title: Cellular distribution of copper to superoxide dismutase involves scaffolding by membranes.
abstract: Efficient delivery of copper ions to specific intracellular targets requires copper chaperones that acquire metal cargo through unknown mechanisms. Here we demonstrate that the human and yeast copper chaperones (CCS) for superoxide dismutase 1 (SOD1), long thought to exclusively reside in the cytosol and mitochondrial intermembrane space, can engage negatively charged bilayers through a positively charged lipid-binding interface. The significance of this membrane-binding interface is established through SOD1 activity and genetic complementation studies in Saccharomyces cerevisiae, showing that recruitment of CCS to the membrane is required for activation of SOD1. Moreover, we show that a CCS:SOD1 complex binds to bilayers in vitro and that CCS can interact with human high affinity copper transporter 1. Shifting current paradigms, we propose that CCS-dependent copper acquisition and distribution largely occur at membrane interfaces and that this emerging role of the bilayer may reflect a general mechanistic aspect of cellular transition metal ion acquisition.
authors.affiliation: Department of Molecular Biosciences and Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pope
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: De Feo
authors.forename: Vinzenz M
authors.initials: VM
authors.lastname: Unger
mesh_terms: D001693:Biological Transport, Active / Q000502:physiology; D003300:Copper / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005816:Genetic Complementation Test; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008051:Lipid Bilayers / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: C114678:CCS protein, human; C491960:CCS1 protein, S cerevisiae; D008051:Lipid Bilayers; D018832:Molecular Chaperones; C000606290:SOD1 protein, human; D029701:Saccharomyces cerevisiae Proteins; D003300:Copper; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: copper homeostasis; copper transfer; copper uptake; membrane scaffold