INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
Copper Transfer Mechanism from the Human Chaperone Atox1 to a Metal-Binding Domain of Wilson Disease Protein
RODRIGUEZ GRANILLO, A.; CRESPO, A.; ESTRIN, D.A.; WITTUNG-STAFSHEDE, P.
JOURNAL OF PHYSICAL CHEMISTRY B - (Print)
AMER CHEMICAL SOC
Lugar: Columbus, OH; Año: 2010 vol. 114 p. 3698 - 3698
The molecular details of how copper (Cu) is transferred from the human Cu chaperone Atox1 to metal-binding domains (MBDs) of P1B-type ATPases are still unclear. Here, we use a computational approach,employing quantum mechanics/molecular mechanics (QM/MM) methods, to shed light on the reactionmechanism [probable intermediates, Cu(I) coordination geometries, activation barriers, and energetics] ofCu(I) transfer from Atox1 to the fourth MBD of Wilson disease protein (WD4). Both Atox1 and WD4 havesolvent-exposed metal-binding motifs with two Cys residues that coordinate Cu(I). After assessing the existenceof all possible 2-, 3- and 4-coordinate Cu-intermediate species, one dominant reaction path emerged. First,without activation barrier, WD4s Cys1 binds Cu(I) 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 involvesboth of the Cys residues in WD4 and Cys1 of Atox1. This species can then form the product by decoordinationof Atox1s Cys1 (barrier of about 8 kcal/mol). Overall, the Cu-transfer reaction from Atox1 to WD4 appearsto be kinetically accessible but less energetically favorable (∆E ) 7.7 kcal/mol). Our results provide uniqueinsights into the molecular mechanism of protein-mediated Cu(I) transfer in the secretory pathway and are inagreement with existing experimental data.