title: Structural basis behind the interaction of Zn²⁺ with the protein α-synuclein and the Aβ peptide: a comparative analysis.
abstract: α-Synuclein (AS) aggregation is associated to neurodegeneration in Parkinson's disease (PD). At the same time, alterations in metal ion homeostasis may play a pivotal role in the progression of AS amyloid assembly and the onset of PD. Elucidation of the structural basis directing AS-metal interactions and their effect on AS aggregation constitutes a key step towards understanding the role of metal ions in AS amyloid formation and neurodegeneration. Despite of the reported evidences that link Zn(2+) with the pathophysiology of PD and the fact that this metal ion was shown to promote AS fibrillation in vitro, neither the structural characterization of the binding sites nor the identification of the amino acids involved in the interaction of Zn(2+) with the protein AS has been carried out. By using NMR spectroscopy, we have addressed here unknown structural details related to the binding of Zn(2+) to the protein AS through the design of site-directed and domain truncated mutants of AS. The binding of zinc to the Aβ peptide was also studied and discussed comparatively. Although the results of this study contribute to the understanding of the structural and molecular basis behind the acceleration of AS fibrillation mediated by Zn(2+), the low affinity that characterizes the interaction of Zn(2+) with AS contrasts strongly with the high-affinity features reported for the binding of this metal ion to other target proteins linked to human amylodosis such as Aβ peptide and the Islet Amyloid Polypeptide (IAPP), challenging the biological relevance of zinc interactions in the pathogenesis of PD.
authors: Instituto de Biología Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina.
authors: Ariel A
authors: AA
authors: Valiente-Gabioud
authors: Valentina
authors: V
authors: Torres-Monserrat
authors: Laura
authors: L
authors: Molina-Rubino
authors: Andres
authors: A
authors: Binolfi
authors: Christian
authors: C
authors: Griesinger
authors: Claudio O
authors: CO
authors: Fernández
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001665:Binding Sites; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D051844:alpha-Synuclein; D015032:Zinc