CTR3/YLR411W Summary Help

Standard Name CTR3 1
Systematic Name YLR411W
Feature Type ORF, Verified
Description High-affinity copper transporter of the plasma membrane; acts as a trimer; gene is disrupted by a Ty2 transposon insertion in many laboratory strains of S. cerevisiae (1, 2 and see Summary Paragraph)
Name Description Copper TRansport 1
Chromosomal Location
ChrXII:947253 to 947978 | ORF Map | GBrowse
Gbrowse
Gene Ontology Annotations All CTR3 GO evidence and references
  View Computational GO annotations for CTR3
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Regulators 50 genes
Resources
Classical genetics
null
Large-scale survey
overexpression
Resources
8 total interaction(s) for 7 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 1
  • Affinity Capture-RNA: 3
  • PCA: 2

Genetic Interactions
  • Synthetic Growth Defect: 2

Resources
Expression Summary
histogram
Resources
Length (a.a.) 241
Molecular Weight (Da) 27,534
Isoelectric Point (pI) 7.65
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrXII:947253 to 947978 | ORF Map | GBrowse
SGD ORF map
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..726 947253..947978 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000004403
SUMMARY PARAGRAPH for CTR3

Copper is a necessary cofactor for several enzymes in yeast, including the iron transporter component Fet3p, superoxide dismutase Sod1p, and the mitochondrial protein Cox17p; however, copper is toxic in high concentrations, so its import must be regulated. S. cerevisiae can acquire copper through the high affinity transporters Ctr1p and Ctr3p, the low-affinity transporter Fet4p, or by mobilizing vacuolar copper via Ctr2p (3, 4).

CTR1 encodes a high-affinity copper transporter responsible for copper uptake in low environmental copper (5, 6). Ctr1p is an O-glycosylated protein (6) that binds four copper(I) ions (7) and forms complexes with two or three copies at the plasma membrane (5, 6, 8).

The CTR3 open reading frame encodes a second high-affinity copper(I) transporter, but the promoter is interrupted by insertion of a Ty2 element in the widely used laboratory strain S288C. In strains where the Ty2 element is missing, such as several clinical isolates, CTR3 is functional and, when CTR1 is deleted, restores copper and iron uptake and respiration (1). Ctr3p forms a homotrimer on the plasma membrane (2).

A third copper transporter, Ctr2p, assembles as a homomultimer on the vacuolar membrane and can export stored copper to the cytoplasm (3, 9). CTR2 is not essential, not even in a ctr1 ctr3 background, and ctr2 mutants accumulate excess copper in the vacuole and are resistant to toxic high levels of copper (9, 10). A randomly-generated mutant Ctr2p that localizes to the plasma membrane is capable of restoring copper import into a ctr1 ctr3 mutant (9). CTR2 and CTR3 are homologous to each other but not to CTR1 (1).

CTR1 and CTR3 transcription is activated in response to low copper levels and suppressed in response to high copper levels by the transcription factor Mac1p (6, 1, 11, 12, 13, 14, 15). Mac1p binds a copper-responsive element (CuRE) in the CTR1 and CTR3 promoters (11, 12, 16, 17). Mac1p requires copper to bind CuRE, but exogenously-added copper disrupts binding (18). Ctr2 is not copper-regulated and is not induced in ctr1 ctr3 mutants (3).

In high copper, ctr1p is degraded at the plasma membrane (19); Mac1p is required (20). Ctr3 does not undergo degradation, nor does it get internalized, in high copper (2). Like copper, cisplatin causes cell-surface degradation of Ctr1p, and loss of Ctr1p may be a mechanism of acquired resistance to cisplatin in cancer patients (21).

A number of homologs of CTR genes, listed here, complement deletion of CTR1 and CTR3. Human hCTR1 (OMIM) and hCTR2 (OMIM) are both found on chromosome 9q31-32 (22, 23, 24, 25). The S. pombe copper transporter Ctr4 resembles a fusion of domains from both CTR1 and CTR3 (26); both S. pombe ctr4+ and ctr5+ are necessary to restore high-affinity copper transport (27). Podospora anserina PaCtr2 partially complements ctr1, while PaCtr1 and PaCtr3 fully complement ctr1 (28). Drosophila melanogaster has three CTR1 homologs that are expressed at different stages of development (25). Other complementing homologs are found in mouse (23), Candida albicans (29), Arabidopsis thaliana (10), and the Italian wall lizard Podarcis sicula (24).

