Copper-Transfer Mechanism from the Human Chaperone Atox1 to a Metal-Binding Domain of Wilson Disease Protein

The molecular details of how copper (Cu) is transferred from the human Cu chaperone Atox1 to metal-binding domains (MBDs) of P-1B-type ATPases are Still Unclear. Here, We use 11 computational approach, employing quantum mechanics/molecular mechanics (QM/MM) methods, to shed light oil the reaction mechanism [probable intermediates, Cu(I) coordination geometries, activation barriers, and energetics) of Cu(I) transfer from Atox1 to the fourth MBD of Wilson disease protein (WD4). Both Atox1 and WD4 have solvent-exposed metal-binding motif's with two Cys residues that coordinate Cu(1). After assessing the existence of all possible 2-, 3- and 4-coordinate Cu-intermediate species, one dominant reaction path emerged. First, Without activation barrier, WD4's Cys I binds Cu(l) in Atox1 to form a 3-coordinated intermediate. Next, with an activation barrier of about 9.5 kcal/mol, a second 3-coordinated intermediate forms that involves both of the Cys residues in WD4 and Cys I of Atox1. This species call then form the product by decoordination of Atox1's Cys I (barrier of about 8 kcal/mol). Overall, the Cu-transfer reaction from Atox1 to WD4 appears to be kinetically accessible but less energetically favorable (Delta E = 7.7 kcal/mol). Our results provide unique insights into the molecular mechanism of protein-mediated Cu(l) transfer in the secretory pathway and are in agreement with existing experimental data.