Copper binding to the physiological form of the alpha-synuclein protein
Final Report Abstract
In patients with Parkinson’s disease, there is a loss of neurons from a certain part of the brain. Those dead neurons contain Lewy bodies, which consist of aggregates of a protein named acetylated α-synuclein (AcAS). It is an intrinsically disordered protein: a protein without a clear shape, but an ensemble of shapes. Aggregation of AcAS seems to be one of the primary events of Parkinson’s disease. Copper ions might modulate AcAS aggregation. The interaction of copper ions with AcAS is not completely understood yet. How this interaction enhances the aggregation propensity of AcAS is not known either. In this work, based on experimental findings, we have predicted AcAS conformational ensemble and the copper binding mode to AcAS. We have found the two most plausible modes of copper interacting with AcAS. This may constitute the first step towards investigating the aggregation propensities of AcAS in the presence of copper by molecular simulations.
Publications
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(2015). Copper Binding to the N-Terminally Acetylated, Naturally Occurring Form of Alpha-Synuclein Induces Local Helical Folding. Journal of the American Chemical Society, 137(20), 6444–6447
Miotto, Marco C.; Valiente-Gabioud, Ariel A.; Rossetti, Giulia; Zweckstetter, Markus; Carloni, Paolo; Selenko, Philipp; Griesinger, Christian; Binolfi, Andres & Fernández, Claudio O.
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(2016). Conformational ensemble of human α-synuclein physiological form predicted by molecular simulations. Physical Chemistry Chemical Physics, 18(8), 5702–5706
Rossetti, G.; Musiani, F.; Abad, E.; Dibenedetto, D.; Mouhib, H.; Fernandez, C. O. & Carloni, P.
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(2016). Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity. Proceedings of the National Academy of Sciences, 113(42), E6506–E6515
Villar-Piqué, Anna; Lopes da Fonseca, Tomás; Sant’Anna, Ricardo; Szegö, Éva Mónika; Fonseca-Ornelas, Luis; Pinho, Raquel; Carija, Anita; Gerhardt, Ellen; Masaracchia, Caterina; Abad Gonzalez, Enrique; Rossetti, Giulia; Carloni, Paolo; Fernández, Claudio O.; Foguel, Debora; Milosevic, Ira; Zweckstetter, Markus; Ventura, Salvador & Outeiro, Tiago Fleming
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Structural Predictions of Intrinsically Disordered Proteins with Computational Methods. E. Abad, G. Rossetti. Chapter at NIC Symposium 2016 – Proceedings. ISBN 978-3-95806-109-5
E. Abad, G. Rossetti
