INVESTIGADORES
BINOLFI Andres
artículos
Título:
Bioinorganic Chemistry of Parkinson's Disease: Structural Determinants for the Copper-Mediated Amyloid Formation of Alpha-Synuclein
Autor/es:
ANDRÉS BINOLFI; ESAÚ EMANUEL RODRIGUEZ; DANIELA VALENSIN; NICOLA D'AMELIO; EMILIANO IPPOLITI; GONZALO OBAL; ROSARIO DURÁN; ALESSANDRA MAGISTRATO; OTTO PRITSCH; MARKUS ZWECKSTETTER; GIANNI VALENSIN; PAOLO CARLONI; LILIANA QUINTANAR; CHRISTIAN GRIESINGER; CLAUDIO O. FERNÁNDEZ
Revista:
INORGANIC CHEMISTRY
Editorial:
AMER CHEMICAL SOC
Referencias:
Lugar: Washington; Año: 2010 vol. 49 p. 10668 - 10679
ISSN:
0020-1669
Resumen:
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 bionorganic chemistry of PD.