title: Copper-transporting P-type ATPases use a unique ion-release pathway.
abstract: Heavy metals in cells are typically regulated by PIB-type ATPases. The first structure of the class, a Cu(+)-ATPase from Legionella pneumophila (LpCopA), outlined a copper transport pathway across the membrane, which was inferred to be occluded. Here we show by molecular dynamics simulations that extracellular water solvated the transmembrane (TM) domain, results indicative of a Cu(+)-release pathway. Furthermore, a new LpCopA crystal structure determined at 2.8-Å resolution, trapped in the preceding E2P state, delineated the same passage, and site-directed-mutagenesis activity assays support a functional role for the conduit. The structural similarities between the TM domains of the two conformations suggest that Cu(+)-ATPases couple dephosphorylation and ion extrusion differently than do the well-characterized PII-type ATPases. The ion pathway explains why certain Menkes' and Wilson's disease mutations impair protein function and points to a site for inhibitors targeting pathogens.
authors: 1] Department of Physiology and Biophysics, University of California at Irvine, Irvine, California, USA. [2] [3].
authors: Magnus
authors: M
authors: Andersson
authors: 1] Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. [2] [3].
authors: Daniel
authors: D
authors: Mattle
authors: Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Oleg
authors: O
authors: Sitsel
authors: Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Tetyana
authors: T
authors: Klymchuk
authors: Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Anna Marie
authors: AM
authors: Nielsen
authors: Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors: Lisbeth Birk
authors: LB
authors: Møller
authors: Department of Physiology and Biophysics, University of California at Irvine, Irvine, California, USA.
authors: Stephen H
authors: 0000000185407907
authors: SH
authors: White
authors: Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Poul
authors: 0000000309486628
authors: P
authors: Nissen
authors: Centre for Membrane Pumps in Cells and Disease (PUMPkin), Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Pontus
authors: P
authors: Gourdon
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D007477:Ions; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation
chemical_list: D007477:Ions; D003300:Copper; D000251:Adenosine Triphosphatases