Affinage

SLC31A1

High affinity copper uptake protein 1 · UniProt O15431

Length
190 aa
Mass
21.1 kDa
Annotated
2026-06-10
81 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC31A1 (hCTR1) is the principal high-affinity plasma membrane importer of copper, first defined by its ability to restore Cu-dependent growth, iron transport, and SOD1 function in copper-uptake-deficient yeast and to raise cellular copper levels (PMID:9207117). It is a homotrimeric, pore-forming transporter with three transmembrane domains, an extracellular N-terminus and a cytoplasmic C-terminus, mediating saturable Cu uptake (Km ~3.5 µM) (PMID:12034741, PMID:12466020, PMID:19240214). Copper transit is staged: the Met-rich extracellular N-terminal domain binds multiple Cu(I) ions and undergoes a Cu(I)-triggered conformational change that engages the membrane to initiate internalization of metal (PMID:23962988, PMID:31461100), TM2 lines the central translocation pore (PMID:19240214), and progressive Cu(I) loading drives rearrangement of the C-terminal region, which acts as a gate and shuttle delivering copper toward intracellular metallochaperones including transfer to Atox1 (PMID:35202609, PMID:39858521, PMID:22552365, PMID:28383086). The protein is post-translationally controlled by O-linked glycosylation at Thr-27, which protects the N-terminus from proteolytic cleavage that otherwise reduces transport activity, while N-linked glycosylation at Asn-15 is dispensable (PMID:17525160), and by copper-stimulated clathrin-dependent endocytosis with subsequent recycling that tunes surface transporter levels (PMID:12501239, PMID:19740744). In polarized epithelia hCTR1 localizes to the basolateral membrane, where it dominates copper influx (PMID:17627945). Functionally, hCTR1 supplies copper to cuproenzymes: its overexpression restores SOD1 and ceruloplasmin activity in the CNS (PMID:29906423), and its loss depletes mitochondrial copper and impairs respiration (PMID:40048660, PMID:41040850). SLC31A1 expression is heavily regulated at multiple levels — transcriptionally through Sp1, ATF3/SPI1, ELF3, SRF, Grhl2, and ZNF711/JHDM2A-mediated H3K9me2 demethylation (PMID:24132751, PMID:38462020, PMID:34521054, PMID:39287710), and post-transcriptionally through PTBP1-mediated mRNA destabilization and METTL3/YTHDF2 m6A-dependent decay (PMID:32207235, PMID:40088504). Bi-allelic loss-of-function variants in SLC31A1 cause early-onset epileptic encephalopathy with neurodevelopmental delay and impaired mitochondrial respiration in patient cells (PMID:41040850).

Mechanistic history

Synthesis pass · year-by-year structured walk · 33 steps
  1. 1997 High

    Established that the human gene encodes a functional high-affinity copper uptake transporter, defining its core physiological activity.

    Evidence Functional complementation of a yeast ctr1 mutant with rescue of growth, iron transport, SOD1, and elevated copper by atomic absorption spectroscopy

    PMID:9207117

    Open questions at the time
    • Did not resolve transporter topology or oligomeric architecture
    • No direct measurement of transport mechanism in human cells
  2. 2002 High

    Defined membrane topology and transport kinetics, showing an extracellular N-terminus, intracellular C-terminus, and saturable copper uptake.

    Evidence Baculovirus expression in Sf9 cells, FLAG epitope accessibility, copper uptake kinetics, tryptic mapping, and mutagenesis of Cys-161/Cys-189

    PMID:12034741

    Open questions at the time
    • Oligomeric state inferred but not structurally resolved
    • Role of cytoplasmic loop cleavage in vivo unclear
  3. 2002 Medium

    Characterized hCTR1 maturation by glycosylation and revealed cell-type-dependent localization between plasma membrane and intracellular compartments.

    Evidence Immunofluorescence, biosynthetic labeling, Western blot, and endocytosis inhibition in HeLa cells

    PMID:12023893

    Open questions at the time
    • Determinants of differential localization not identified
    • Functional consequence of the perinuclear pool not established
  4. 2002 High

    Showed copper itself triggers clathrin-dependent endocytosis and degradation of hCTR1, establishing a copper-responsive regulatory loop.

    Evidence Confocal microscopy, clathrin inhibitors, transferrin co-localization, and surface protein assays in HEK293 cells

    PMID:12501239

    Open questions at the time
    • Whether internalization is required for transport vs. regulatory only was unresolved
    • Conflicting with later endogenous-protein findings
  5. 2003 Medium

    Demonstrated CTR1 self-association through N-terminal domains, supporting a homotrimeric channel model.

    Evidence Yeast two-hybrid across human/mouse/rat/yeast CTR1, glycosylation-site mapping, and immunofluorescence

    PMID:12466020

    Open questions at the time
    • Self-interaction shown by single method (Y2H)
    • Trimeric stoichiometry inferred, not directly measured
  6. 2004 Medium

    Revealed that cisplatin rapidly down-regulates hCTR1 protein with functional loss of copper uptake, linking the transporter to platinum-drug pharmacology.

    Evidence Western blot, confocal microscopy, and 64Cu uptake in A2780 ovarian carcinoma cells

    PMID:15475465

    Open questions at the time
    • Mechanism of cisplatin-induced loss not defined
    • Whether hCTR1 directly transports cisplatin left open
  7. 2005 Medium

    Challenged the obligatory-internalization model by showing endogenous hCTR1 remains stably at the plasma membrane and mediates uptake without copper-induced internalization.

