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, Da Nae R. Woodard, Milo M. Lin, Marc I. Diamond, Lukasz A. Joachimiak

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article number2493
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Tauopathies
mutations
Agglomeration
tau Proteins
Mutation
Amyloid Plaques
Alternative Splicing
Missense Mutation
Recombinant Proteins
Amyloid
Proline
Neurodegenerative Diseases
Computer Simulation
proteins
pathogenesis
Mass Spectrometry
splicing
Neurodegenerative diseases
genes
upstream

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Tau local structure shields an amyloid-forming motif and controls aggregation propensity. / Chen, Dailu; Drombosky, Kenneth W.; Hou, Zhiqiang; Sari, Levent; Kashmer, Omar M.; Ryder, Bryan D.; Perez, Valerie A.; Woodard, Da Nae R.; Lin, Milo M.; Diamond, Marc I.; Joachimiak, Lukasz A.

In: Nature communications, Vol. 10, No. 1, 2493, 01.12.2019.

Research output: Contribution to journalArticle

Chen, Dailu ; Drombosky, Kenneth W. ; Hou, Zhiqiang ; Sari, Levent ; Kashmer, Omar M. ; Ryder, Bryan D. ; Perez, Valerie A. ; Woodard, Da Nae R. ; Lin, Milo M. ; Diamond, Marc I. ; Joachimiak, Lukasz A. / Tau local structure shields an amyloid-forming motif and controls aggregation propensity. In: Nature communications. 2019 ; Vol. 10, No. 1.
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AU - Ryder, Bryan D.

AU - Perez, Valerie A.

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