Remote His50 Acts as a Coordination Switch in the High-Affinity N-Terminal Centered Copper(II) Site of α-Synuclein

Parkinson’s disease (PD) etiology is closely linked to the aggregation of α-synuclein (αS). Copper(II) ions can bind to αS and may impact its aggregation propensity. As a consequence, deciphering the exact mode of CuII binding to αS is important in the PD context. Several previous reports have shown some discrepancies in the description of the main CuII site in αS, which are resolved here by a new scenario. Three CuII species can be encountered, depending on the pH and the Cu:αS ratio. At low pH, CuII is bound to the N-terminal part of the protein by the N-terminal amine, the adjacent deprotonated amide group of the Asp2 residue, and the carboxylate group from the side chain of the same Asp2. At pH 7.4, the imidazole group of remote His50 occupies the fourth labile equatorial position of the previous site. At high CuII:αS ratio (>1), His50 leaves the coordination sphere of the first Cu site centered at the N-terminus, because a second weak affinity site centered on His50 is now filled with CuII. In this n...