title: Ctr2 regulates biogenesis of a cleaved form of mammalian Ctr1 metal transporter lacking the copper- and cisplatin-binding ecto-domain.
abstract: Copper is an essential catalytic cofactor for enzymatic activities that drive a range of metabolic biochemistry including mitochondrial electron transport, iron mobilization, and peptide hormone maturation. Copper dysregulation is associated with fatal infantile disease, liver, and cardiac dysfunction, neuropathy, and anemia. Here we report that mammals regulate systemic copper acquisition and intracellular mobilization via cleavage of the copper-binding ecto-domain of the copper transporter 1 (Ctr1). Although full-length Ctr1 is critical to drive efficient copper import across the plasma membrane, cleavage of the ecto-domain is required for Ctr1 to mobilize endosomal copper stores. The biogenesis of the truncated form of Ctr1 requires the structurally related, previously enigmatic copper transporter 2 (Ctr2). Ctr2(-/-) mice are defective in accumulation of truncated Ctr1 and exhibit increased tissue copper levels, and X-ray fluorescence microscopy demonstrates that copper accumulates as intracellular foci. These studies identify a key regulatory mechanism for mammalian copper transport through Ctr2-dependent accumulation of a Ctr1 variant lacking the copper- and cisplatin-binding ecto-domain.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27708.
authors.forename: Helena
authors.initials: H
authors.lastname: Öhrvik
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nose
authors.forename: L Kent
authors.initials: LK
authors.lastname: Wood
authors.forename: Byung-Eun
authors.initials: BE
authors.lastname: Kim
authors.forename: Sophie-Charlotte
authors.initials: SC
authors.lastname: Gleber
authors.forename: Martina
authors.initials: M
authors.lastname: Ralle
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Thiele
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D015139:Blotting, Southern; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002945:Cisplatin / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D000079923:Copper Transporter 1; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D017434:Protein Structure, Tertiary / Q000235:genetics; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D000080083:SLC31 Proteins
chemical_list: D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D000080083:SLC31 Proteins; C490077:Slc31a1 protein, mouse; C585492:Slc31a2 protein, mouse; D003300:Copper; D002945:Cisplatin
keywords: endosome; lysosome; platinum; protein regulation; uptake