Remodeling of the Conformational Dynamics of Noncanonical DNA Structures by Monomeric and Aggregated α‑Synuclein

• Published in: Journal of the American Chemical Society 2020-10, Vol.142 (43), p.18299-18303
• Main Authors: Knop, Jim-Marcel, Mukherjee, Sanjib K., Oliva, Rosario, Möbitz, Simone, Winter, Roland
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - chemistry; amyloid; Base Sequence; brain; Communication; death; DNA; DNA - chemistry; energy transfer; Fluorescence Resonance Energy Transfer; G-Quadruplexes; genomics; Nucleic Acid Conformation; Protein Aggregates; species; telomeres
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.0c07192

Research on Parkinson’s disease most often focuses on the ability of the protein α-synuclein (α-syn) to form oligomers and amyloid fibrils, and how such species promote brain death. However, there are indications that α-syn also plays a gene-regulatory role in the cell nucleus. Noncanonical tetrahelical nucleic acids, G-quadruplexes (G4Q), and i-motifs have been shown to play an important role in the control of genomic events. Using the conformation-sensitive single-molecule Förster resonance energy transfer technique we show that monomeric and oligomeric α-syn affect G4Qs and i-motifs in a different way and lead to remodeling of their conformational substates. Aggregated α-syn destabilizes the G4Q leading to unfolding. In contrast, both monomeric and aggregated α-syn enhance folding of the i-motif sequence of telomeric DNA. Importantly, macromolecular crowding is able to partially rescue G4Q from unfolding.