    Evidence Western blot, confocal microscopy, siRNA knockdown, and copper uptake with membrane fractionation in HEK293 cells

    PMID:15634665

    Open questions at the time
    • Conflicts with overexpression-based internalization data
    • Cell-type dependence of endocytic response unresolved
  8. 2007 High

    Identified O-glycosylation at Thr-27 as a protective modification preventing proteolytic cleavage that reduces transport activity, distinguishing it from dispensable N-glycosylation.

    Evidence Site-directed mutagenesis, glycosidase treatment, O-glycosylation-deficient CHO cells, and copper uptake assays

    PMID:17525160

    Open questions at the time
    • Identity of the responsible protease not determined
    • Regulatory cues controlling cleavage in vivo unknown
  9. 2007 High

    Established that hCTR1 is basolaterally targeted in polarized epithelia, defining the direction of physiological copper acquisition from blood.

    Evidence Cell surface biotinylation, confocal microscopy, copper influx measurement in Caco2/T84/MDCK cells and mouse intestine

    PMID:17627945

    Open questions at the time
    • Basolateral targeting signals not mapped
    • Apical copper entry route in intestine left to other transporters
  10. 2007 Medium

    Assigned a structural role to Cys-189 in folding and dimerization of the N-terminal region.

    Evidence Solution NMR and mutagenesis on a truncated residue 45–190 construct

    PMID:17959139

    Open questions at the time
    • Truncated construct in micelles, not full-length protein
    • Relevance to trimeric assembly of the intact transporter unclear
  11. 2009 High

    Provided the first 3D architecture, confirming a homotrimeric pore with TM2 lining the central channel and direct Cu(I) coordination.

    Evidence Electron crystallography at 7 Å, Cu(I) binding assays, and mutagenesis

    PMID:19240214

    Open questions at the time
    • Resolution insufficient for side-chain detail
    • Conformational states during transport not captured
  12. 2009 Medium

    Defined a reversible, acute regulatory cycle of copper-dependent internalization and recycling of overexpressed hCTR1.

    Evidence Surface biotinylation, reversible biotinylation, isotopic copper uptake, and cycloheximide chase in HEK293 cells

    PMID:19740744

    Open questions at the time
    • Shown for overexpressed not endogenous protein
    • Trafficking machinery mediating recycling not identified
  13. 2011 Medium

    Indicated hCTR1 contributes to iron and zinc uptake in addition to copper, broadening its metal-handling role.

    Evidence shRNA knockdown in Caco-2 cells with radioisotope/ICP metal uptake measurement

    PMID:22068728

    Open questions at the time
    • Direct vs. indirect effect on Fe/Zn not distinguished
    • No reconstitution of multi-metal transport
  14. 2012 Medium

    Mapped structure-function determinants of metal accumulation, establishing the C-terminal motif as essential and dissecting residues that differentially affect copper vs. cisplatin handling.

    Evidence Stable mutant cell lines (H139R, Y156A, C189S, ΔC), ICP-MS metal accumulation, and cytotoxicity assays

    PMID:22552365

    Open questions at the time
    • Mechanistic basis for differential Cu/cisplatin handling unresolved
    • Single-lab mutant panel
  15. 2013 Medium

    Quantified the metal-binding thermodynamics of the N-terminal domain, defining tight Cu(I) binding via Met-rich motifs and weaker Cu(II)/Ag(I) coordination.

    Evidence Metal binding thermodynamics and peptide biochemistry on the isolated N-terminal domain

    PMID:23962988

    Open questions at the time
    • Isolated peptide, not full-length transporter
    • Coupling of binding to transport not demonstrated
  16. 2013 Medium

    Refuted hCTR1 as the major platinum-drug entry route, redefining its relationship to cisplatin as regulatory rather than transport-mediating.

    Evidence Copper/platinum uptake assays in CTR1-knockout MEFs, overexpression mutants, and sensitive/resistant tumor cells

    PMID:23543413

    Open questions at the time
    • Contradicts earlier cisplatin-transport claims
    • Single-lab reassessment
  17. 2013 Medium

    Showed cisplatin induces hCTR1 transcription indirectly by competing for copper and elevating the Sp1 activator, linking metal status to transporter expression.

    Evidence Reporter assays, Western blot, and copper transport competition with multiple metals in cells

    PMID:24132751

    Open questions at the time
    • Direct Sp1 promoter occupancy not shown here
    • Generality across cell types untested
  18. 2017 Medium

    Demonstrated metal transfer from the hCTR1 C-terminal motif to the chaperone Atox1, connecting the transporter to downstream copper distribution.

    Evidence In vitro platinum transfer assay with the C8 peptide, mass spectrometry, and biophysical characterization

    PMID:28383086

    Open questions at the time
    • Peptide domain rather than full-length protein
    • Physiological copper (vs. platinum) handoff inferred
  19. 2018 Medium

    Established in vivo that hCTR1 delivers copper to CNS cuproenzymes by rescuing SOD1 and ceruloplasmin activity.

    Evidence hCTR1 overexpression in SOD1G37R ALS mice with enzymatic activity assays and Western blot

    PMID:29906423

    Open questions at the time
    • Disease-modifying significance beyond enzyme rescue unclear
    • Single model system
  20. 2019 Medium

    Identified the Cu(I)-induced conformational change of the N-terminal domain that engages the membrane as the initiating step of copper internalization.

