Hairpin trimer transition state of amyloid fibril

Levent Sari, Sofia Bali, Lukasz A. Joachimiak and Milo M. Lin ()
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Levent Sari: University of Texas Southwestern Medical Center
Sofia Bali: University of Texas Southwestern Medical Center
Lukasz A. Joachimiak: Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center
Milo M. Lin: University of Texas Southwestern Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46446-x

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