Heterogeneous Dynamics of the Fuzzy Coat of Full-Length Phospho-Mimetic Tau Fibrils
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nihms-2146582.pdf
Description
Accepted version
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3.57 MB
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Adobe PDF
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accf8c5233bf06970384453c51558689
Author(s)
Zhang, Jia Yi
Dregni, Aurelio J
Hong, Mei
Date Issued
January 14, 2026
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society
Citation
Heterogeneous Dynamics of the Fuzzy Coat of Full-Length Phospho-Mimetic Tau Fibrils. Jia Yi Zhang, Aurelio J. Dregni, and Mei Hong. Journal of the American Chemical Society 2026 148 (1), 1623-1637.
Version
Author's final manuscript
Abstract
The β-sheet core of many amyloid proteins in neurodegenerative diseases is surrounded by dynamically disordered segments that contact cellular species. Recent data suggest that this "fuzzy coat" may also regulate the prion-like propagation of amyloid proteins. Here we report the site-specific dynamics of the fuzzy coat of a full-length tau fibril, assembled without anionic cofactors in the presence of four phospho-mimetic glutamate mutations at the PHF1 epitope of Alzheimer's disease tau. The rigid core structure of this 4E tau was recently determined to consist of three β-strands, resembling the structure of three-layered tau aggregates in certain tauopathies. Using solid-state and solution NMR, we measured chemical shifts, peak intensities, and motional amplitudes of the dynamic residues in this 4E tau fibril and investigated the polarization transfer between the dynamic and the rigid segments. These data indicate that the 4E tau fuzzy coat contains three types of dynamic residues: type-1 residues undergo fast large-amplitude motion, type-2 residues undergo fast but intermediate-amplitude motion, and type-3 residues undergo microsecond motion. We estimate the number of residues in each category and propose the likely model for the packing of this fuzzy coat around the rigid core. A truncated tau fibril with the same rigid-core structure as 4E tau shows different fuzzy coat dynamics, indicating that the rigid-core structure is insufficient for defining all the properties of the fibrils. Our fuzzy coat model provides insight into the potential mechanism of prion-like propagation of tau aggregates and suggests how cellular species bind pathological tau aggregates.
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DOI of Published Version
https://doi.org/10.1021/jacs.5c18540