    Evidence Biophysical assays, live cell imaging, and membrane interaction assays

    PMID:31461100

    Open questions at the time
    • Membrane interaction characterized for isolated domain
    • Coupling to pore-mediated translocation not resolved
  21. 2020 Medium

    Revealed post-transcriptional control by PTBP1, which destabilizes SLC31A1 mRNA and modulates cisplatin sensitivity.

    Evidence RNA immunoprecipitation, dual-luciferase, RNA stability assays, transcriptome sequencing, and xenografts

    PMID:32207235

    Open questions at the time
    • Binding site on mRNA not mapped
    • Single-lab dataset
  22. 2021 Medium

    Defined an epigenetic activation mechanism in which ZNF711 recruits JHDM2A to demethylate H3K9me2 at the SLC31A1 promoter, controlling cisplatin influx.

    Evidence ChIP, CAPTURE, Co-IP, luciferase reporter, and siRNA knockdown

    PMID:34521054

    Open questions at the time
    • Direct ZNF711 DNA contact vs. cofactor recruitment not fully separated
    • Single-lab mechanism
  23. 2022 Medium

    Showed each monomer can bind up to five Cu(I) ions with progressive loading driving C-terminal rearrangement, supporting a gate-and-shuttle model for copper delivery.

    Evidence EPR and UV-vis spectroscopy with all-atom molecular dynamics on full-length protein

    PMID:35202609

    Open questions at the time
    • Simulation-dependent interpretation
    • Direct structural snapshots of gating absent
  24. 2022 Medium

    Demonstrated physiological regulation of CTR1 localization in vivo, showing relocalization from apical membrane to cytoplasm protects against renal copper toxicity.

    Evidence RT-qPCR and immunohistochemistry in a Menkes disease mosaic mutant mouse model

    PMID:36232742

    Open questions at the time
    • Trafficking trigger for relocalization not defined
    • Mouse-model specific
  25. 2023 Low

    Proposed ATF3 and SPI1 as transcriptional activators driving SLC31A1-dependent copper accumulation and cuproptosis in cardiomyocytes.

    Evidence Transcription factor overexpression, Western blot, and bioinformatic prediction validated experimentally

    PMID:36675183

    Open questions at the time
    • No direct ChIP confirmation of promoter binding
    • Overexpression-only validation, single lab
  26. 2024 Medium

    Identified ELF3 as a direct transcriptional activator of SLC31A1 driving renal copper accumulation and mitochondrial injury in cisplatin-induced AKI.

    Evidence Luciferase reporter, ChIP, siRNA knockdown, and an in vivo mouse AKI model

    PMID:38462020

    Open questions at the time
    • Interplay with other SLC31A1 transcription factors unresolved
    • Single-lab mechanism
  27. 2024 Medium

    Showed Grhl2, induced via H3K18 lactylation, transcriptionally activates SLC31A1 to drive trophoblast cuproptosis in preeclampsia.

    Evidence Luciferase reporter, ChIP-PCR, lentivirus knockdown, H3K18la ChIP, and in vitro/in vivo models

    PMID:39287710

    Open questions at the time
    • Generalizability beyond trophoblast context untested
    • Single-lab study
  28. 2025 Medium

    Linked m6A modification by METTL3/YTHDF2 to destabilization of SLC31A1 mRNA, controlling trophoblast copper supply and migration.

    Evidence m6A and protein RNA immunoprecipitation, Western blot, functional cell assays, and an in vivo preeclampsia rat model

    PMID:40088504

    Open questions at the time
    • Specific m6A sites not mapped
    • Single-lab dataset
  29. 2025 Medium

    Connected YTHDF1/MeCP2-driven promoter methylation to SLC31A1 suppression, with loss depleting mitochondrial copper and promoting cardiac fibrosis.

    Evidence AAV9 shRNA in vivo, ChIP, Co-IP, respirometry, and ICP-MS with SLC31A1 reconstitution rescue

    PMID:40048660

    Open questions at the time
    • Hierarchy among the many SLC31A1 regulators unclear
    • Single-lab mechanism
  30. 2025 Low

    Proposed SRF as a transcription factor for SLC31A1 promoting copper accumulation and cuproptosis in NSCLC.

    Evidence Transcription factor overexpression and RNA sequencing with bioinformatic prediction

    PMID:39930648

    Open questions at the time
    • No direct ChIP of SRF on the SLC31A1 promoter
    • Overexpression-only evidence, single lab
  31. 2025 Medium

    Resolved dynamic gating, showing Cu(I)-dependent movement of extracellular and intracellular chains into the channel lumen consistent with a ball-and-chain mechanism modulated by lipids.

    Evidence Distance EPR in micelles and native cell membranes

    PMID:39858521

    Open questions at the time
    • Single biophysical method
    • Lipid dependence not mapped to defined species
  32. 2025 Medium

    Established SLC31A1 as a Mendelian disease gene, with bi-allelic loss-of-function causing epileptic encephalopathy and impaired mitochondrial respiration.

    Evidence Multi-family study with RNA sequencing, Western blot, and high-resolution respirometry in patient fibroblasts

    PMID:41040850

    Open questions at the time
    • Tissue-specific copper deficiency mechanism in brain not detailed
    • Genotype-phenotype range across variants incomplete
  33. 2026 Medium

    Demonstrated pharmacological inhibition of hCTR1, with rosmarinic acid binding the N-terminal domain to lower copper affinity and block uptake.

