title: Allostery in a disordered protein: oxidative modifications to α-synuclein act distally to regulate membrane binding.
abstract: Both oxidative stress and aggregation of the protein α-synuclein (aS) have been implicated as key factors in the etiology of Parkinson's disease. Specifically, oxidative modifications to aS disrupt its binding to lipid membranes, an interaction considered critical to its native function. Here we seek to provide a mechanistic explanation for this phenomenon by investigating the effects of oxidative nitration of tyrosine residues on the structure of aS and its interaction with lipid membranes. Membrane binding is mediated by the first ∼95 residues of aS. We find that nitration of the single tyrosine (Y39) in this domain disrupts binding due to electrostatic repulsion. Moreover, we observe that nitration of the three tyrosines (Y125/133/136) in the C-terminal domain is equally effective in perturbing binding, an intriguing result given that the C-terminus is not thought to interact directly with the lipid bilayer. Our investigations show that tyrosine nitration results in a change of the conformational states populated by aS in solution, with the most prominent changes occurring in the C-terminal region. These results lead us to suggest that nitration of Y125/133/136 reduces the membrane-binding affinity of aS through allosteric coupling by altering the ensemble of conformational states and depopulating those capable of membrane binding. While allostery is a well-established concept for structured proteins, it has only recently been discussed in the context of disordered proteins. We propose that allosteric regulation through modification of specific residues in, or ligand binding to, the C-terminus may even be a general mechanism for modulating aS function.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Sevcsik
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Trexler
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Dunn
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rhoades
mesh_terms: D000494:Allosteric Regulation; D006801:Humans; D057446:Hydrodynamics; D008051:Lipid Bilayers; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism; D009154:Mutation; D009566:Nitrates / Q000737:chemistry; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D014443:Tyrosine / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D008051:Lipid Bilayers; D008563:Membrane Lipids; D009566:Nitrates; D051844:alpha-Synuclein; D014443:Tyrosine