Molecular characterization of an aggregation-prone variant of alpha-synuclein used to model synucleinopathies

Publication date: Available online 30 October 2019Source: Biochimica et Biophysica Acta (BBA) - Proteins and ProteomicsAuthor(s): Caterina Masaracchia, Annekatrin König, Ariel A. Valiente-Gabioud, Pablo Peralta, Filippo Favretto, Timo Strohäker, Diana F. Lázaro, Markus Zweckstetter, Claudio O. Fernandez, Tiago F. OuteiroAbstractThe misfolding and aggregation of alpha-synuclein (aSyn) are thought to be central events in synucleinopathies. The physiological function of aSyn has been related to vesicle binding and trafficking, but the precise molecular mechanisms leading to aSyn pathogenicity are still obscure. In cell models, aSyn does not readily aggregate, even upon overexpression. Therefore, cellular models that enable the study of aSyn aggregation are essential tools for our understanding of the molecular mechanisms that govern such processes. Here, we investigated the structural features of SynT, an artificial variant of aSyn that has been widely used as a model of aggregation in mammalian cell systems, since it is more prone to aggregation than aSyn. Using Nuclear Magnetic Resonance (NMR) spectroscopy we performed a detailed structural characterization of SynT through a systematic comparison with normal, unmodified aSyn. Interestingly, we found that the conformations adopted by SynT resemble those described for the unmodified protein, demonstrating the usefulness of SynT as a model for aSyn aggregation. However, subtle differences were observed at the N-terminal region...

Source: Biochimica et Biophysica Acta (BBA) Proteins and Proteomics - October 31, 2019 Category: Biochemistry Source Type: research