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 Cu(II) binding to αS is important in the PD context. Several previous reports have shown some discrepancies in the description of the main Cu(II) site in αS, which are resolved here by a new scenario. Three Cu(II) species can be encountered, depending on the pH and the Cu:αS ratio. At low pH, Cu(II) 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):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 Cu(II). 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 αS protein, having various aggregation propensity.
†CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, F-31077 Toulouse Cedex 4, France.|‡Université de Toulouse, UPS, INPT, F-31077 Toulouse Cedex 4, France.|§Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro 2, 53100 Siena, Italy.
Riccardo
R
De Ricco
§Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro 2, 53100 Siena, Italy.
Daniela
D
Valensin
∇Department of Chemistry, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy.
Simone
S
Dell'Acqua
∇Department of Chemistry, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy.
Luigi
L
Casella
⊥Institute for Integrative Biology of the Cell (I2BC), Laboratoire Stress Oxydant et Détoxication, CNRS UMR9198, Université Paris-Saclay, 91191 Gif sur Yvette Cedex, France.
Pierre
P
Dorlet
†CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, F-31077 Toulouse Cedex 4, France.|‡Université de Toulouse, UPS, INPT, F-31077 Toulouse Cedex 4, France.
Peter
P
Faller
†CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099, F-31077 Toulouse Cedex 4, France.|‡Université de Toulouse, UPS, INPT, F-31077 Toulouse Cedex 4, France.
Christelle
C
Hureau
D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D003300:Copper / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D066329:Protein Aggregates; D011485:Protein Binding; D017510:Protein Folding; D060327:Solid-Phase Synthesis Techniques; D051844:alpha-Synuclein / Q000737:chemistry*
D010455:Peptides; D066329:Protein Aggregates; D051844:alpha-Synuclein; D001224:Aspartic Acid; D006639:Histidine; D003300:Copper