ArticleCommunications biology2021
Conformational distortion in a fibril-forming oligomer arrests alpha-Synuclein fibrillation and minimizes its toxic effects.
Article in Communications biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Pro-Oxidative and Inflammatory Actions of Extracellular Hemoglobin and Heme: Molecular Events and Implications for Alzheimer's and Parkinson Disease.Biomolecules & therapeutics · 2025Review
- Production of Distinct Fibrillar, Oligomeric, and Other Aggregation States from Network Models of Multibody Interaction.Journal of chemical theory and computation · 2024Article
- Cryo-EM structures of pathogenic fibrils and their impact on neurodegenerative disease research.Neuron · 2024Review
- Inhibition of toxic metal-alpha synuclein interactions by human serum albumin.Chemical science · 2024Article
- The 75-99 C-Terminal Peptide of URG7 Protein Promotes α-Synuclein Disaggregation.International journal of molecular sciences · 2024Article
- A Zn-dependent structural transition of SOD1 modulates its ability to undergo phase separation.The EMBO journal · 2023Article
- Multiple Antimicrobial Effects of Hybrid Peptides Synthesized Based on the Sequence of Ribosomal S1 Protein fromInternational journal of molecular sciences · 2022Article
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Authors and funding
8 authors.
Funding
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Abstract
The fibrillation pathway of alpha-Synuclein, the causative protein of Parkinson's disease, encompasses transient, heterogeneous oligomeric forms whose structural understanding and link to toxicity are not yet understood. We report that the addition of the physiologically-available small molecule heme at a sub-stoichiometric ratio to either monomeric or aggregated α-Syn, targets a His50 residue critical for fibril-formation and stabilizes the structurally-heterogeneous populations of aggregates into a minimally-toxic oligomeric state. Cryo-EM 3D reconstruction revealed a 'mace'-shaped structure of this monodisperse population of oligomers, which is comparable to a solid-state NMR Greek key-like motif (where the core residues are arranged in parallel in-register sheets with a Greek key topology at the C terminus) that forms the fundamental unit/kernel of protofilaments. Further structural analyses suggest that heme binding induces a distortion in the Greek key-like architecture of the mace oligomers, which impairs their further appending into protofilaments and fibrils. Additionally, our study reports a novel mechanism of prevention as well as reclamation of amyloid fibril formation by blocking an inter-protofilament His50 residue using a small molecule.
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