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Tbio High affinity copper uptake protein 1

High-affinity, saturable copper transporter involved in dietary copper uptake.

The protein encoded by this gene is a high-affinity copper transporter found in the cell membrane. The encoded protein functions as a homotrimer to effect the uptake of dietary copper. [provided by RefSeq, Aug 2011]

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Property Summary

NCBI Gene PubMed Count 62
PubMed Score 84.19
PubTator Score 185.65

Knowledge Summary

Patent

No data available

TINX Plot

  Disease (3)

Disease Target Count Z-score Confidence
Cancer 2346 3.081 1.5

Expression

  Differential Expression (6)

Disease log2 FC p
pancreatic cancer 1.100 3.8e-03
glioblastoma 1.200 4.6e-03
pancreatic ductal adenocarcinoma liver m... -1.752 7.1e-04
pancreatic carcinoma 1.100 3.8e-03
subependymal giant cell astrocytoma 1.111 3.4e-02
ovarian cancer 2.400 5.4e-06

Synonym

Accession O15431 A8K8Z6 Q53GR5 Q5T1M4
Symbols CTR1
COPT1

Gene

SLC31A1

PANTHER Protein Class (2)

PDB

2LS2   2LS3   2LS4  

  Ortholog (1)

Species Source Disease
Chimp OMA EggNOG

 UniProt Keyword (14)

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 GO Function (2)

 GO Component (5)

 GO Process (5)

 Compartment GO Term (15)

 MGI Phenotype (13)

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 GWAS Trait (1)

 HCA RNA Cell Line (56)

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Pathway (21)

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Gene RIF (54)

