6ODG

SVQIVY, Crystal Structure of a tau protein fragment

6ODG の概要

• エントリーDOI: 10.2210/pdb6odg/pdb
• 分子名称: Microtubule-associated protein tau (2 entities in total)
• 機能のキーワード: amyloid, tau, microed, protein fibril
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 1415.63

構造登録者

Eisenberg, D.S.,Boyer, D.R.,Sawaya, M.R.,Seidler, P.M. (登録日: 2019-03-26, 公開日: 2019-10-02, 最終更新日: 2024-03-13)

主引用文献

Seidler, P.M.,Boyer, D.R.,Murray, K.A.,Yang, T.P.,Bentzel, M.,Sawaya, M.R.,Rosenberg, G.,Cascio, D.,Williams, C.K.,Newell, K.L.,Ghetti, B.,DeTure, M.A.,Dickson, D.W.,Vinters, H.V.,Eisenberg, D.S.
Structure-based inhibitors halt prion-like seeding by Alzheimer's disease-and tauopathy-derived brain tissue samples.
J.Biol.Chem., 294:16451-16464, 2019

PubMed Abstract: In Alzheimer's disease (AD) and tauopathies, tau aggregation accompanies progressive neurodegeneration. Aggregated tau appears to spread between adjacent neurons and adjacent brain regions by prion-like seeding. Hence, inhibitors of this seeding offer a possible route to managing tauopathies. Here, we report the 1.0 Å resolution micro-electron diffraction structure of an aggregation-prone segment of tau with the sequence SVQIVY, present in the cores of patient-derived fibrils from AD and tauopathies. This structure illuminates how distinct interfaces of the parent segment, containing the sequence VQIVYK, foster the formation of distinct structures. Peptide-based fibril-capping inhibitors designed to target the two VQIVYK interfaces blocked proteopathic seeding by patient-derived fibrils. These VQIVYK inhibitors add to a panel of tau-capping inhibitors that targets specific polymorphs of recombinant and patient-derived tau fibrils. Inhibition of seeding initiated by brain tissue extracts differed among donors with different tauopathies, suggesting that particular fibril polymorphs of tau are associated with certain tauopathies. Donors with progressive supranuclear palsy exhibited more variation in inhibitor sensitivity, suggesting that fibrils from these donors were more polymorphic and potentially vary within individual donor brains. Our results suggest that a subset of inhibitors from our panel could be specific for particular disease-associated polymorphs, whereas inhibitors that blocked seeding by extracts from all of the tauopathies tested could be used to broadly inhibit seeding by multiple disease-specific tau polymorphs. Moreover, we show that tau-capping inhibitors can be transiently expressed in HEK293 tau biosensor cells, indicating that nucleic acid-based vectors can be used for inhibitor delivery.

PubMed: 31537646
DOI: 10.1074/jbc.RA119.009688

実験手法

X-RAY DIFFRACTION (1 Å)