    Evidence Direct binding assay, cellular copper uptake assay, and ternary complex characterization

    PMID:41494012

    Open questions at the time
    • No structural resolution of the ternary complex
    • Selectivity and in vivo efficacy untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the gating, oligomeric channel architecture, and copper handoff to chaperones are integrated into a unified vectorial transport cycle in the intact human transporter remains incompletely defined.
  • No high-resolution structure of full-length transporter in distinct conformational states
  • Reconciliation of conflicting endogenous vs. overexpressed internalization data
  • Hierarchy and crosstalk among the many transcriptional and post-transcriptional regulators unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140104 molecular carrier activity 3
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-382551 Transport of small molecules 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ATOX1ELF3METTL3PTBP1SP1SRFYTHDF2ZNF711
Complex memberships
hCTR1 homotrimer

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 hCTR1 (SLC31A1) was identified as a human high-affinity copper uptake transporter by functional complementation of yeast ctr1 mutant; expression in ctr1 yeast restored growth on non-fermentable media, rescued iron transport and SOD1 defects, and increased cellular copper levels measured by atomic absorption spectroscopy. Yeast complementation, atomic absorption spectroscopy, functional rescue assay Proceedings of the National Academy of Sciences of the United States of America High 9207117
2002 hCTR1 is delivered to the plasma membrane in Sf9 insect cells where it mediates saturable copper uptake with a Km of ~3.5 µM. The N-terminus is extracellular and the C-terminus is intracellular, established by FLAG-epitope accessibility before and after permeabilization. Cys-161 and Cys-189 are not essential for copper transport but may stabilize oligomerization. Tryptic cleavage occurs in the cytoplasmic loop and is prevented by copper. Baculovirus expression, copper uptake assay, FLAG epitope accessibility, tryptic digestion, site-directed mutagenesis The Journal of biological chemistry High 12034741
2002 hCTR1 is synthesized as a 28 kDa N-glycosylated precursor and matures to ~35 kDa; subcellular localization differs between cell types (plasma membrane vs. intracellular vesicular perinuclear compartment). Inhibition of endocytosis by methyl-β-cyclodextrin partially redistributes hCTR1 to the cell surface of HeLa cells. Unlike copper-ATPases, hCTR1 localization is not influenced by copper concentration. Immunofluorescence, biosynthetic labeling, Western blot, endocytosis inhibition The Biochemical journal Medium 12023893
2002 Copper exposure at the plasma membrane of HEK293 cells stimulates clathrin-dependent endocytosis and subsequent degradation of hCTR1; low micromolar copper concentrations are sufficient; newly internalized hCTR1 co-localizes with transferrin, indicating use of the clathrin pathway. Western blot, confocal microscopy, clathrin inhibitors, transferrin co-localization, surface protein assay The Journal of biological chemistry High 12501239
2003 hCTR1 has three transmembrane domains with an extracellular N-terminus and cytoplasmic C-terminus; CTR1 proteins self-interact through N-terminal domains, as shown by yeast two-hybrid with human, mouse, rat, and yeast CTR1. Interaction is not copper-dependent. Multiple N-terminal regions are required for self-interaction, suggesting homotrimeric channel formation. Yeast two-hybrid, glycosylation-site insertion/deletion mapping, indirect immunofluorescence The Biochemical journal Medium 12466020
2005 Endogenous hCTR1 in HEK293 cells resides stably at the plasma membrane and copper treatment does not significantly alter initial copper uptake rates or cause detectable internalization; siRNA knockdown of hCTR1 reduced copper transport, confirming it mediates uptake. These data argue that internalization is not a required step in the copper transport mechanism for endogenous hCTR1. Western blot, confocal microscopy, siRNA knockdown, copper uptake assay, membrane fractionation The Journal of biological chemistry Medium 15634665
2007 O-linked glycosylation at Thr-27 of the extracellular N-terminus of hCTR1 protects the protein from proteolytic cleavage. T27A mutation or expression in O-glycosylation-deficient CHO cells causes cleavage producing a 17 kDa fragment missing ~30 N-terminal residues, reducing copper transport activity by ~50%. N-linked glycosylation at Asn-15 is dispensable for plasma membrane trafficking and transport. Site-directed mutagenesis, glycosidase treatment, CHO glycosylation-deficient cell expression, copper uptake assay, Western blot The Journal of biological chemistry High 17525160
2007 In polarized intestinal epithelial cells (Caco2, T84), hCTR1 is localized predominantly to the basolateral membrane, not the apical membrane, and basolateral copper uptake greatly exceeds apical uptake. hCTR1-mediated high-affinity transport is saturable only at the basolateral surface; similar basolateral localization is found in renal MDCK and opossum kidney cells. Cell surface biotinylation, confocal microscopy, copper influx measurement, immunohistochemistry, hCTR1 overexpression The Journal of biological chemistry High 17627945
2009 Three-dimensional structure of hCTR1 solved by electron crystallography at 7 Å in-plane resolution reveals a homotrimeric pore-forming architecture. TM2 lines the central pore. hCTR1 stably binds 2 Cu(I) ions via 3-coordinate Cu-S bonds; mutation of one putative binding site alters coordination chemistry. Electron crystallography, Cu(I) binding assay, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 19240214
