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• W2777736071 abstract "Aggregation of α-synuclein (α-Syn) into neurotoxic oligomers and amyloid fibrils is suggested to be the pathogenic mechanism for Parkinson’s disease (PD). Recent studies have indicated that oligomeric species of α-Syn are more cytotoxic than their mature fibrillar counterparts, which are responsible for dopaminergic neuronal cell death in PD. Therefore, the effective therapeutic strategies for tackling aggregation-associated diseases would be either to prevent aggregation or to modulate the aggregation process to minimize the formation of toxic oligomers during aggregation. In this work, we showed that arginine-substituted α-Syn ligands, based on the most aggregation-prone sequence of α-Syn, accelerate the protein aggregation in a concentration-dependent manner. To elucidate the mechanism by which Arg-substituted peptides could modulate α-Syn aggregation kinetics, we performed surface plasmon resonance (SPR) spectroscopy, nuclear magnetic resonance (NMR) studies, and all-atom molecular dynamics (MD) simulation. The SPR analysis showed a high binding potency of these peptides with α-Syn but one that was nonspecific in nature. The two-dimensional NMR studies suggest that a large stretch within the C-terminus of α-Syn displays a chemical shift perturbation upon interacting with Arg-substituted peptides, indicating C-terminal residues of α-Syn might be responsible for this class of peptide binding. This is further supported by MD simulation studies in which the Arg-substituted peptide showed the strongest interaction with the C-terminus of α-Syn. Overall, our results suggest that the binding of Arg-substituted ligands to the highly acidic C-terminus of α-Syn leads to reduced charge density and flexibility, resulting in accelerated aggregation kinetics. This may be a potentially useful strategy while designing peptides, which act as α-Syn aggregation modulators." @default.
• W2777736071 created "2018-01-05" @default.
• W2777736071 creator A5044904934 @default.
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• W2777736071 creator A5088280897 @default.
• W2777736071 date "2018-01-22" @default.
• W2777736071 modified "2023-10-16" @default.
• W2777736071 title "Complexation of NAC-Derived Peptide Ligands with the C-Terminus of α-Synuclein Accelerates Its Aggregation" @default.
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• W2777736071 doi "https://doi.org/10.1021/acs.biochem.7b01090" @default.
• W2777736071 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29286644" @default.
• W2777736071 hasPublicationYear "2018" @default.
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