title: Biochemical characterization of P-type copper ATPases.
abstract: Copper ATPases, in analogy with other members of the P-ATPase superfamily, contain a catalytic headpiece including an aspartate residue reacting with ATP to form a phosphoenzyme intermediate, and transmembrane helices containing cation-binding sites [TMBS (transmembrane metal-binding sites)] for catalytic activation and cation translocation. Following phosphoenzyme formation by utilization of ATP, bound copper undergoes displacement from the TMBS to the lumenal membrane surface, with no H+ exchange. Although PII-type ATPases sustain active transport of alkali/alkali-earth ions (i.e. Na+, Ca2+) against electrochemical gradients across defined membranes, PIB-type ATPases transfer transition metal ions (i.e. Cu+) from delivery to acceptor proteins and, prominently in mammalian cells, undergo trafficking from/to various membrane compartments. A specific component of copper ATPases is the NMBD (N-terminal metal-binding domain), containing up to six copper-binding sites in mammalian (ATP7A and ATP7B) enzymes. Copper occupancy of NMBD sites and interaction with the ATPase headpiece are required for catalytic activation. Furthermore, in the presence of copper, the NMBD allows interaction with protein kinase D, yielding phosphorylation of serine residues, ATP7B trafficking and protection from proteasome degradation. A specific feature of ATP7A is glycosylation and stabilization on plasma membranes. Cisplatin, a platinum-containing anti-cancer drug, binds to copper sites of ATP7A and ATP7B, and undergoes vectorial displacement in analogy with copper.
authors.affiliation: *California Pacific Medical Center Research Institute, San Francisco, CA 94920, U.S.A.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Inesi
authors.affiliation: †Department of Biochemistry and Molecular Biology, Central University of Kerala, Padennakkad (P.O), Nileshwar, Kasaragod-671 314, Kerala, India.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Pilankatta
authors.affiliation: ‡Department of Chemistry "Ugo Schiff", University of Florence, 50019 Sesto Fiorentino, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Tadini-Buoninsegni
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055162:Biocatalysis; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D006801:Humans; D017434:Protein Structure, Tertiary
chemical_list: D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases