9MC2

Cryo-EM structure of dopaminated Tau fibril

9MC2 の概要

• エントリーDOI: 10.2210/pdb9mc2/pdb
• EMDBエントリー: 63785
• 分子名称: Microtubule-associated protein tau (1 entity in total)
• 機能のキーワード: amyloid, protein fibril
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 82505.26

構造登録者

Liu, Z.,Li, X.,Liu, C. (登録日: 2025-03-17, 公開日: 2026-02-04)

主引用文献

Liu, Z.,Li, X.,Wang, Q.,Liu, K.,Zeng, W.,Li, D.,Zhao, K.,Ma, Y.,Long, H.,Zhang, S.,Li, D.,Sun, B.,Le, W.,Wang, C.,He, Z.,Kang, W.,Xiao, W.,Liu, C.
Dopamine-Induced Tau Modification Prevents Pathological Phosphorylation and Generates a Distinct Fibril Polymorph.
J.Am.Chem.Soc., 2026

PubMed Abstract: Amyloid aggregation of tau is the key pathological event in various tauopathies including Alzheimer's and Pick's disease. Recently, dopamination was identified to modify tau on cysteine, which protects against tau pathology, yet its structural and functional consequences remain unclear. Here, we show that dopamination of the three-repeat (3R) tau fragment K19 alleviates disease-associated tau phosphorylation and alters the tau fibril structure. Solution NMR analysis reveals that dopamine modification at Cys322 of tau suppresses phosphorylation at several pathogenic sites across the microtubule-binding region. Dopaminated tau also exhibited greatly diminished fibrillization and reduced seeding activity in cells. Finally, we determined the cryo-EM structure of dopaminated tau fibrils at 3.55 Å resolution, revealing a unique fibril polymorph with the smallest core region reported to date for tau. The dopaminated fibril core comprises only 11 residues (centered on the VQIVYK motif) and is stabilized by a minimal hydrophobic interface, explaining its decreased stability compared to that of unmodified tau fibrils. Our results provide atomic-level insight into how dopamine modification imparts a protective effect on tau and underscore the profound influence of post-translational modifications in modulating amyloid protein structure and pathology.

PubMed: 41555553
DOI: 10.1021/jacs.5c22156

実験手法

ELECTRON MICROSCOPY (3.55 Å)