Solution structure of the fourth metal-binding domain from the Menkes copper-transporting ATPase

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Abstract
Menkes disease is an X-linked disorder in copper transport that results in death during early childhood. The solution structures of both apo and Ag(l)-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 βαββαβ fold. Structural differences between the two forms are limited to the metal-binding loop, which is disordered in the apo structure but well ordered in the Ag(l)-bound structure. Ag(l) binds in a linear bicoordinate manner to the two Cys residues of the conserved GMTCxxC motif; Cu(l) likely coordinates in a similar manner. Menkes mbd4 is thus the first bicoordinate copper-binding protein to be characterized structurally. Sequence comparisons with other heavy-metal-binding domains reveal a conserved hydrophobic core and metal-binding motif.