Uncovering the Binding and Specificity of β-Wrapins for Amyloid-β and α-Synuclein

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• 作者：Asuka A. Orr ; Michael M. Wördehoff ; Wolfgang HoyerPhanourios Tamamis
• 刊名：Journal of Physical Chemistry B
• 出版年：2016
• 出版时间：December 22, 2016
• 年：2016
• 卷：120
• 期：50
• 页码：12781-12794
• 全文大小：652K
• ISSN：1520-5207

文摘

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 ₁₈VFFAED₂₃ and α-syn ₃₈LYVGSK₄₃ 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.