title: Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein.
abstract: The intrinsically disordered and amyloidogenic protein α-synuclein (AS) has been linked to several neurodegenerative states, including Parkinson's disease. Here, nanoelectrospray-ionization mass spectrometry (nano-ESI-MS), ion mobility (IM), and native top-down electron transfer dissociation (ETD) techniques are employed to study AS interaction with small molecules known to modulate its aggregation, such as epigallocatechin-3-gallate (EGCG) and dopamine (DA). The complexes formed by the two ligands under identical conditions reveal peculiar differences. While EGCG engages AS in compact conformations, DA preferentially binds to the protein in partially extended conformations. The two ligands also have different effects on AS structure as assessed by IM, with EGCG leading to protein compaction and DA to its extension. Native top-down ETD on the protein-ligand complexes shows how the different observed modes of binding of the two ligands could be related to their known opposite effects on AS aggregation. The results also show that the protein can bind either ligand in the absence of any covalent modifications, such as oxidation.
authors.affiliation: Biomolecular & Analytical Mass Spectrometry, University of Antwerp , Groenenborgerlaan 171, 2020 Antwerp, Belgium.
authors.forename: Albert
authors.initials: A
authors.lastname: Konijnenberg
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca , Piazza della Scienza 2, 20126 Milan, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Ranica
authors.affiliation: Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA) and ELETTRA-Sincrotrone Trieste S.C.p.A , 34136 Trieste, Italy.
authors.forename: Joanna
authors.initials: J
authors.lastname: Narkiewicz
authors.affiliation: Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA) and ELETTRA-Sincrotrone Trieste S.C.p.A , 34136 Trieste, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca , Piazza della Scienza 2, 20126 Milan, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Grandori
authors.affiliation: Biomolecular & Analytical Mass Spectrometry, University of Antwerp , Groenenborgerlaan 171, 2020 Antwerp, Belgium.|Astbury Centre for Structural Molecular Biology, University of Leeds , Leeds, LS2 9JT, U.K.|School of Molecular and Cellular Biology, University of Leeds , Leeds, LS2 9JT, U.K.
authors.forename: Frank
authors.initials: F
authors.lastname: Sobott
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca , Piazza della Scienza 2, 20126 Milan, Italy.|Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia (CNISM), UdR of Milano-Bicocca, and Milan Center of Neuroscience (NeuroMI), 20126 Milan, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Natalello
mesh_terms: D001665:Binding Sites; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry; D004298:Dopamine / Q000737:chemistry*; D015394:Molecular Structure; D036103:Nanotechnology; D021241:Spectrometry, Mass, Electrospray Ionization; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D051844:alpha-Synuclein; D002392:Catechin; C045651:epigallocatechin gallate; D004298:Dopamine