title: Structural models of the human copper P-type ATPases ATP7A and ATP7B.
abstract: The human copper exporters ATP7A and ATP7B contain domains common to all P-type ATPases as well as class-specific features such as six sequential heavy-metal binding domains (HMBD1-HMBD6) and a type-specific constellation of transmembrane helices. Despite the medical significance of ATP7A and ATP7B related to Menkes and Wilson diseases, respectively, structural information has only been available for isolated, soluble domains. Here we present homology models based on the existing structures of soluble domains and the recently determined structure of the homologous LpCopA from the bacterium Legionella pneumophila. The models and sequence analyses show that the domains and residues involved in the catalytic phosphorylation events and copper transfer are highly conserved. In addition, there are only minor differences in the core structures of the two human proteins and the bacterial template, allowing protein-specific properties to be addressed. Furthermore, the mapping of known disease-causing missense mutations indicates that among the heavy-metal binding domains, HMBD5 and HMBD6 are the most crucial for function, thus mimicking the single or dual HMBDs found in most copper-specific P-type ATPases. We propose a structural arrangement of the HMBDs and how they may interact with the core of the proteins to achieve autoinhibition.
authors.affiliation: Centre for Membrane Pumps in Cells and Disease, Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus, Denmark.
authors.forename: Pontus
authors.initials: P
authors.lastname: Gourdon
authors.forename: Oleg
authors.initials: O
authors.lastname: Sitsel
authors.forename: Jesper
authors.initials: J
authors.lastname: Lykkegaard Karlsen
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Birk Møller
authors.forename: Poul
authors.initials: P
authors.lastname: Nissen
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry*; D000595:Amino Acid Sequence; D027682:Cation Transport Proteins / Q000737:chemistry*; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D006801:Humans; D016952:Legionella pneumophila / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein
chemical_list: D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases