Deconvoluting the Cu(II) binding sites at the N-terminal region of Alpha-Synuclein

ANDRÉS BINOLFI; GONZALO R. LAMBERTO; ROSARIO DURÁN; LILIANA QUINTANAR; ESAU E RODRIGUEZ; CARLOS W. BERTONCINI; JOSE M SOUZA; CARLOS CERVEÑANSKY; MARKUS ZWECKSTETTER; CHRISTIAN GRIESINGER; CLAUDIO O. FERNÁNDEZ

Mexico DF, Mexico

Workshop; USA-Mexico Workshop in Biological Chemistry: Multidisciplinary Approaches to Protein Folding; 2009

The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson’s disease (PD) and protein-metal interactions play a major role in AS fibrillation. Our previous studies established a hierarchy in AS-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. In this work the structural properties of the AS-Cu(II) complexes were determined by the combined application of high and low resolution spectroscopic techniques. Two independent, non-interacting copper-binding sites could be deflected at the N-terminal region of AS, with significant difference in their affinities for the metal ion. A comparative spectroscopic analysis between different variants of the protein and synthetic peptides allowed us to deconvolute the Cu(II) binding modes and to assign unequivocally the high affinity site to the N-terminal amino group of Met1 and the low affinity site to that involving the imidazol ring of the sole His residue. These new insights into the bioinorganic chemistry of PD are central to understand the role of Cu(II) in the fibrillization process of AS.