Tau local structure shields an amyloid-forming motif and controls aggregation propensity
| Autor: | Dailu Chen, Da Nae R. Woodard, Levent Sari, Omar M. Kashmer, Lukasz A. Joachimiak, Valerie A. Perez, Kenneth W. Drombosky, Marc I. Diamond, Milo M. Lin, Bryan D. Ryder, Zhiqiang Hou |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Prions Science In silico Amino Acid Motifs Tau protein Mutation Missense General Physics and Astronomy tau Proteins Peptide 02 engineering and technology Protein aggregation Protein Aggregation Pathological Mass Spectrometry Article General Biochemistry Genetics and Molecular Biology Quantitative Biology::Cell Behavior 03 medical and health sciences Microscopy Electron Transmission mental disorders Humans Missense mutation Computer Simulation lcsh:Science Gene chemistry.chemical_classification Quantitative Biology::Biomolecules Intrinsically disordered proteins Multidisciplinary biology Chemistry HEK 293 cells Alternative splicing General Chemistry 021001 nanoscience & nanotechnology Recombinant Proteins Cell biology HEK293 Cells 030104 developmental biology Tauopathies biology.protein lcsh:Q 0210 nano-technology |
| Zdroj: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-14 (2019) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-10355-1 |
| Popis: | Tauopathies are neurodegenerative diseases characterized by intracellular amyloid deposits of tau protein. Missense mutations in the tau gene (MAPT) correlate with aggregation propensity and cause dominantly inherited tauopathies, but their biophysical mechanism driving amyloid formation is poorly understood. Many disease-associated mutations localize within tau’s repeat domain at inter-repeat interfaces proximal to amyloidogenic sequences, such as 306VQIVYK311. We use cross-linking mass spectrometry, recombinant protein and synthetic peptide systems, in silico modeling, and cell models to conclude that the aggregation-prone 306VQIVYK311 motif forms metastable compact structures with its upstream sequence that modulates aggregation propensity. We report that disease-associated mutations, isomerization of a critical proline, or alternative splicing are all sufficient to destabilize this local structure and trigger spontaneous aggregation. These findings provide a biophysical framework to explain the basis of early conformational changes that may underlie genetic and sporadic tau pathogenesis. The biophysical mechanisms of how disease-associated tau mutations drive amyloid formation are not well understood. Here the authors use biophysical approaches, cell models and MD simulations and find that the intrinsically disordered repeat domain of tau encodes a metastable local structure and perturbations through mutations and proline isomerization cause an aggregation phenotype in vitro and in cells. |
| Databáze: | OpenAIRE |
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