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Hairpin trimer transition state of amyloid fibril

Author

Listed:
  • Levent Sari

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

  • Sofia Bali

    (University of Texas Southwestern Medical Center
    Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center)

  • Lukasz A. Joachimiak

    (Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Milo M. Lin

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center
    Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

Protein fibril self-assembly is a universal transition implicated in neurodegenerative diseases. Although fibril structure/growth are well characterized, fibril nucleation is poorly understood. Here, we use a computational-experimental approach to resolve fibril nucleation. We show that monomer hairpin content quantified from molecular dynamics simulations is predictive of experimental fibril formation kinetics across a tau motif mutant library. Hairpin trimers are predicted to be fibril transition states; one hairpin spontaneously converts into the cross-beta conformation, templating subsequent fibril growth. We designed a disulfide-linked dimer mimicking the transition state that catalyzes fibril formation, measured by ThT fluorescence and TEM, of wild-type motif - which does not normally fibrillize. A dimer compatible with extended conformations but not the transition-state fails to nucleate fibril at any concentration. Tau repeat domain simulations show how long-range interactions sequester this motif in a mutation-dependent manner. This work implies that different fibril morphologies could arise from disease-dependent hairpin seeding from different loci.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46446-x
    DOI: 10.1038/s41467-024-46446-x
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    References listed on IDEAS

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    1. 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.
    2. 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.
    3. Yang Shi & Wenjuan Zhang & Yang Yang & Alexey G. Murzin & Benjamin Falcon & Abhay Kotecha & Mike Beers & Airi Tarutani & Fuyuki Kametani & Holly J. Garringer & Ruben Vidal & Grace I. Hallinan & Tammar, 2021. "Structure-based classification of tauopathies," Nature, Nature, vol. 598(7880), pages 359-363, October.
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