PMID Text
26851002 High CTR1 Expression is associated with poor response to chemotherapy in Muscle-invasive Bladder Cancer.
26745413 C-Terminus of Human Copper Importer Ctr1 Acts as a Binding Site and Transfers Copper to Atox1
26205368 Studied the interaction of CTR1 and CTR2 in fully malignant HEK293T and OVCAR8 human ovarian cancer cells using a CRISPR-Cas9 knock out system.
26067577 Gene silencing of either CTR1 or DMT1 did not affect copper accumulation in cells, but deficiency in both CTR1 and DMT1 resulted in a complete inhibition of copper uptake.
26061257 Two methionine residues in the MXXXM motif of of the CTR1 second transmembrane domain are important for binding to silver.
25823781 allele distribution of the SLC31A1 was not different between group N and O, and out of the 11 SNPs of the SLC22A2 gene only the allele distribution of the nonsynonymous SNP was significantly different between patients who experienced ototoxicity
24837030 The data collected here shows that the Atox1 keeps its dimer nature also in the presence of the CTR1 c-terminal domain; however, two geometrical states are assumed by the Atox1.
24800945 NSC73306 is a transport substrate of CTR1
24792335 CTR1 expression may be necessary for therapeutic efficacy of platinum based drugs in non-small cell lung cancer treatment.
24703712 Data suggest that SLC31A1 and SLC31A2, despite being structurally closely related and sharing important amino acid motifs, play different roles in copper homeostasis and in platinum-based chemotherapy of neoplasms. [REVIEW]
24614111 CTR1, ATP7A, and lysyl oxidase were upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension and pulmonary arterial smooth muscle cells.
24485600 Extracellular copper concentrations regulate the levels of CTR1 through internalisation and degradation, the addition of prolactin, inhibits the degradation of CTR1, thus promoting copper uptake by mammary epithelial cells.
24132751 Cisplatin transcriptionally induces the expression of human Ctr1 in time- and concentration-dependent manners.
24039729 Knockdown of CTR1 expression in human umbilical cord endothelial cells increases cell proliferation and migration.
23963605 Duodenal CTR1 mRNA and protein expression was decreased in Wilson's disease patients, while ATP7A mRNA and protein production was increased. This can be a defense mechanism against systemic copper overload resulting from functional impairment of ATP7B.
23827522 This study demonistrated that Inhibition of human high-affinity copper importer Ctr1 orthologous in the nervous system of Drosophila ameliorates Abeta42-induced Alzheimer's disease-like symptoms.
23782748 The patients with tumors showing high expression levels of at least one of OATP1B3 and CTR1 had potentially longer disease-free survival.
23658018 Results show that hCTR1 elements on the intracellular side of the hCTR1 pore, including the carboxyl tail, are not essential for permeation, but serve to regulate the rate of copper entry.
23426973 Depletion of glutathione decreases cellular copper uptake mediated by human copper transporter 1.
23010323 Our findings imply that reduced CTR1 expression accounts for decreased cisplatin accumulation and represents one of the determinants of cisplatin resistance in A2780cis cell line
22962276 This review explains how modulating cellular copper availability could influence treatment efficacy in platinum-based cancer chemotherapy through hCtr1 regulation[review]
22725681 genetic association study in Han population in China: Data suggest that SNPs in SLC31A1 (rs7851395; rs12686377) are associated with resistance to platinum compounds as antineoplastics and survival outcomes in non-small cell lung carcinoma patients.
22684009 basal expression of Ctr1 is regulated by HIF2alpha; however, the induction by hypoxia is a HIF2alpha-independent event
22569840 Structure of CTR1 confirms that two triads of methionine residues delineate the intramembranous region of the transporter, and further identifies two additional methionine triads that are located in the extracellular N-terminal part of the transporter.
22552365 The cells expressing the hCTR1 mutants of histidine-rich motifs in the N-terminus (H22-24A, NHA) resulted in a higher basal copper level in the steady state compared to those expressing wild-type protein.
22516052 CTR1 plays an essential role in cisplatin toxicity and could be considered as a predictor for pretreatment evaluation in lung cancer patients.