2009 Overexpressed hCTR1 in HEK293 cells undergoes copper-dependent internalization (~40% reduction in surface levels within 10 min at ≥2.5 µM copper) without detectable degradation within 2 h; upon copper removal, internalized hCTR1 is recycled back to the plasma membrane within 30 min. This provides a reversible, acute regulatory mechanism for copper uptake. Cell surface biotinylation, reversible biotinylation assay, isotopic copper uptake, cycloheximide chase The Journal of biological chemistry Medium 19740744
2004 Cisplatin (DDP) rapidly down-regulates hCTR1 protein levels in human ovarian carcinoma A2780 cells in a concentration- and time-dependent manner (within 1 min at 2 µM), reducing 64Cu uptake by 50%, demonstrating functional relevance of the protein loss. Western blot, confocal microscopy, 64Cu uptake assay Clinical cancer research Medium 15475465
2007 NMR and mutagenesis showed that Cys-189 (but not Cys-161) in hCTR1 is required for correct folding and dimer formation of the truncated construct spanning residues 45-190. Solution NMR, site-directed mutagenesis Biochimica et biophysica acta Medium 17959139
2011 shRNA knockdown of hCTR1 in Caco-2 cells reduces not only copper uptake (by 38.5%) but also iron uptake (by 41%) and zinc content (by 22.7%), indicating hCTR1 can transport Fe and Zn in addition to Cu. shRNA knockdown, radioisotope/ICP-based metal uptake measurement Biological trace element research Medium 22068728
2013 The N-terminal extracellular domain of hCTR1 binds three Cu(I) ions tightly (log K = 14.92) via Met-rich motifs and two Cu(II) ions through ATCUN and His-rich motifs with lower affinity; Ag(I) binds with same stoichiometry but lower affinity than Cu(I). Metal binding thermodynamics (ITC/spectroscopy), peptide biochemistry Chemical communications Medium 23962988
2013 hCTR1 is not the major entry route for cisplatin or related platinum drugs; copper causes regulatory endocytosis of hCTR1 but cisplatin does not trigger the same internalization; platinum drug uptake is not saturable at relevant concentrations and is not protein-mediated, as shown in MEFs with and without CTR1, overexpressing/mutant hCTR1 HEK293 cells, and cisplatin-sensitive vs. resistant ovarian tumor cells. Copper/platinum uptake assays, CTR1 knockout MEFs, overexpression mutants, endocytosis assays Molecular pharmacology Medium 23543413
2013 Cisplatin transcriptionally induces hCTR1 expression by competing with copper for hCTR1-mediated transport, reducing cellular copper and leading to upregulation of Sp1, a positive transcriptional regulator of hCTR1. Ag(I) and Zn(II) similarly induce hCTR1/Sp1 expression, while Cd(II) suppresses hCTR1 by inhibiting Sp1. Reporter assay, Western blot, copper transport competition assay Journal of biological inorganic chemistry Medium 24132751
2012 hCTR1 mutants H139R and Y156A show reduced copper but not cisplatin accumulation; C189S retains partial ability to accumulate both copper and cisplatin; C-terminal truncation (hCTR1ΔC) abolishes accumulation of both copper and cisplatin, establishing the C-terminal motif as crucial for transporter function. Stable mutant cell lines, ICP-MS metal accumulation, cytotoxicity assays Metallomics Medium 22552365
2015 The second transmembrane domain (TMD2) of hCTR1 self-assembles into a trimer in SDS micelles; the trimer binds Ag(I) at 3:2 (peptide:Ag) stoichiometry. The MXXXM motif in TMD2 is required for trimeric assembly and high-affinity Ag(I) binding; methionine-to-leucine substitution reduces binding affinity by one order of magnitude. NMR, circular dichroism, isothermal titration calorimetry, electrophoresis The journal of physical chemistry B Medium 26061257
2017 The platinated C-terminal metal-binding motif of hCTR1 (C8 peptide adduct) transfers platinum to the copper chaperone Atox1; cisplatin and transplatin adducts are reactive with Atox1 while the oxaliplatin adduct is much less reactive, causing protein unfolding of Atox1 and consistent with differential cellular uptake of platinum drugs via hCTR1. In vitro platinum transfer assay, mass spectrometry, biophysical characterization Metallomics Medium 28383086
2019 Cu(I) binding to the N-terminal metal binding domain (MBD) of hCTR1 induces a conformational change that promotes interaction of the MBD with cell membranes; this membrane interaction was confirmed in living cells and proposed as the first step to initiate cellular copper internalization. Biophysical assays, live cell imaging, membrane interaction assay Chemical communications Medium 31461100
2021 ZNF711 recruits the histone demethylase JHDM2A to the SLC31A1 promoter, reducing H3K9me2 levels and activating SLC31A1 transcription, thereby enhancing cisplatin uptake. ZNF711 down-regulation suppresses SLC31A1 expression and reduces cisplatin influx, promoting resistance; co-treatment with BIX-01294 (histone methylation inhibitor) restored cisplatin sensitivity. ChIP assay, CAPTURE approach, Co-IP, luciferase reporter assay, siRNA knockdown EBioMedicine Medium 34521054
2020 RNA-binding protein PTBP1 binds SLC31A1 mRNA and reduces its stability, decreasing SLC31A1 expression. PTBP1 knockdown upregulates SLC31A1 (confirmed by RNA immunoprecipitation, luciferase reporter assay, RNA stability assay), restoring cisplatin uptake and sensitivity; SLC31A1 silencing abrogates the chemosensitizing effect of PTBP1 knockdown. RNA immunoprecipitation, dual-luciferase reporter, RNA stability assay, transcriptome sequencing, in vivo xenograft Journal of cellular and molecular medicine Medium 32207235
