title: Three-dimensional structure of the human copper transporter hCTR1.
abstract: Copper uptake proteins (CTRs), mediate cellular acquisition of the essential metal copper in all eukaryotes. Here, we report the structure of the human CTR1 protein solved by electron crystallography to an in plane resolution of 7 A. Reminiscent of the design of traditional ion channels, trimeric hCTR1 creates a pore that stretches across the membrane bilayer at the interface between the subunits. Assignment of the helices identifies the second transmembrane helix as the key element lining the pore, and reveals how functionally important residues on this helix could participate in Cu(I)-coordination during transport. Aligned with and sealing both ends of the pore, extracellular and intracellular domains of hCTR1 appear to provide additional metal binding sites. Consistent with the existence of distinct metal binding sites, we demonstrate that hCTR1 stably binds 2 Cu(I)-ions through 3-coordinate Cu-S bonds, and that mutations in one of these putative binding sites results in a change of coordination chemistry.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 333 Cedar Street New Haven, CT 06510, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: De Feo
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Aller
authors.forename: Gnana S
authors.initials: GS
authors.lastname: Siluvai
authors.forename: Ninian J
authors.initials: NJ
authors.lastname: Blackburn
authors.forename: Vinzenz M
authors.initials: VM
authors.lastname: Unger
mesh_terms: D001665:Binding Sites / Q000235:genetics; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000235:genetics; D003300:Copper / Q000737:chemistry; D000079923:Copper Transporter 1; D020285:Cryoelectron Microscopy; D003460:Crystallization; D006801:Humans; D009154:Mutation; D011487:Protein Conformation
chemical_list: D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C490079:SLC31A1 protein, human; D003300:Copper