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 a alpha-synuclein (alpha S). Coppet(II) ions can bind to alpha S and may impact its aggregation propensity As a consequence, deciphering the exact mode of Cull binding to alpha S is important in the PD context. Several previous reports have shown some discrepancies in the description of the main Cu-II site in alpha S, Which are resolved here by a new scenario. Three Cull species can be encountered, depending on the pH and the Cu:alpha S ratio. At low pH, Cull 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 Cu-II:alpha S 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 Cull. In this new scheme, the remote His plays the role of a molecular switch and it can be anticipated that the binding of the remote His to the Cu-II ion can induce different folding of the alpha S protein having various aggregation propensity.