Molecular characterization of a copper transport protein in S. cerevisiae: An unexpected role for copper in iron transport

Dancis, Andrew; Yuan, Daniel; Haile, David J.; Askwith, Candice C.; Eide, David J.; Moehle, Charles M.; Kaplan, Jerry; Klausner, Richard D.

doi:10.1016/0092-8674(94)90345-x

Cited by 664 publications

(667 citation statements)

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“…The inability to use a nonfermentable carbon source is just one aspect of ctr1 mutation. It has been shown that the ctr1 strain is less sensitive to the killing by high level of copper and that overexpression of CTR1 renders the transformed strain more sensitive (30). We find a similar situation for hCTR1: overexpression of hCTR1 in either CTR1 or ctr1 background makes them more vulnerable to copper overload compared with vector-alone-derived strains (Fig.…”

Section: Resultssupporting

confidence: 69%

“…The CCC2 protein is both functionally and structurally similar to the gene products defective in Menkes syndrome and Wilson disease described above. Although no mammalian copper uptake gene has been isolated, in yeast three copper uptake genes, CTR1, CTR2, and CTR3, have been identified (18)(19)(20). CTR1 and CTR3 are high-affinity copper transport proteins, and mutations in both CTR1 and CTR3 are required to eliminate high-affinity copper uptake in yeast.…”

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confidence: 99%

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hCTR1: A human gene for copper uptake identified by complementation in yeast

Zhou

Gitschier

1997

Proc. Natl. Acad. Sci. U.S.A.

509

336

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The molecular mechanisms responsible for the cellular uptake of copper in mammalian cells are unknown. We describe isolation of a human gene involved in this process by complementation of the yeast high-affinity copper uptake mutant, ctr1. Besides complementing ctr1 growth defect on nonfermentable media, the human gene also rescues iron transport and SOD1 defects in ctr1 yeast. Overexpression of the gene in yeast leads to vulnerability to the toxicity of copper overload. In addition, its expression in ctr1 yeast significantly increases the level of cellular copper, as demonstrated by atomic absorption. We propose this gene as a candidate for high-affinity copper uptake in humans and by analogy have named it hCTR1. The hCTR1 and yeast CTR1 predicted transmembrane proteins are 29% identical, but the human protein is substantially smaller in both the extracellular metal-binding and intracellular domains. An additional human gene similar to hCTR1, here named hCTR2, was identified in a database search. Both hCTR1 and hCTR2 are expressed in all human tissues examined, and both genes are located in 9q31͞32. These studies, together with the previously recognized functional and sequence similarity between the Menkes͞Wilson copper export proteins and CCC2 in yeast, demonstrate that similar copper homeostatic mechanisms are used in these evolutionarily divergent organisms.

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Section: Resultssupporting

confidence: 69%

mentioning

confidence: 99%

hCTR1: A human gene for copper uptake identified by complementation in yeast

Zhou

Gitschier

1997

Proc. Natl. Acad. Sci. U.S.A.

509

336

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“…Several lines of evidence point to Cu(I) as the active redox state for Ctr1, 21,26,[29][30][31] and we have previously shown that isolated Mets domains are capable of binding Cu(I) selectively over Cu(II). 32 Additionally, yCtr1 is unable to transport Zn(II) or other divalent metal ions but readily takes in Ag(I) as a surrogate for Cu(I).…”

Section: Introductionmentioning

confidence: 92%

“…[21][22][23][24] The protein likely exists as a homotrimer in its active form. 21,[25][26][27] The unique feature of the amino-terminal region of Ctr1, which is the first gate of entry for cellular copper, is the presence of methioninerich domains arranged as MXXM or MXM motifs containing 3-5 methionine residues per ''Mets'' motif. Yeast yCtr1 has 8 Mets motifs, with a total of 30 methionine residues in the B140-residue extracellular domain, whereas human hCtr1 has two Mets motifs in a 65-residue extracellular region.…”

Section: Introductionmentioning

confidence: 99%

Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1

2010

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“…The human genome encodes two CTRs (hCTR1, SLC31A1; and hCTR2, SLC31A2). hCTR1 was identified as a highaffinity CTR by functional complementation of a yeast strain deficient in high-affinity copper uptake [29][30][31][32]. The characterization of CTR1 as a high-affinity CTR marked the start of extensive studies on the structure, function, and cellular localization of the CTR protein family [2,6,7,[33][34][35][36][37][38][39][40][41][42].…”

Section: Introductionmentioning

confidence: 99%