ArticleScience advances2025
Massively parallel genetic perturbation suggests the energetic structure of an amyloid-β transition state.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Oxidative stress and inflammation in neurodegenerative disorders.Archives of toxicology · 2026Review
- Amyloid fibril polymorphism: Structural mechanisms of assembly and the links to disease.Current opinion in structural biology · 2026Review
- Mutational Scanning of α-Synuclein using a Clickable Protein Tag Reveals Determinants of Membrane-Induced Aggregation.bioRxiv : the preprint server for biology · 2026Article
- Concentration-dependent mutational scanning probes the cellular folding landscape of α-synuclein in yeast.Protein science : a publication of the Protein Society · 2026Article
- Concentration-Dependent Mutational Scanning Probes the Cellular Folding Landscape of α-Synuclein in Yeast.bioRxiv : the preprint server for biology · 2025Article
- AmyloGram reveals amyloidogenic potential in stroke thrombus proteomes.The Biochemical journal · 2025Article
- Global Analysis of Aggregation Determinants in Small Protein Domains.bioRxiv : the preprint server for biology · 2025Article
- Variant scoring tools for deep mutational scanning.Molecular systems biology · 2025Review
- Employing deep mutational scanning in theProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Biophysical insights into the molecular mechanisms of beta amyloid aggregation and its toxic effects in Alzheimer's disease.Frontiers in molecular biosciences · 2025Review
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Abstract
Amyloid aggregates are pathological hallmarks of many human diseases, but how soluble proteins nucleate to form amyloids is poorly understood. Here, we use combinatorial mutagenesis, a kinetic selection assay, and machine learning to massively perturb the energetics of the nucleation reaction of amyloid-β (Aβ42), the protein that aggregates in Alzheimer's disease. In total, we measure the nucleation rates of >140,000 variants of Aβ42 to accurately quantify the changes in free energy of activation of the reaction for all possible amino acid substitutions in a protein and, in addition, to quantify >600 energetic interactions between mutations. Strong energetic couplings suggest that the Aβ42 nucleation reaction transition state is structured in a short C-terminal region, providing a structural model for the reaction that may initiate Alzheimer's disease. Using this approach it should be possible to reveal the energetic structures of additional amyloid transition states and, in combination with additional selection assays, protein transition states more generally.
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