Orr Asuka A, Wördehoff Michael M, Hoyer Wolfgang, Tamamis Phanourios
Artie McFerrin Department of Chemical Engineering, Texas A&M University , College Station, Texas 77843-3122, United States.
Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40204 Düsseldorf, Germany.
J Phys Chem B. 2016 Dec 22;120(50):12781-12794. doi: 10.1021/acs.jpcb.6b08485. Epub 2016 Dec 9.
Amyloidogenic proteins amyloid-β peptide (Aβ) and α-synuclein (α-syn) self-assemble into fibrillar amyloid deposits, senile plaques and Lewy bodies, pathological features of Alzheimer's and Parkinson's diseases, respectively. Interestingly, a portion of Alzheimer's disease cases also exhibit aggregation of α-syn into Lewy bodies, and growing evidence also suggests that Aβ and α-syn oligomers are toxic. Therefore, the simultaneous inhibition through sequestration of the two amyloidogenic proteins may constitute a promising therapeutic strategy. Recently discovered β-wrapin proteins pave the way toward this direction as they can inhibit the aggregation and toxicity of both Aβ and α-syn. Here, we used computational methods, primarily molecular dynamics simulations and free energy calculations, to shed light into the key interaction-based commonalities leading to the dual binding properties of β-wrapins for both amyloidogenic proteins, to identify which interactions potentially act as switches diminishing β-wrapins' binding activity for Aβ/α-syn, and to examine the binding properties of the current most potent β-wrapin for Aβ. Our analysis provides insights into the distinct role of the key determinants leading to β-wrapin binding to Aβ and α-syn, and suggests that the Aβ VFFAED and α-syn LYVGSK are key domains determining the binding specificity of a β-wrapin. Our findings can potentially lead to the discovery of novel therapeutics for Alzheimer's and Parkinson's diseases.
淀粉样蛋白生成蛋白β淀粉样肽（Aβ）和α-突触核蛋白（α-syn）会自组装成纤维状淀粉样沉积物、老年斑和路易小体，分别是阿尔茨海默病和帕金森病的病理特征。有趣的是，一部分阿尔茨海默病病例也表现出α-syn聚集成路易小体，并且越来越多的证据还表明Aβ和α-syn寡聚体具有毒性。因此，通过隔离这两种淀粉样蛋白生成蛋白来同时抑制可能构成一种有前景的治疗策略。最近发现的β-包裹蛋白为这个方向铺平了道路，因为它们可以抑制Aβ和α-syn的聚集及毒性。在这里，我们使用计算方法，主要是分子动力学模拟和自由能计算，来阐明导致β-包裹蛋白对两种淀粉样蛋白生成蛋白具有双重结合特性的基于关键相互作用的共性，确定哪些相互作用可能作为开关减弱β-包裹蛋白对Aβ/α-syn的结合活性，并研究目前对Aβ最有效的β-包裹蛋白的结合特性。我们的分析深入了解了导致β-包裹蛋白与Aβ和α-syn结合的关键决定因素的不同作用，并表明Aβ的VFFAED和α-syn的LYVGSK是决定β-包裹蛋白结合特异性的关键结构域。我们的发现可能会促成针对阿尔茨海默病和帕金森病的新型疗法的发现。
