Wang Ruiqing, Alagbe Busayo D, Ashbaugh Henry S, Gibb Bruce C
Department of Chemistry, Tulane University, New Orleans, Louisiana 70118, United States.
Department of Chemical and Biomolecular Engineering, Tulane University, New Orleans, Louisiana 70118, United States.
ACS Omega. 2025 May 21;10(21):22216-22223. doi: 10.1021/acsomega.5c02618. eCollection 2025 Jun 3.
α-Synuclein (α-Syn) is linked to the pathogenesis of Parkinson's disease by its misfolding, aggregation, and accumulation in Lewy bodies, the characteristic amyloids of Parkinson's. terminal binding to phospholipid membranes and the resulting random-coil to helical transition are key to the aggregation of α-Syn. However, despite the recognized affinity for the -terminal domain for phospholipids, the anion affinity for this region has not been comprehensively examined. To probe the effects of monovalent anion binding to the -terminus, we report here on studies with the 15-mer -terminal peptide of α-Syn and two mutants in which all three lysines of the wild-type sequence are replaced with either arginine or histidine (MDVFMGLSAEGV; = K, R, or H). Our studies reveal that charge-diffuse anions have a measurable affinity, binding weakly to the midsection of the sequences. However, binding does not induce significant long-range ordering. Nevertheless, MD simulations do reveal a compaction of the peptides in the presence of ClO , supporting the conclusion that anion binding screens the positively charged residues, reducing the effective net positive charge of the peptide and inducing aggregation. Aggregation studies revealed that this reverse Hofmeister effect correlates with anion affinity and that at intermediate salt concentrations or low pH, aggregation follows the Finke-Watzky model. Our findings suggest that changes in simple salt concentrations are unlikely to affect the structure of the -terminal region of α-Syn and highlight that multipoint interactions between polyanionic phospholipid membranes are a necessary requirement for the random-coil to helical transition observed in the wild type.
α-突触核蛋白（α-Syn）通过其错误折叠、聚集并在路易小体（帕金森病的特征性淀粉样蛋白）中积累，与帕金森病的发病机制相关联。α-Syn与磷脂膜的末端结合以及由此产生的从无规卷曲到螺旋的转变是其聚集的关键。然而，尽管已认识到α-Syn的C末端结构域对磷脂有亲和力，但该区域对阴离子的亲和力尚未得到全面研究。为了探究单价阴离子与C末端结合的影响，我们在此报告了对α-Syn的15聚体C末端肽以及两个突变体的研究，其中野生型序列中的所有三个赖氨酸分别被精氨酸或组氨酸取代（MDVFMGLSAEGV；K = K、R或H）。我们的研究表明，电荷扩散阴离子具有可测量的亲和力，与序列中部弱结合。然而，结合不会诱导显著的长程有序。尽管如此，分子动力学模拟确实揭示了在ClO⁻存在下肽的压缩，支持了阴离子结合屏蔽带正电残基、降低肽的有效净正电荷并诱导聚集的结论。聚集研究表明，这种反向霍夫迈斯特效应与阴离子亲和力相关，并且在中等盐浓度或低pH下，聚集遵循芬克 - 瓦茨基模型。我们的研究结果表明，简单盐浓度的变化不太可能影响α-Syn C末端区域的结构，并强调多阴离子磷脂膜之间的多点相互作用是野生型中观察到的从无规卷曲到螺旋转变的必要条件。
