Hairpin trimer transition state of amyloid fibril
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 mon...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46446-x |
| _version_ | 1827301029073387520 |
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| author | Levent Sari Sofia Bali Lukasz A. Joachimiak Milo M. Lin |
| author_facet | Levent Sari Sofia Bali Lukasz A. Joachimiak Milo M. Lin |
| author_sort | Levent Sari |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T16:16:08Z |
| format | Article |
| id | doaj.art-08974af95d9b441db7954aee485d0416 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T16:16:08Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-08974af95d9b441db7954aee485d04162024-03-31T11:25:10ZengNature PortfolioNature Communications2041-17232024-03-0115111110.1038/s41467-024-46446-xHairpin trimer transition state of amyloid fibrilLevent Sari0Sofia Bali1Lukasz A. Joachimiak2Milo M. Lin3Green Center for Systems Biology, University of Texas Southwestern Medical CenterMolecular Biophysics Graduate Program, University of Texas Southwestern Medical CenterCenter for Alzheimer’s and Neurodegenerative Diseases, Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical CenterGreen Center for Systems Biology, University of Texas Southwestern Medical CenterAbstract 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.https://doi.org/10.1038/s41467-024-46446-x |
| spellingShingle | Levent Sari Sofia Bali Lukasz A. Joachimiak Milo M. Lin Hairpin trimer transition state of amyloid fibril Nature Communications |
| title | Hairpin trimer transition state of amyloid fibril |
| title_full | Hairpin trimer transition state of amyloid fibril |
| title_fullStr | Hairpin trimer transition state of amyloid fibril |
| title_full_unstemmed | Hairpin trimer transition state of amyloid fibril |
| title_short | Hairpin trimer transition state of amyloid fibril |
| title_sort | hairpin trimer transition state of amyloid fibril |
| url | https://doi.org/10.1038/s41467-024-46446-x |
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