دورية أكاديمية
Hairpin trimer transition state of amyloid fibril
العنوان: | Hairpin trimer transition state of amyloid fibril |
---|---|
المؤلفون: | Levent Sari, Sofia Bali, Lukasz A. Joachimiak, Milo M. Lin |
المصدر: | Nature, Nature Communications. 15(1):1-11 |
سنة النشر: | 2024 |
الوصف: | 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. |
نوع الوثيقة: | redif-article |
اللغة: | English |
DOI: | 10.1038/s41467-024-46446 |
الإتاحة: | https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46446-x.html |
رقم الأكسشن: | edsrep.a.nat.natcom.v15y2024i1d10.1038.s41467.024.46446.x |
قاعدة البيانات: | RePEc |
كن أول من يترك تعليقا!