Crystal structure of a copper-transporting PIB-type ATPase

• Published in: Nature (London) Vol. 475; no. 7354; pp. 59 - 64
• Main Authors: Gourdon, Pontus, Liu, Xiang-Yu, Skjørringe, Tina, Morth, J. Preben, Møller, Lisbeth Birk, Pedersen, Bjørn Panyella, Nissen, Poul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.07.2011; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/737; 631/45/535; Adenosine Triphosphatases - genetics; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Binding Sites; Biological and medical sciences; Biological Transport; Calcium; Cation Transport Proteins - genetics; Cell Membrane - metabolism; Copper; Copper - metabolism; Copper-transporting ATPases; Crystalline structure; Crystallography; Crystallography, X-Ray; Cytoplasm - metabolism; Detoxification; Disease; Diseases; Extruding; Fundamental and applied biological sciences. Psychology; Heavy metals; Hepatolenticular Degeneration - genetics; Homeostasis; Humanities and Social Sciences; Humans; Legionella pneumophila; Legionella pneumophila - chemistry; Menkes Kinky Hair Syndrome - genetics; Models, Molecular; Molecular biophysics; multidisciplinary; Mutation; Mutation, Missense - genetics; Mutations; Phosphorylation; Protein Structure, Tertiary; Proteins; Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry; Science; Science (multidisciplinary); Structure in molecular biology; Structure-Activity Relationship; Viability; Legionellaceae; Enzyme; Adenosinetriphosphatase; Detoxification; Homeostasis; Bacteria; Hydrolases; Legionella pneumophila; Copper; Heavy metal; Crystalline structure
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10191

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. Copper transport dissected Class IB P-type ATPases perform an important cellular function by regulating the levels of heavy metals, copper in particular, thus providing protein cofactors and maintaining appropriate intracellular concentrations to prevent toxic reactions. In humans, defects in two proteins of this class (the copper pumps ATP7A and ATP7B) give rise to the severe Menkes' and Wilson's diseases. The X-ray crystal structure of a class IB P-type Cu+-ATPase has now been determined in its copper-free state. The structure of CopA from Legionella pneumophila suggests that the copper-transport pathway has three main stages: a cytoplasmic 'entry' site, binding sites in the membrane and an extracellular 'exit' site.