Conformational Basis for Asymmetric Seeding Barrier in Filaments of Three- and Four-Repeat Tau

被引：56

作者：

Siddiqua, Ayisha ^{[1
]}

Luo, Yin ^{[2
,3
]}

Meyer, Virginia ^{[1
]}

Swanson, Michael A. ^{[1
]}

Yu, Xiang ^{[4
]}

Wei, Guanghong ^{[2
,3
]}

Zheng, Jie ^{[4
]}

Eaton, Gareth R. ^{[1
]}

Ma, Buyong ^{[5
]}

Nussinov, Ruth ^{[5
,6
]}

Eaton, Sandra S. ^{[1
]}

Margittai, Martin ^{[1
]}

机构：

[1] Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA

[2] Fudan Univ, State Key Lab Surface Phys, Key Lab Computat Phys Sci MOE, Shanghai 200433, Peoples R China

[3] Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China

[4] Univ Akron, Dept Chem & Biomol Engn, Akron, OH 44325 USA

[5] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program,Frederick Natl Lab, Frederick, MD 21702 USA

[6] Tel Aviv Univ, Dept Human Genet & Mol Med, Sackler Inst Mol Med, Sackler Sch Med, IL-69978 Tel Aviv, Israel

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2012年 / 134卷 / 24期

基金：

高等学校博士学科点专项科研基金; 美国国家科学基金会;

关键词：

ELECTRON-ELECTRON RESONANCE; PAIRED HELICAL FILAMENTS; ALPHA-SYNUCLEIN; ALZHEIMERS-DISEASE; STRAIN VARIATION; AMYLOID FIBRILS; MOLECULAR-BASIS; IN-VITRO; PROTEIN; AGGREGATION;

D O I：

10.1021/ja303498q

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Tau pathology in Alzheimer's disease is intimately linked to the deposition of proteinacious filaments, which akin to infectious prions, have been proposed to spread via seeded conversion. Here we use double electron electron resonance (DEER) spectroscopy in combination with extensive computational analysis to show that filaments of three- (3R) and four-repeat (4R) tau are conformationally distinct. Distance measurements between spin labels in the third repeat, reveal tau amyloid filaments as ensembles of known beta-strand-turn-beta-strand U-turn motifs. Whereas filaments seeded with 3R tau are structurally homogeneous, filaments seeded with 4R tau are heterogeneous, composed of at least three distinct conformers. These findings establish a molecular basis for the seeding barrier between different tau isoforms and offer a new powerful approach for investigating the composition and dynamics of amyloid fibril ensembles.

引用

页码：10271 / 10278

页数：8