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. © 2016 American Chemical Society.

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein / Konijnenberg, A.; Ranica, S.; Narkiewicz, Joanna; Legname, Giuseppe; Grandori, R.; Sobott, F.; Natalello, A.. - In: ANALYTICAL CHEMISTRY. - ISSN 0003-2700. - 88:17(2016), pp. 8468-8475. [10.1021/acs.analchem.6b00731]

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

Narkiewicz, Joanna;Legname, Giuseppe;
2016-01-01

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. © 2016 American Chemical Society.
2016
88
17
8468
8475
http://eprints.whiterose.ac.uk/105252/1/AnalChem%202016%20Author%20Version.pdf
Konijnenberg, A.; Ranica, S.; Narkiewicz, Joanna; Legname, Giuseppe; Grandori, R.; Sobott, F.; Natalello, A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11767/17369
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