Tau local structure shields an amyloid-forming motif and controls aggregation propensity.

Autor:	Chen D; Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.; Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Drombosky KW; Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Hou Z; Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Sari L; Green Center for Molecular, Computational and Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Kashmer OM; Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Ryder BD; Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.; Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Perez VA; Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.; Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Woodard DR; Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Lin MM; Green Center for Molecular, Computational and Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Diamond MI; Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Joachimiak LA; Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Lukasz.Joachimiak@utsouthwestern.edu.; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Lukasz.Joachimiak@utsouthwestern.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2019 Jun 07; Vol. 10 (1), pp. 2493. Date of Electronic Publication: 2019 Jun 07.
DOI:	10.1038/s41467-019-10355-1
Abstrakt:	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 306 VQIVYK 311 . We use cross-linking mass spectrometry, recombinant protein and synthetic peptide systems, in silico modeling, and cell models to conclude that the aggregation-prone 306 VQIVYK 311 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.
Databáze:	MEDLINE
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