Last updated: 2005-08-04 Contact SGD

References cited on this page View Complete Literature Guide for CTR3
1) Knight SA, et al.  (1996) A widespread transposable element masks expression of a yeast copper transport gene. Genes Dev 10(15):1917-29
2) Pena MM, et al.  (2000) Characterization of the Saccharomyces cerevisiae high affinity copper transporter Ctr3. J Biol Chem 275(43):33244-51
3) Portnoy ME, et al.  (2001) Metal transporters that contribute copper to metallochaperones in Saccharomyces cerevisiae. Mol Genet Genomics 265(5):873-82
4) Hassett R, et al.  (2000) The Fe(II) permease Fet4p functions as a low affinity copper transporter and supports normal copper trafficking in Saccharomyces cerevisiae. Biochem J 351 Pt 2():477-84
5) Dancis A, et al.  (1994) Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport. Cell 76(2):393-402
6) Dancis A, et al.  (1994) The Saccharomyces cerevisiae copper transport protein (Ctr1p). Biochemical characterization, regulation by copper, and physiologic role in copper uptake. J Biol Chem 269(41):25660-7
7) Xiao Z, et al.  (2004) C-terminal domain of the membrane copper transporter Ctr1 from Saccharomyces cerevisiae binds four Cu(I) ions as a cuprous-thiolate polynuclear cluster: sub-femtomolar Cu(I) affinity of three proteins involved in copper trafficking. J Am Chem Soc 126(10):3081-90
8) Puig S, et al.  (2002) Biochemical and genetic analyses of yeast and human high affinity copper transporters suggest a conserved mechanism for copper uptake. J Biol Chem 277(29):26021-30
9) Rees EM, et al.  (2004) Mobilization of intracellular copper stores by the ctr2 vacuolar copper transporter. J Biol Chem 279(52):54221-9
10) Kampfenkel K, et al.  (1995) Molecular characterization of a putative Arabidopsis thaliana copper transporter and its yeast homologue. J Biol Chem 270(47):28479-86
11) Labbe S, et al.  (1997) Copper-specific transcriptional repression of yeast genes encoding critical components in the copper transport pathway. J Biol Chem 272(25):15951-8
12) Yamaguchi-Iwai Y, et al.  (1997) Homeostatic regulation of copper uptake in yeast via direct binding of MAC1 protein to upstream regulatory sequences of FRE1 and CTR1. J Biol Chem 272(28):17711-8
13) Pena MM, et al.  (1998) Dynamic regulation of copper uptake and detoxification genes in Saccharomyces cerevisiae. Mol Cell Biol 18(5):2514-23
14) Jensen LT, et al.  (1998) Mapping of the DNA binding domain of the copper-responsive transcription factor Mac1 from Saccharomyces cerevisiae. J Biol Chem 273(37):23805-11
15) Gross C, et al.  (2000) Identification of the copper regulon in Saccharomyces cerevisiae by DNA microarrays. J Biol Chem 275(41):32310-6
16) Joshi A, et al.  (1999) Evidence for (Mac1p)2.DNA ternary complex formation in Mac1p-dependent transactivation at the CTR1 promoter. J Biol Chem 274(1):218-26
17) Jamison McDaniels CP, et al.  (1999) The yeast transcription factor Mac1 binds to DNA in a modular fashion. J Biol Chem 274(38):26962-7
18) Heredia J, et al.  (2001) Phosphorylation and Cu+ coordination-dependent DNA binding of the transcription factor Mac1p in the regulation of copper transport. J Biol Chem 276(12):8793-7
19) Ooi CE, et al.  (1996) Copper-dependent degradation of the Saccharomyces cerevisiae plasma membrane copper transporter Ctr1p in the apparent absence of endocytosis. EMBO J 15(14):3515-23
20) Yonkovich J, et al.  (2002) Copper ion-sensing transcription factor Mac1p post-translationally controls the degradation of its target gene product Ctr1p. J Biol Chem 277(27):23981-4
21) Ishida S, et al.  (2002) Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci U S A 99(22):14298-302
22) Zhou B and Gitschier J  (1997) hCTR1: a human gene for copper uptake identified by complementation in yeast. Proc Natl Acad Sci U S A 94(14):7481-6
23) Lee J, et al.  (2000) Isolation of a murine copper transporter gene, tissue specific expression and functional complementation of a yeast copper transport mutant. Gene 254(1-2):87-96
24) Riggio M, et al.  (2002) High affinity copper transport protein in the lizard Podarcis sicula: molecular cloning, functional characterization and expression in somatic tissues, follicular oocytes and eggs. Biochim Biophys Acta 1576(1-2):127-35
25) Zhou H, et al.  (2003) A copper-regulated transporter required for copper acquisition, pigmentation, and specific stages of development in Drosophila melanogaster. J Biol Chem 278(48):48210-8
26) Labbe S, et al.  (1999) A copper-sensing transcription factor regulates iron uptake genes in Schizosaccharomyces pombe. J Biol Chem 274(51):36252-60
27) Zhou H and Thiele DJ  (2001) Identification of a novel high affinity copper transport complex in the fission yeast Schizosaccharomyces pombe. J Biol Chem 276(23):20529-35
28) Borghouts C, et al.  (2002) Copper homeostasis and aging in the fungal model system Podospora anserina: differential expression of PaCtr3 encoding a copper transporter. Int J Biochem Cell Biol 34(11):1355-71
29) Marvin ME, et al.  (2003) The Candida albicans CTR1 gene encodes a functional copper transporter. Microbiology 149(Pt 6):1461-74