22354499 There was little difference in rates/kinetics of uptake of copper in the Ctr1+/+ and -/- cells. Endocytosis was not involved.
22068728 Data show that both shRNA-DMT1 and shRNA-hCTR1 cells had lower apical Fe uptake, Cu uptake, and Zn content compared to control cells.
21602128 Cisplatin induces drug resistant phenotype by decreasing the protein level of CTR1 in human esophageal squamous carcinoma cell line EC109.
21072377 Compared the binding interactions between cisplatin, carboplatin and oxaliplatin with synthetic peptides corresponding to hCtr1 Mets motifs.
20699218 Data show apical localization of Ctr1 in intestinal epithelia and suggest that increased Ctr1 apical localization in response to dietary copper limitation may represent an adaptive response to modulate Ctr1 availability at the site of copper absorption.
20569931 Ctr1 is an important transport protein in the accumulation of silver in mammalian cells.
20534491 Identified as dominant hinge regions, CTR1's MxxxM and GxxxG motifs were shown to have significant roles in functional movements characterized by the two slowest modes of motion.
19929093 Sequence analysis demonstrated SLC31A1 on chromosome 9 was rearranged with breaks occurring within its intron. SLC31A1 lies close to BSPRY which is a candidate for cleft lip/palate involvement.
19856191 findings reveal a high level of conservation between the mammalian and insect Ctr1-type copper importers
19740744 Copper-dependent internalization and recycling of hCTR1 provides an acute and reversible mechanism for the regulation of cellular copper entry.
19684018 Data indicate that human copper transporter 1 cleavage occurs in a late endosomal, Rab9-positive compartment prior to delivery of the transporter to the plasma membrane.
19669174 Results describe the interactions of a peptide corresponding to the N-terminal domain of the human copper transporter 1 with cisplatin and its analogues, at the molecular level.
19529937 Results demonstrate that co-exposure of tumor cells to emodin or DRB with cisplatin inhibits platinum drug uptake by impacting the hCtr1 transporter.
19240214 structure of the human CTR1 protein solved by electron crystallography to an in plane resolution of 7 A
19147760 Proteasomal inhibition prevents cisplatin-induced down-regulation of hCTR1 in ovarian cancer cells and enhanced drug uptake and cell killing in a synergistic manner
19144690 Downregulation of Ctr1 suppresses cisplatin nephrotoxicity, including cell death by both apoptosis and necrosis.
17959139 The results of NMR methods and site-directed mutagenesis of the two cysteine residues demonstrate that Cys-189 but not Cys-161 is essential for both dimer formation and proper folding of the protein.
17627945 hCTR1 plays a key role in the physiologically important delivery of copper from blood to intracellular proteins, whereas its role in the initial apical uptake of dietary copper is indirect.
16501047 formation of a putative pore for metal ions at the interface of three identical subunits deviates from the structural design of typical primary and secondary active transporters
16356544 Hormones have a role in the formation of the active hCTR1 protein in human placental cells.
15634665 Internalization of endogenous human Ctr1 in response to elevated extracellular copper levels does not play a significant regulatory role in copper homeostasis.
15326162 there is a direct interaction between cisplatin and the hCtr1 protein; cisplatin and copper have distinct biochemical consequences on this transporter
14976198 there are common biochemical mechanisms regulate both transport and trafficking functions of hCtr1
12501239 hCtr1-mediated copper uptake into mammalian cells is regulated by a post-translational mechanism involving copper-stimulated endocytosis and degradation of the transporter
12466020 Results suggest that human copper transporter 1 (CTR1) spans the membrane at least six times, permitting formation of a channel, which is consistent with its proposed role as a copper transporter.
12177073 observations demonstrate that, although Ctr1 is critical for both cellular copper uptake and embryonic development, mammals possess additional biochemically distinct functional copper transport activities
12023893 biochemical characterization and subcellular localization
11983704 fundamentally conserved mechanism for high affinity copper uptake through the Ctr proteins in yeast and humans

