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

Dailu Chen, Kenneth W. Drombosky, Zhiqiang Hou, Levent Sari, Omar M. Kashmer, Bryan D. Ryder, Valerie A. Perez, DaNae R. Woodard, Milo M. Lin, Marc I. Diamond and Lukasz A. Joachimiak ()
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Dailu Chen: University of Texas Southwestern Medical Center
Kenneth W. Drombosky: University of Texas Southwestern Medical Center
Zhiqiang Hou: University of Texas Southwestern Medical Center
Levent Sari: Computational and Systems Biology, University of Texas Southwestern Medical Center
Omar M. Kashmer: University of Texas Southwestern Medical Center
Bryan D. Ryder: University of Texas Southwestern Medical Center
Valerie A. Perez: University of Texas Southwestern Medical Center
DaNae R. Woodard: University of Texas Southwestern Medical Center
Milo M. Lin: Computational and Systems Biology, University of Texas Southwestern Medical Center
Marc I. Diamond: University of Texas Southwestern Medical Center
Lukasz A. Joachimiak: University of Texas Southwestern Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10355-1

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