Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
Department of Physics, University of Alberta, Edmonton, AB, Canada.
Commun Biol. 2021 May 3;4(1):518. doi: 10.1038/s42003-021-02026-z.
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.
α-突触核蛋白（帕金森病的致病蛋白）的纤维形成途径包含瞬态、异质寡聚体形式，其结构理解及其与毒性的联系尚不清楚。我们报告称，在单体或聚集的α-突触核蛋白中添加生理上可利用的小分子血红素以亚化学计量比，靶向对于纤维形成至关重要的 His50 残基，并将结构异质的聚集物稳定为低毒寡聚体状态。冷冻电镜 3D 重建揭示了这种单分散寡聚物群体的“狼牙棒”形状结构，与固态 NMR 希腊钥匙样基序（核心残基在 C 末端以希腊钥匙拓扑排列在平行的对准片上）相当，形成原纤维的基本单位/核心。进一步的结构分析表明，血红素结合诱导狼牙棒寡聚物中希腊钥匙样结构的扭曲，从而阻止它们进一步添加到原纤维和纤维中。此外，我们的研究报告了一种通过使用小分子阻断丝状纤维形成过程中丝状纤维间 His50 残基的新的预防和回收机制。
