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

Author

Listed:
  • Dailu Chen

    (University of Texas Southwestern Medical Center
    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
    University of Texas Southwestern Medical Center)

  • Omar M. Kashmer

    (University of Texas Southwestern Medical Center)

  • Bryan D. Ryder

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Valerie A. Perez

    (University of Texas Southwestern Medical Center
    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
    University of Texas Southwestern Medical Center)

  • Marc I. Diamond

    (University of Texas Southwestern Medical Center)

  • Lukasz A. Joachimiak

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

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.

Suggested Citation

  • 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 & Lukasz A. Joachimiak, 2019. "Tau local structure shields an amyloid-forming motif and controls aggregation propensity," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10355-1
    DOI: 10.1038/s41467-019-10355-1
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    Cited by:

    1. Vishruth Mullapudi & Jaime Vaquer-Alicea & Vaibhav Bommareddy & Anthony R. Vega & Bryan D. Ryder & Charles L. White & Marc. I. Diamond & Lukasz A. Joachimiak, 2023. "Network of hotspot interactions cluster tau amyloid folds," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Nikolaos Louros & Martin Wilkinson & Grigoria Tsaka & Meine Ramakers & Chiara Morelli & Teresa Garcia & Rodrigo Gallardo & Sam D’Haeyer & Vera Goossens & Dominique Audenaert & Dietmar Rudolf Thal & Ia, 2024. "Local structural preferences in shaping tau amyloid polymorphism," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Dailu Chen & Sofia Bali & Ruhar Singh & Aleksandra Wosztyl & Vishruth Mullapudi & Jaime Vaquer-Alicea & Parvathy Jayan & Shamiram Melhem & Harro Seelaar & John C. Swieten & Marc I. Diamond & Lukasz A., 2023. "FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Levent Sari & Sofia Bali & Lukasz A. Joachimiak & Milo M. Lin, 2024. "Hairpin trimer transition state of amyloid fibril," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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