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Bioinorganic Chemistry of Parkinson’s Disease: Affinity and Structural Features of Cu(I) Binding to the Full-Length β‑Synuclein Protein
journal contribution
posted on 2017-08-18, 12:11 authored by Marco
C. Miotto, Mayra D. Pavese, Liliana Quintanar, Markus Zweckstetter, Christian Griesinger, Claudio O. FernándezAlterations
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.