Conformational Basis for Asymmetric Seeding Barrier in Filaments of Three- and Four-Repeat Tau
| Autor: | Xiang Yu, Martin Margittai, Michael A. Swanson, Jie Zheng, Gareth R. Eaton, Ruth Nussinov, Ayisha Siddiqua, Guanghong Wei, Yin Luo, Virginia Meyer, Sandra S. Eaton, Buyong Ma |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Repetitive Sequences Amino Acid Amyloid Tau pathology tau Proteins macromolecular substances Biochemistry Protein Structure Secondary Article Catalysis 03 medical and health sciences 0302 clinical medicine Colloid and Surface Chemistry Protein structure Alzheimer Disease mental disorders Humans Protein Isoforms Computational analysis Conformational isomerism 030304 developmental biology 0303 health sciences Chemistry Spectrum Analysis General Chemistry Tau isoforms Crystallography Homogeneous Biophysics Seeding 030217 neurology & neurosurgery |
| Zdroj: | Journal of the American Chemical Society |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/ja303498q |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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