Disease relevance of CTR1

• The cytosolic C-terminal domain of the membrane copper transporter Ctr1 from the yeast Saccharomyces cerevisiae, Ctr1c, was expressed in E. coli as an oxygen-sensitive soluble protein with no significant secondary structure [1].

High impact information on CTR1

• We report the identification and characterization of CTR1, a gene in the yeast S. cerevisiae that encodes a multispanning plasma membrane protein specifically required for high affinity copper transport into the cell [2].
• CTR1 mutants and deletion strains have profound deficiency in ferrous iron uptake, thus revealing a requirement for copper in mediating ferrous transport into the cell [2].
• In such strains inactivation of both CTR1 and CTR3 is required to generate lethal copper-deficient phenotypes [3].
• In the budding yeast Saccharomyces cerevisiae, transcription of genes encoding for the high-affinity iron (FET3, FTR1) and copper (CTR1) transporters does not occur in the absence of heme [4].
• Human CTR1 is a high-affinity copper transporter that also mediates the uptake of the anticancer drug cisplatin by largely unknown transport mechanisms [5].

Biological context of CTR1

• Evidence for (Mac1p)2.DNA ternary complex formation in Mac1p-dependent transactivation at the CTR1 promoter [6].
• In contrast, a screen of high-copy number plasmid libraries for clones able to increase tolerance to alkaline pH revealed only two genes: FET4 (encoding a low affinity transporter for copper, iron, and zinc) and CTR1 (encoding a high affinity copper transporter) [7].
• This BSD2 control of ion transport occurs independently of the CTR1 and FET4 metal transport systems [8].
• A copper-dependent reporter gene construct, CUP1-lacZ, is not expressed in CTR1 mutants to the same level as in wild-type strains, and Cu,Zn superoxide dismutase activity is deficient in these mutants [9].
• We conclude from these experiments that Mac1(t) binds in a modular fashion to DNA, with its RGRP AT-hook motif interacting with the TTT sequence at the 5' end of the CTR1 CuRE site, and with another DNA-binding module(s) binding in the adjacent major groove in the GCTCA sequence [10].

Anatomical context of CTR1

• Accessory genes required for the functioning of this transport system include a plasma-membrane copper transporter (CTR1), an intracellular copper transporter (CCC2), and a putative transcription factor (AFT1) [11].
• Mutations in CTR1 result in altered cellular responses to extracellular copper, demonstrating a physiologic role for CTR1 in the delivery of copper to the cytosol [9].
• Analysis of two of these genes that have been cloned reveals that ethylene signalling involves a combination of a protein (ETR1) with similarity to bacterial histidine kinases and a protein (CTR1) with similarity to Raf-1, a protein kinase involved in multiple signalling cascades in eukaryotic cells [12].
• Whereas Ctr2 exhibits structural similarity to the Ctr1 plasma membrane copper importer, microscopic and biochemical fractionation studies localize Ctr2 to the vacuole membrane [13].
• Localization of the Raf-like kinase CTR1 to the endoplasmic reticulum of Arabidopsis through participation in ethylene receptor signaling complexes [14].

Associations of CTR1 with chemical compounds

• High affinity copper uptake mediated by the copper transport protein encoded by CTR1 is required to provide the FET3 protein with copper, and thus copper uptake is indirectly required for ferrous iron uptake [15].
• We have used hydroxyl radical footprinting, missing nucleoside, and methylation interference experiments to investigate the structure of the complex of the DNA binding domain of Mac1 (called here Mac1(t)) with the two CuRE sites found in the yeast CTR1 promoter [10].
• The copper transporter CTR1 regulates cisplatin uptake in Saccharomyces cerevisiae [16].
• CTR1-deficient cells also demonstrated impaired accumulation of the DDP analogs carboplatin, oxaliplatin, and ZD0473 [cis-amminedichloro(2-methylpyridine) platinum (II)] [16].
• The pathway also contains a negative regulator of ethylene responses, CTR1, which closely resembles members of the Raf protein kinase family [17].

Physical interactions of CTR1

• MAC1 then binds directly and specifically to the CTR1 and FRE1 promoter elements, inducing transcription of those target genes [18].

Other interactions of CTR1

• Whereas the CTR1 and CTR3 genes are similarly regulated at the transcriptional level in response to copper, post-transcriptional regulation of these proteins is distinct [19].
• In contrast, deletion of CTR1 or of FET4 did not suppress the copper sensitivity in the fet3delta strain; these genes encode the two major copper transporters in laboratory yeast strains [20].
• The beneficial effect of overexpression of CTR1 requires a functional high affinity iron transport system, as it was abolished by deletion of FET3, a component of the high affinity transport system, or CCC2, which is required for assembly of the transport system [7].
• Cells harboring the MAC1(up1) allele fail to attenuate FRE1 and CTR1 expression in a Cu-dependent manner [21].
• A C-terminal domain of the membrane copper pump Ctr1 exchanges copper(I) with the copper chaperone Atx1 [22].

Analytical, diagnostic and therapeutic context of CTR1

• Here we report the 6-A projection structure obtained for human CTR1 by using electron crystallography of 2D protein crystals in a native phospholipid bilayer [5].

References