Structural basis behind the interaction of Zn2+ with the protein α-synuclein 6 and the Aβ peptide: A comparative analysis

VALIENTE-GABIOUD, AA; TORRES-MONSERRAT , V; MOLINA-RUBINO, L; BINOLFI, A; GRIESINGER, C; FERNANDEZ, CO

JOURNAL OF INORGANIC BIOCHEMISTRY

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2012 p. 1 - 10

0162-0134

α-Synuclein (AS) aggregation is associated to neurodegeneration in Parkinson´s disease (PD). At the same 24time, alterations in metal ion homeostasis may play a pivotal role in the progression of AS amyloid assembly 25and the onset of PD. Elucidation of the structural basis directing AS?metal interactions and their effect on AS 26aggregation constitutes a key step towards understanding the role of metal ions in AS amyloid formation and 27neurodegeneration. Despite of the reported evidences that link Zn2+ with the pathophysiology of PD and the 28fact that this metal ion was shown to promote AS fibrillation in vitro, neither the structural characterization 29of the binding sites nor the identification of the amino acids involved in the interaction of Zn2+ with the pro- 30tein AS has been carried out. By using NMR spectroscopy, we have addressed here unknown structural details 31related to the binding of Zn2+ to the protein AS through the design of site-directed and domain truncated 32mutants of AS. The binding of zinc to the Aβ peptide was also studied and discussed comparatively. Although 33the results of this study contribute to the understanding of the structural and molecular basis behind the ac- 34celeration of AS fibrillation mediated by Zn2+, the low affinity that characterizes the interaction of Zn2+ with 35AS contrasts strongly with the high-affinity features reported for the binding of this metal ion to other target 36proteins linked to human amylodosis such as Aβ peptide and the Islet Amyloid Polypeptide (IAPP), challeng- 37ing the biological relevance of zinc interactions in the pathogenesis of PD.