2022 Electron paramagnetic resonance (EPR), UV-visible spectroscopy, and all-atom simulations show that each hCTR1 monomer binds up to five Cu(I) ions; progressive Cu(I) binding triggers structural rearrangement in the C-terminal region, suggesting the C-terminus acts as both a channel gate and a shuttle delivering copper from the extracellular selectivity filter to intracellular metallochaperones. EPR spectroscopy, UV-vis spectroscopy, all-atom molecular dynamics simulation Biophysical journal Medium 35202609
2022 In Menkes disease mosaic mutant mice with renal copper overload, Slc31a1 mRNA is not upregulated compared to copper-injected wild-type mice; in 45-day-old mutants, Slc31a1 expression is reduced relative to wild-type. CTR1 protein is relocalized from the apical membrane to the cytoplasm in proximal tubule epithelial cells in copper-loaded suckling/young mutants, preventing copper transport from primary urine and protecting against copper toxicity. RT-qPCR, immunohistochemistry, mouse model of Menkes disease International journal of molecular sciences Medium 36232742
2018 Overexpression of hCTR1 in SOD1G37R ALS mice increases copper levels in spinal cord and restores activity of both SOD1 and ceruloplasmin (which accumulate in copper-deficient form), demonstrating that hCTR1 delivers copper to cuproenzymes in the CNS. Transgenic mouse model, enzymatic activity assays, Western blot Experimental neurology Medium 29906423
2024 ELF3 (E74-like ETS transcription factor 3) directly binds the SLC31A1 promoter and transcriptionally activates its expression in cisplatin-induced AKI; ELF3 is upregulated by cisplatin and positively correlates with SLC31A1 expression. SLC31A1 knockdown reduces renal copper accumulation, mitigates mitochondrial dysfunction and apoptosis in cisplatin-AKI models. Luciferase reporter assay, ChIP, siRNA knockdown, in vivo mouse AKI model Chemico-biological interactions Medium 38462020
2023 ATF3 and SPI1 function as transcriptional activators of SLC31A1 in AGE-induced cuproptosis in cardiomyocytes; overexpression of ATF3 or SPI1 validated their ability to upregulate SLC31A1 expression, promoting copper accumulation and cuproptosis features including loss of Fe-S cluster proteins and decreased lipoylation. Transcription factor overexpression, Western blot, bioinformatics prediction validated experimentally International journal of molecular sciences Low 36675183
2025 YTHDF1 recognizes and promotes translation of MeCP2 mRNA; elevated MeCP2 increases methylation of CpG islands in the SLC31A1 promoter, suppressing SLC31A1 transcription. SLC31A1 deficiency in cardiac fibroblasts depletes mitochondrial copper, enhances glycolysis, promotes fibroblast proliferation, and triggers cardiac fibrosis. Reconstitution of SLC31A1 in YTHDF1/MeCP2-deficient cells rescued mitochondrial copper and reversed fibrosis. AAV9 shRNA in vivo, ChIP, co-IP, Western blot, respirometry, inductively coupled plasma mass spectrometry European heart journal Medium 40048660
2025 SRF (serum response factor) is a transcription factor for SLC31A1; SRF overexpression upregulates SLC31A1, promoting intracellular copper accumulation and cuproptosis in NSCLC cells treated with celastrol. Transcription factor overexpression, RNA sequencing, bioinformatics prediction validated by overexpression International immunopharmacology Low 39930648
2025 METTL3 adds m6A modifications to SLC31A1 mRNA, which are recognized by YTHDF2, reducing SLC31A1 mRNA stability and expression in trophoblasts; METTL3 knockdown rescues SLC31A1 expression and restores trophoblast migration and invasion, while SLC31A1 silencing reverses these effects. m6A RNA immunoprecipitation, RNA immunoprecipitation (METTL3 and YTHDF2 interactions), Western blot, functional cell assays, in vivo PE rat model Placenta Medium 40088504
2025 EPR distance measurements in micelles and native cell membranes show that at specific Cu(I) concentrations, the extracellular N-terminal chains of hCTR1 move closer to the channel lumen while the intracellular part also penetrates the lumen, suggesting a ball-and-chain gating mechanism; membrane lipid composition influences the gating mechanism. Distance electron paramagnetic resonance (EPR) in vitro and in cells Biomolecules Medium 39858521
2024 Grhl2 transcriptionally activates SLC31A1 expression; high lactate levels in preeclampsia increase H3K18 lactylation at the Grhl2 promoter, upregulating Grhl2, which drives SLC31A1 transcription and increases intracellular copper, inducing trophoblast cuproptosis and inhibiting proliferation/invasion. Luciferase reporter assay, ChIP-PCR, lentivirus knockdown, H3K18la ChIP, in vitro and in vivo models Journal of assisted reproduction and genetics Medium 39287710
2026 Rosmarinic acid (RA) directly binds the N-terminal copper-binding domain of hCTR1 and forms a ternary RA/Cu/hCTR1 complex, lowering Cu(II)-binding affinity of hCTR1. RA inhibits the copper-mediated membrane interaction of hCTR1 N-terminal domain and significantly inhibits hCTR1-mediated copper uptake under high copper conditions. Direct binding assay, cellular copper uptake assay, ternary complex characterization Inorganic chemistry Medium 41494012
2025 Bi-allelic loss-of-function variants in SLC31A1 cause early-onset epileptic encephalopathy with severe neurodevelopmental delay and hypotonia; patient fibroblasts show impaired mitochondrial respiration measured by high-resolution respirometry, implicating SLC31A1-dependent copper supply as essential for mitochondrial function. RNA sequencing, Western blot, high-resolution respirometry in patient fibroblasts Brain communications Medium 41040850

