title: Ctr1 Intracellular Loop Is Involved in the Copper Transfer Mechanism to the Atox1 Metallochaperone.
abstract: Understanding the human copper cycle is essential to understand the role of metals in promoting neurological diseases and disorders. One of the cycles controlling the cellular concentration and distribution of copper involves the copper transporter, Ctr1; the metallochaperone, Atox1; and the ATP7B transporter. It has been shown that the C-terminus of Ctr1, specifically the last three amino acids, HCH, is involved in both copper coordination and the transfer mechanism to Atox1. In contrast, the role of the intracellular loop of Ctr1, which is an additional intracellular segment of Ctr1, in facilitating the copper transfer mechanism has not been investigated yet. Here, we combine various biophysical methods to explore the interaction between this Ctr1 segment and metallochaperone Atox1 and clearly demonstrate that the Ctr1 intracellular loop (1) can coordinate Cu(I) via interactions with the side chains of one histidine and two methionine residues and (2) closely interacts with the Atox1 metallochaperone. Our findings are another important step in elucidating the mechanistic details of the eukaryotic copper cycle.
authors.affiliation: The Department of Chemistry, Faculty of Exact Science, Bar Ilan University , Ramat-Gan 5290002, Israel.
authors.forename: Ariel R
authors.initials: AR
authors.lastname: Levy
authors.affiliation: The Department of Chemistry, Faculty of Exact Science, Bar Ilan University , Ramat-Gan 5290002, Israel.
authors.forename: Matan
authors.initials: M
authors.lastname: Nissim
authors.affiliation: The Department of Chemistry, Faculty of Exact Science, Bar Ilan University , Ramat-Gan 5290002, Israel.
authors.forename: Netanel
authors.initials: N
authors.lastname: Mendelman
authors.affiliation: The Department of Chemistry, Faculty of Exact Science, Bar Ilan University , Ramat-Gan 5290002, Israel.
authors.forename: Jordan
authors.initials: J
authors.lastname: Chill
authors.affiliation: The Department of Chemistry, Faculty of Exact Science, Bar Ilan University , Ramat-Gan 5290002, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Ruthstein
mesh_terms: D027682:Cation Transport Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D000079922:Copper Transport Proteins; D000079923:Copper Transporter 1; D006801:Humans; D056511:Metallochaperones / Q000737:chemistry / Q000378:metabolism*; D018832:Molecular Chaperones
chemical_list: C474500:ATOX1 protein, human; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D000079923:Copper Transporter 1; D056511:Metallochaperones; D018832:Molecular Chaperones; C490079:SLC31A1 protein, human; D003300:Copper