SOLUTION STRUCTURE OF THE 4TH METAL-BINDING DOMAIN FROM THE MENKES COPPER-TRANSPORTING ATPASE

Menkes disease is an X-linked disorder in copper transport that result s in death during early childhood. The solution structures of both apo and Ag(I)-bound forms of the fourth metal-binding domain (mbd4) from the Menkes copper-transporting ATPase have been solved. The 72-residue mbd4 has a ferredoxin-like beta alpha beta beta alpha beta fold. Stru ctural differences between the two forms are limited to the metal-bind ing loop, which is disordered in the apo structure but well ordered in the Ag(I)-bound structure. Ag(I) binds in a linear bicoordinate manne r to the two Cys residues of the conserved GMTCxxC motif; Cu(I) likely coordinates in a similar manner. Menkes mbd4 is thus the first bicoor dinate copper-binding protein to be characterized structurally. Sequen ce comparisons with other heavy-metal-binding domains reveal a conserv ed hydrophobic core and metal-binding motif.