AA Sequence 

MDHSHHMGMSYMDSNSTMQPSHHHPTTSASHSHGGGDSSMMMMPMTFYFGFKNVELLFSGLVINTAGEMA      1 - 70
GAFVAVFLLAMFYEGLKIARESLLRKSQVSIRYNSMPVPGPNGTILMETHKTVGQQMLSFPHLLQTVLHI     71 - 140
IQVVISYFLMLIFMTYNGYLCIAVAAGAGTGYFLFSWKKAVVVDITEHCH                        141 - 190
//

Text Mined References (66)

PMID Year Title
26851002 2016 Copper Transporter-CTR1 Expression and Pathological Outcomes in Platinum-treated Muscle-invasive Bladder Cancer Patients.
26745413 2016 The C-Terminus of Human Copper Importer Ctr1 Acts as a Binding Site and Transfers Copper to Atox1.
26205368 2015 The copper transporter 1 (CTR1) is required to maintain the stability of copper transporter 2 (CTR2).
26067577 2015 Copper uptake by DMT1: a compensatory mechanism for CTR1 deficiency in human umbilical vein endothelial cells.
26061257 2015 Self-Assembly of the Second Transmembrane Domain of hCtr1 in Micelles and Interaction with Silver Ion.
25823781 2015 Human OCT2 variant c.808G>T confers protection effect against cisplatin-induced ototoxicity.
24837030 2014 Probing the structural flexibility of the human copper metallochaperone Atox1 dimer and its interaction with the CTR1 c-terminal domain.
24800945 2014 Uptake of compounds that selectively kill multidrug-resistant cells: the copper transporter SLC31A1 (CTR1) increases cellular accumulation of the thiosemicarbazone NSC73306.
24792335 2014 Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer.
24703712 2015 The role of Ctr1 and Ctr2 in mammalian copper homeostasis and platinum-based chemotherapy.
24614111 2014 Upregulated copper transporters in hypoxia-induced pulmonary hypertension.
24485600 2014 Copper and lactational hormones influence the CTR1 copper transporter in PMC42-LA mammary epithelial cell culture models.
24132751 2014 Regulation of the high-affinity copper transporter (hCtr1) expression by cisplatin and heavy metals.
24039729 2013 CTR1 silencing inhibits angiogenesis by limiting copper entry into endothelial cells.
23963605 2013 Intestinal expression of metal transporters in Wilson's disease.
23827522 2013 Inhibition of human high-affinity copper importer Ctr1 orthologous in the nervous system of Drosophila ameliorates A?42-induced Alzheimer's disease-like symptoms.
23782748 2013 Prognostic value of organic anion transporting polypeptide 1B3 and copper transporter 1 expression in endometrial cancer patients treated with paclitaxel and carboplatin.
23658018 2013 Rate and regulation of copper transport by human copper transporter 1 (hCTR1).
23426973 2013 Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1.
23303382 2013 Genome-wide association study of serum albumin:globulin ratio in Korean populations.
23186163 2013 Toward a comprehensive characterization of a human cancer cell phosphoproteome.
23010323 2012 Relevance of copper transporter 1 for cisplatin resistance in human ovarian carcinoma cells.
22962276 2012 Role of the human high-affinity copper transporter in copper homeostasis regulation and cisplatin sensitivity in cancer chemotherapy.
22725681 2012 Genetic polymorphism of copper transporter protein 1 is related to platinum resistance in Chinese non-small cell lung carcinoma patients.
22684009 2012 Basal expression of copper transporter 1 in intestinal epithelial cells is regulated by hypoxia-inducible factor 2?.
22569840 2012 An all-atom model of the structure of human copper transporter 1.
22552365 2012 Comparison between copper and cisplatin transport mediated by human copper transporter 1 (hCTR1).
22516052 2012 Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients.
22354499 2012 Uptake of copper from plasma proteins in cells where expression of CTR1 has been modulated.
22068728 2012 Iron, copper, and zinc transport: inhibition of divalent metal transporter 1 (DMT1) and human copper transporter 1 (hCTR1) by shRNA.
21602128 2011 [Cisplatin induces drug resistance in human esophageal squamous carcinoma cell line EC109 by decreasing CTR1 protein expression].
21072377 2010 Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1.
20699218 2010 Ctr1 is an apical copper transporter in mammalian intestinal epithelial cells in vivo that is controlled at the level of protein stability.
20569931 2010 Ctr1 transports silver into mammalian cells.
20534491 2010 C(alpha)-trace model of the transmembrane domain of human copper transporter 1, motion and functional implications.
19929093 2009 Searching for genes for cleft lip and/or palate based on breakpoint analysis of a balanced translocation t(9;17)(q32;q12).
19856191 2010 Human copper transporter Ctr1 is functional in Drosophila, revealing a high degree of conservation between mammals and insects.
19740744 2009 Copper-dependent recycling of hCTR1, the human high affinity copper transporter.
19684018 2009 Human copper transporter 1 lacking O-linked glycosylation is proteolytically cleaved in a Rab9-positive endosomal compartment.
19669174 2009 Reactivity of platinum-based antitumor drugs towards a Met- and His-rich 20mer peptide corresponding to the N-terminal domain of human copper transporter 1.
19529937 2010 Protein kinase inhibitors emodin and dichloro-ribofuranosylbenzimidazole modulate the cellular accumulation and cytotoxicity of cisplatin in a schedule-dependent manner.
19240214 2009 Three-dimensional structure of the human copper transporter hCTR1.
19147760 2009 Enhanced delivery of cisplatin to intraperitoneal ovarian carcinomas mediated by the effects of bortezomib on the human copper transporter 1.
19144690 2009 The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity.
17974005 2007 The full-ORF clone resource of the German cDNA Consortium.
17959139 2007 NMR and mutagenesis of human copper transporter 1 (hCtr1) show that Cys-189 is required for correct folding and dimerization.
17627945 2007 Human copper transporter hCTR1 mediates basolateral uptake of copper into enterocytes: implications for copper homeostasis.
17525160 2007 O-linked glycosylation at threonine 27 protects the copper transporter hCTR1 from proteolytic cleavage in mammalian cells.
16501047 2006 Projection structure of the human copper transporter CTR1 at 6-A resolution reveals a compact trimer with a novel channel-like architecture.
16356544 Expression, localisation and hormone regulation of the human copper transporter hCTR1 in placenta and choriocarcinoma Jeg-3 cells.
15634665 2005 Stable plasma membrane levels of hCTR1 mediate cellular copper uptake.
15489334 2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
15326162 2004 Cisplatin stabilizes a multimeric complex of the human Ctr1 copper transporter: requirement for the extracellular methionine-rich clusters.
15164053 2004 DNA sequence and analysis of human chromosome 9.
14976198 2004 Identification of methionine-rich clusters that regulate copper-stimulated endocytosis of the human Ctr1 copper transporter.
14702039 2004 Complete sequencing and characterization of 21,243 full-length human cDNAs.
12501239 2003 Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1.
12477932 2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.
12466020 2003 The N-terminus of the human copper transporter 1 (hCTR1) is localized extracellularly, and interacts with itself.
12177073 2002 Characterization of mouse embryonic cells deficient in the ctr1 high affinity copper transporter. Identification of a Ctr1-independent copper transport system.
12034741 2002 Molecular characterization of hCTR1, the human copper uptake protein.
11983704 2002 Biochemical and genetic analyses of yeast and human high affinity copper transporters suggest a conserved mechanism for copper uptake.
11734551 2002 Biochemical characterization of the human copper transporter Ctr1.
11054564 2000 Characterization of the hCTR1 gene: genomic organization, functional expression, and identification of a highly homologous processed gene.
9207117 1997 hCTR1: a human gene for copper uptake identified by complementation in yeast.
8125298 1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.