Bioinorganic chemistry of Parkinson's disease: structural determinants for the copper-mediated amyloid formation of alpha-synuclein.
The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD). A central, unresolved question in the pathophysiology of PD relates to the role of AS-metal interactions in amyloid fibril formation and neurodegeneration. Our previous works established a hierarchy in alpha-synuclein-metal ion interactions, where Cu(II) binds specifically to the protein and triggers its aggregation under conditions that might be relevant for the development of PD. Two independent, non-interacting copper-binding sites were identified at the N-terminal region of AS, with significant difference in their affinities for the metal ion. In this work we have solved unknown details related to the structural binding specificity and aggregation enhancement mediated by Cu(II). The high-resolution structural characterization of the highest affinity N-terminus AS-Cu(II) complex is reported here. Through the measurement of AS aggregation kinetics we proved conclusively that the copper-enhanced AS amyloid formation is a direct consequence of the formation of the AS-Cu(II) complex at the highest affinity binding site. The kinetic behavior was not influenced by the His residue at position 50, arguing against an active role for this residue in the structural and biological events involved in the mechanism of copper-mediated AS aggregation. These new findings are central to elucidate the mechanism through which the metal ion participates in the fibrillization of AS and represent relevant progress in the understanding of the bioinorganic chemistry of PD.
Instituto de Biología Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina.
Andrés
A
Binolfi
Esaú E
EE
Rodriguez
Daniela
D
Valensin
Nicola
N
D'Amelio
Emiliano
E
Ippoliti
Gonzalo
G
Obal
Rosario
R
Duran
Alessandra
A
Magistrato
Otto
O
Pritsch
Markus
M
Zweckstetter
Gianni
G
Valensin
Paolo
P
Carloni
Liliana
L
Quintanar
Christian
C
Griesinger
Claudio O
CO
Fernández
D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D015393:Chemistry, Bioinorganic; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010300:Parkinson Disease; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
D000682:Amyloid; D051844:alpha-Synuclein; D003300:Copper