title: Crystal structure of a copper-transporting PIB-type ATPase.
abstract: Heavy-metal homeostasis and detoxification is crucial for cell viability. P-type ATPases of the class IB (PIB) are essential in these processes, actively extruding heavy metals from the cytoplasm of cells. Here we present the structure of a PIB-ATPase, a Legionella pneumophila CopA Cu(+)-ATPase, in a copper-free form, as determined by X-ray crystallography at 3.2 Å resolution. The structure indicates a three-stage copper transport pathway involving several conserved residues. A PIB-specific transmembrane helix kinks at a double-glycine motif displaying an amphipathic helix that lines a putative copper entry point at the intracellular interface. Comparisons to Ca(2+)-ATPase suggest an ATPase-coupled copper release mechanism from the binding sites in the membrane via an extracellular exit site. The structure also provides a framework to analyse missense mutations in the human ATP7A and ATP7B proteins associated with Menkes' and Wilson's diseases.
authors.affiliation: Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
authors.forename: Pontus
authors.initials: P
authors.lastname: Gourdon
authors.forename: Xiang-Yu
authors.initials: XY
authors.lastname: Liu
authors.forename: Tina
authors.initials: T
authors.lastname: Skjørringe
authors.forename: J Preben
authors.initials: JP
authors.lastname: Morth
authors.forename: Lisbeth Birk
authors.initials: LB
authors.lastname: Møller
authors.forename: Bjørn Panyella
authors.initials: BP
authors.lastname: Pedersen
authors.forename: Poul
authors.initials: P
authors.lastname: Nissen
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D001692:Biological Transport; D002118:Calcium; D027682:Cation Transport Proteins / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D006527:Hepatolenticular Degeneration / Q000235:genetics; D006801:Humans; D016952:Legionella pneumophila / Q000737:chemistry*; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics; D017434:Protein Structure, Tertiary; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D027682:Cation Transport Proteins; C071263:CopA protein, Bacteria; D003300:Copper; D000251:Adenosine Triphosphatases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C081184:ATP7A protein, human; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases; D002118:Calcium