Source papers

Stage 0 corpus · 81 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 hCTR1: a human gene for copper uptake identified by complementation in yeast. Proceedings of the National Academy of Sciences of the United States of America 453 9207117
2002 Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. The Journal of biological chemistry 267 12501239
2009 Three-dimensional structure of the human copper transporter hCTR1. Proceedings of the National Academy of Sciences of the United States of America 213 19240214
2023 ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury. International journal of molecular sciences 195 36675183
2002 Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1). The Biochemical journal 150 12023893
2002 Molecular characterization of hCTR1, the human copper uptake protein. The Journal of biological chemistry 144 12034741
2019 Blockage of SLC31A1-dependent copper absorption increases pancreatic cancer cell autophagy to resist cell death. Cell proliferation 138 30706544
2004 Cisplatin rapidly down-regulates its own influx transporter hCTR1 in cultured human ovarian carcinoma cells. Clinical cancer research : an official journal of the American Association for Cancer Research 117 15475465
2016 Transcriptome analysis of copper homeostasis genes reveals coordinated upregulation of SLC31A1,SCO1, and COX11 in colorectal cancer. FEBS open bio 91 27516958
2011 Iron, copper, and zinc transport: inhibition of divalent metal transporter 1 (DMT1) and human copper transporter 1 (hCTR1) by shRNA. Biological trace element research 84 22068728
2009 Copper-dependent recycling of hCTR1, the human high affinity copper transporter. The Journal of biological chemistry 81 19740744
2007 Human copper transporter hCTR1 mediates basolateral uptake of copper into enterocytes: implications for copper homeostasis. The Journal of biological chemistry 81 17627945
2007 O-linked glycosylation at threonine 27 protects the copper transporter hCTR1 from proteolytic cleavage in mammalian cells. The Journal of biological chemistry 75 17525160
2005 Stable plasma membrane levels of hCTR1 mediate cellular copper uptake. The Journal of biological chemistry 68 15634665
2003 The N-terminus of the human copper transporter 1 (hCTR1) is localized extracellularly, and interacts with itself. The Biochemical journal 67 12466020
2008 Elevated glutathione levels confer cellular sensitization to cisplatin toxicity by up-regulation of copper transporter hCtr1. Molecular pharmacology 66 18523133
2013 A re-evaluation of the role of hCTR1, the human high-affinity copper transporter, in platinum-drug entry into human cells. Molecular pharmacology 65 23543413
2021 ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression. EBioMedicine 62 34521054
2022 High expression of cuproptosis-related SLC31A1 gene in relation to unfavorable outcome and deregulated immune cell infiltration in breast cancer: an analysis based on public databases. BMC bioinformatics 61 35996075
2020 PTBP1 modulates osteosarcoma chemoresistance to cisplatin by regulating the expression of the copper transporter SLC31A1. Journal of cellular and molecular medicine 55 32207235
2000 Characterization of the hCTR1 gene: genomic organization, functional expression, and identification of a highly homologous processed gene. Gene 51 11054564
2022 Cuproptosis-Related Gene - SLC31A1, FDX1 and ATP7B - Polymorphisms are Associated with Risk of Lung Cancer. Pharmacogenomics and personalized medicine 50 35923305
2013 Kinetics and thermodynamics of metal binding to the N-terminus of a human copper transporter, hCTR1. Chemical communications (Cambridge, England) 37 23962988
2015 Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer. Oncology letters 33 26622894
2024 The copper transporter, SLC31A1, transcriptionally activated by ELF3, imbalances copper homeostasis to exacerbate cisplatin-induced acute kidney injury through mitochondrial dysfunction. Chemico-biological interactions 29 38462020
2025 SLC31A1 loss depletes mitochondrial copper and promotes cardiac fibrosis. European heart journal 28 40048660
2012 Comparison between copper and cisplatin transport mediated by human copper transporter 1 (hCTR1). Metallomics : integrated biometal science 28 22552365
2023 Identification of cuproptosis-related gene SLC31A1 and upstream LncRNA-miRNA regulatory axis in breast cancer. Scientific reports 27 37884650
2023 Systematic pan-cancer analysis identifies SLC31A1 as a biomarker in multiple tumor types. BMC medical genomics 26 36973786
2018 Carnosine modulates the Sp1-Slc31a1/Ctr1 copper-sensing system and influences copper homeostasis in murine CNS-derived cells. American journal of physiology. Cell physiology 25 30485136
2016 Desferal regulates hCtr1 and transferrin receptor expression through Sp1 and exhibits synergistic cytotoxicity with platinum drugs in oxaliplatin-resistant human cervical cancer cells in vitro and in vivo. Oncotarget 25 27384479
2005 Expression, localisation and hormone regulation of the human copper transporter hCTR1 in placenta and choriocarcinoma Jeg-3 cells. Placenta 25 16356544
2013 Regulation of the high-affinity copper transporter (hCtr1) expression by cisplatin and heavy metals. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 23 24132751
2018 The accumulation of enzymatically inactive cuproenzymes is a CNS-specific phenomenon of the SOD1G37R mouse model of ALS and can be restored by overexpressing the human copper transporter hCTR1. Experimental neurology 21 29906423
