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-Structure paper
Title | Conformational distortion in a fibril-forming oligomer arrests alpha-Synuclein fibrillation and minimizes its toxic effects. |
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Journal, issue, pages | Commun Biol, Vol. 4, Issue 1, Page 518, Year 2021 |
Publish date | May 3, 2021 |
Authors | Ritobrita Chakraborty / Sandip Dey / Pallabi Sil / Simanta Sarani Paul / Dipita Bhattacharyya / Anirban Bhunia / Jayati Sengupta / Krishnananda Chattopadhyay / |
PubMed 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 ...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. |
External links | Commun Biol / PubMed:33941845 / PubMed Central |
Methods | EM (single particle) |
Resolution | 8.9 - 11.0 Å |
Structure data | EMDB-31004: EMDB-31023: EMDB-31024: |
Source |
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