Bioinorganic Chemistry of Parkinson’s Disease: Structural Determinants for the Copper-Mediated Amyloid Formation of Alpha-Synuclein

Abstract

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.

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

“…Our study demonstrated conclusively that the imidazol ring of the histidine residue is the anchoring group for zinc binding to the N-terminal region of AS. However, the affinity features reported for the AS-metal complexes at this site varies from 35 μM in the case of Cu 2+ ions [81] to around 1 mM for Zn 2+ ions. Contrasting with the lack of selectivity that characterizes the binding of metal ions to the C-terminus, a hierarchy seems to exist for AS-metal interactions at the His50 site, likely determined by the nature of the metal ion involved and its coordination geometry preferences.…”

“…Differences in the mean weighted chemical shift (MWΔCS) values for 1 H and 15 N were calculated as [(Δδ 1 H) 2 + (Δδ 15 N/10) 2 ] 1/2 [79]. Intensity profiles (I/I 0 ) were obtained by comparing the intensities of 1 H-15 N HSQC amide cross-peaks registered in the presence (I) and absence (I 0 ) of the metal ion [71,[80][81][82][83]. The I/I 0 ratios of non-overlapping cross-peaks were plotted as a function of the protein sequence to obtain the intensity profiles.…”

Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS–Cu(I) interactions

“…This mechanism is a highly selective, site-specific process that involves interactions of the protein with both oxidation states of the copper ion. Added to the large body of evidence supporting AS-Cu(II) interactions [14][15][16][17][18][19][20], elucidation of the residue-specific basis determining the AS-Cu(I) structural-affinity features is central to establish a connection of the AS-copper interactions with the mechanistic basis-oxidative damage-behind the metal-enhanced AS amyloid assembly. In that direction, we have demonstrated recently that both Met residues in the motif 1 MDVFM 5 constitute key structural determinants for the binding of Cu(I) to the N-terminal region of AS in a Met 1 (S)-Cu(I)-(S)Met 5 coordination environment [21,22].…”

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

“…Moreover, heavy metals have also been paid more attention, because α-syn has multiple binding sites of metal [101]. Many types of research showed that the high metal ions could aggravate the formation of α-syn fibrillation and aggregation, result in the cell injury and consequently contribute to the progressive of PD [7,[102][103][104][105][106]. And MPTP, a well-known neurotoxin, is also associated with the aggregation of α-syn, which was confirmed by a study that the oligomers of SNCA (51 kD) increased in the SNpc of monkeys administrated intravenously with MPTP (0.3 mg/kg) twice a week for three months [107].…”