site will facilitate the rational design of binders to effectively disrupt fibril extension or serve as diagnostic or therapeutic strategies.
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BibTeX
@article{han2026waterpinning,
title = {{A water-pinning hot spot drives templated tau aggregation.}},
author = {Chung-Ta Han and Karen Tsay and Samuel Lobo and Saeed Najafi and Kieran Monahan and Erica Hong and M Scott Shell and Joan-Emma Shea and Songi Han},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2611158123},
url = {https://europepmc.org/article/MED/42863048},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A water-pinning hot spot drives templated tau aggregation.
AU - Chung-Ta Han
AU - Karen Tsay
AU - Samuel Lobo
AU - Saeed Najafi
AU - Kieran Monahan
AU - Erica Hong
AU - M Scott Shell
AU - Joan-Emma Shea
AU - Songi Han
PY - 2026
DA - 2026/10/12
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2611158123
UR - https://europepmc.org/article/MED/42863048
AB - Tau assembles into fibrillar aggregates that are pathological hallmarks of a group of neurodegenerative diseases collectively called tauopathies. Templated aggregation of naïve tau to seeding-competent fibrils that proceed from cell to cell is a key driver of prion-like progression of tauopathies. This study tests the hypothesis that tau, an intrinsically disordered protein, achieves in-register stacking to form seed-competent fibrils by a pinning action of tau to each other and/or the seed surface via a single dominant hotspot to avoid mismatch in tau stacking to fibrils. Structured solvation water has been proposed to be a signature of such hot spots at both the tau fibril-end surface and soluble tau monomers. Although jR2R3-P301L tau exhibits a heterogeneous hydration landscape in its intrinsically disordered state, with enhanced water structuring near the P301L mutation site, it is unclear whether a localized hotspot exists at the fibril end surface and surface water facilitates the initial contacts in templated aggregation. Using rapid ¹H-¹⁵N SOFAST-HMQC NMR to track seed-induced aggregation of jR2R3-P301L in real time, complemented by molecular dynamics simulation of fibril surface hydration, we identify a residue-specific pinning hotspot that is prone to dewetting followed by sequential folding and incorporation of the remaining segment in a two-step dock-and-lock process. Site-specific spin labeling further demonstrates that blocking this pinning hotspot disrupts templated aggregation, leading to shorter fibrils. The identification of a dominant pinning site will facilitate the rational design of binders to effectively disrupt fibril extension or serve as diagnostic or therapeutic strategies.
SN - 0027-8424
SN - 1091-6490
ER -