Bioinorganic Chemistry of Parkinson’s Disease: Affinity and Structural Features of Cu(I) Binding to the Full-Length β‑Synuclein Protein

Alterations in the levels of copper in brain tissue and formation of α-synuclein (αS)-copper complexes might play a key role in the amyloid aggregation of αS and the onset of Parkinson’s disease (PD). Recently, we demonstrated that formation of the high-affinity Cu­(I) complex with the N-terminally acetylated form of the protein αS substantially increases and stabilizes local conformations with α-helical secondary structure and restricted motility. In this work, we performed a detailed NMR-based structural characterization of the Cu­(I) complexes with the full-length acetylated form of its homologue β-synuclein (βS), which is colocalized with αS in vivo and can bind copper ions. Our results show that, similarly to αS, the N-terminal region of βS constitutes the preferential binding interface for Cu­(I) ions, encompassing two independent and noninteractive Cu­(I) binding sites. According to these results, βS binds the metal ion with higher affinity than αS, in a coordination environment that involves the participation of Met-1, Met-5, and Met-10 residues (site 1). Compared to αS, the shift of His from position 50 to 65 in the N-terminal region of βS does not change the Cu­(I) affinity features at that site (site 2). Interestingly, the formation of the high-affinity βS–Cu­(I) complex at site 1 in the N-terminus promotes a short α-helix conformation that is restricted to the 1–5 segment of the AcβS sequence, which differs with the substantial increase in α-helix conformations seen for N-terminally acetylated αS upon Cu­(I) complexation. Our NMR data demonstrate conclusively that the differences observed in the conformational transitions triggered by Cu­(I) binding to AcαS and AcβS find a correlation at the level of their backbone dynamic properties; added to the potential biological implications of these findings, this fact opens new avenues of investigations into the bioinorganic chemistry of PD