9BBL

THF filament generated from 4E-Tau(297-407) under neutral Mg2+ condition

9BBL の概要

• エントリーDOI: 10.2210/pdb9bbl/pdb
• EMDBエントリー: 43824 43826 44421
• 分子名称: Isoform Tau-F of Microtubule-associated protein tau (1 entity in total)
• 機能のキーワード: tau, amyloid fibrils, in vitro, phf, protein fibril
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 414665.89

構造登録者

Duan, P.,El Mammeri, N. (登録日: 2024-04-06, 公開日: 2024-05-08, 最終更新日: 2024-06-05)

主引用文献

Duan, P.,El Mammeri, N.,Hong, M.
Milligram-scale assembly and NMR fingerprint of tau fibrils adopting the Alzheimer's disease fold.
J.Biol.Chem., 300:107326-107326, 2024

PubMed Abstract: In the Alzheimer's disease (AD) brain, the microtubule-associated protein tau aggregates into paired helical filaments in which each protofilament has a C-shaped conformation. In vitro assembly of tau fibrils adopting this fold is highly valuable for both fundamental and applied studies of AD without requiring patient-brain extracted fibrils. To date, reported methods for forming AD-fold tau fibrils have been irreproducible and sensitive to subtle variations in fibrillization conditions. Here, we describe a route to reproducibly assemble tau fibrils adopting the AD fold on the multi-milligram scale. We investigated the fibrillization conditions of two constructs and found that a tau (297-407) construct that contains four AD phospho-mimetic glutamate mutations robustly formed the C-shaped conformation. 2D and 3D correlation solid-state NMR spectra show a single predominant set of chemical shifts, indicating a single molecular conformation. Negative-stain electron microscopy and cryo-EM data confirm that the protofilament formed by 4E-tau (297-407) adopts the C-shaped conformation, which associates into paired, triple, and quadruple helical filaments. In comparison, NMR spectra indicate that a previously reported construct, tau (297-391), forms a mixture of a four-layered dimer structure and the C-shaped structure, whose populations are sensitive to the environmental conditions. The determination of the NMR chemical shifts of the AD-fold tau opens the possibility for future studies of tau fibril conformations and ligand binding by NMR. The quantitative assembly of tau fibrils adopting the AD fold should facilitate the development of diagnostic and therapeutic compounds that target AD tau.

PubMed: 38679331
DOI: 10.1016/j.jbc.2024.107326

実験手法

ELECTRON MICROSCOPY (2.5 Å)