التفاصيل البيبلوغرافية
| 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 |
