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

• Published in: Journal of the American Chemical Society Vol. 134; no. 24; pp. 10271 - 10278
• Main Authors: Siddiqua, Ayisha, Luo, Yin, Meyer, Virginia, Swanson, Michael A, Yu, Xiang, Wei, Guanghong, Zheng, Jie, Eaton, Gareth R, Ma, Buyong, Nussinov, Ruth, Eaton, Sandra S, Margittai, Martin
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 20.06.2012
• Subjects: Alzheimer Disease - metabolism; Amyloid - chemistry; Amyloid - metabolism; Asymmetry; Barriers; Deer; Deposition; Dynamic tests; Filaments; Humans; Models, Molecular; Nucleation; Pathology; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Protein Structure, Secondary; Repetitive Sequences, Amino Acid; Spectrum Analysis; tau Proteins - chemistry; tau Proteins - metabolism
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/ja303498q

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 β-strand–turn−β-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.