2022 Dynamical interplay between the human high-affinity copper transporter hCtr1 and its cognate metal ion. Biophysical journal 19 35202609
2018 Genetic polymorphism of SLC31A1 is associated with clinical outcomes of platinum-based chemotherapy in non-small-cell lung cancer patients through modulating microRNA-mediated regulation. Oncotarget 18 29844858
2024 Comprehensive bioinformatics analytics and in vivo validation reveal SLC31A1 as an emerging diagnostic biomarker for acute myocardial infarction. Aging 17 38713173
2014 Uptake of compounds that selectively kill multidrug-resistant cells: the copper transporter SLC31A1 (CTR1) increases cellular accumulation of the thiosemicarbazone NSC73306. Molecular pharmaceutics 17 24800945
2021 A pharmacogenetics study of platinum-based chemotherapy in lung cancer: ABCG2 polymorphism and its genetic interaction with SLC31A1 are associated with response and survival. Journal of Cancer 15 33531973
2019 Cuprous binding promotes interaction of copper transport protein hCTR1 with cell membranes. Chemical communications (Cambridge, England) 15 31461100
2025 SRF/SLC31A1 signaling promotes cuproptosis induced by celastrol in NSCLC. International immunopharmacology 14 39930648
2024 The STAT1-SLC31A1 axis: Potential regulation of cuproptosis in diabetic retinopathy. Gene 14 39153705
2021 FGF13 enhances resistance to platinum drugs by regulating hCTR1 and ATP7A via a microtubule-stabilizing effect. Cancer science 14 34533854
2024 ARNTL2 facilitates bladder cancer progression through potentiating ENO1-mediated glycolysis in a SLC31A1-independent and -dependent manner. Life sciences 13 39147318
2021 Effects of SLC31A1 and ATP7B polymorphisms on platinum resistance in patients with esophageal squamous cell carcinoma receiving neoadjuvant chemoradiotherapy. Medical oncology (Northwood, London, England) 12 33411033
2023 LNP-miR-155 cy5 Inhibitor Regulates the Copper Transporter via the β-Catenin/TCF4/SLC31A1 Signal for Colorectal Cancer Therapy. Molecular pharmaceutics 10 37358225
2025 Taxifolin regulates SLC31A1-mediated cuproptosis and tumor progression in hepatocellular carcinoma. Human cell 9 39752031
2024 Blocking lactate regulation of the Grhl2/SLC31A1 axis inhibits trophoblast cuproptosis and preeclampsia development. Journal of assisted reproduction and genetics 9 39287710
2022 Decreased Expression of the Slc31a1 Gene and Cytoplasmic Relocalization of Membrane CTR1 Protein in Renal Epithelial Cells: A Potent Protective Mechanism against Copper Nephrotoxicity in a Mouse Model of Menkes Disease. International journal of molecular sciences 9 36232742
2019 IGF1R predicts better survival in high-grade serous epithelial ovarian cancer patients and correlates with hCtr1 levels. Biomarkers in medicine 9 31140856
2025 SLC31A1 promotes chemoresistance through inducing CPT1A-mediated fatty acid oxidation in ER-positive breast cancer. Neoplasia (New York, N.Y.) 8 39904115
2007 NMR and mutagenesis of human copper transporter 1 (hCtr1) show that Cys-189 is required for correct folding and dimerization. Biochimica et biophysica acta 7 17959139
2025 METTL3 suppressing SLC31A1 m6A modification regulates trophoblast migration and invasion. Placenta 6 40088504
2021 MiR-522-3p inhibits proliferation and activation by regulating the expression of SLC31A1 in T cells. Cytotechnology 6 34149179
2017 Platinum transfer from hCTR1 to Atox1 is dependent on the type of platinum complex. Metallomics : integrated biometal science 5 28383086
2013 Characterization of a monoclonal antibody capable of reliably quantifying expression of human Copper Transporter 1 (hCTR1). Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 5 24447817
2025 Fucoxanthin suppresses pancreatic cancer progression by inducing bioenergetics metabolism crisis and promoting SLC31A1‑mediated sensitivity to DDP. International journal of oncology 4 40052552
2025 Calycosin-7-O-β-D-glucoside modulates copper homeostasis through SLC31A1 to mitigate cuproptosis in cerebral ischemia/reperfusion injury. Chemico-biological interactions 4 40812562
2025 Clinical and molecular characterization of SLC31A1-related developmental and epileptic encephalopathy: insights from 13 new cases. Brain communications 4 41040850
2020 Exploring the copper binding ability of Mets7 hCtr-1 protein domain and His7 derivative: An insight in Michael addition catalysis. Journal of peptide science : an official publication of the European Peptide Society 4 33094563
2015 Self-Assembly of the Second Transmembrane Domain of hCtr1 in Micelles and Interaction with Silver Ion. The journal of physical chemistry. B 4 26061257
2025 Exploring the Gating Mechanism of the Human Copper Transporter, hCtr1, Using EPR Spectroscopy. Biomolecules 3 39858521
2025 Plasma IgG and IgM autoantibodies to COPT1 as potential biomarkers for detection of non-small cell lung cancer. Frontiers in immunology 3 40292291
2026 Amyloid beta 42 disrupts cardiac function in Alzheimer's disease mice via SLC31A1 upregulation-mediated cuproptosis. Basic research in cardiology 1 41739158
2025 Single-cell RNA sequencing reveals SLC31A1-mediated M2 polarization of macrophages promotes malignant progression in triple-negative breast cancer. Journal of cancer research and clinical oncology 1 40360897
2018 [Basic Research of the Adenovirus-mediated hCTR1 Transfection on the Treatment of Cisplatin Resistant Cervical Cancer]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 1 29737086
2003 Cloning, characterization and chromosomal localization of the Sus scrofa SLC31A1 gene. Animal genetics 1 12580789
2026 Rosmarinic Acid Is an hCtr1 Inhibitor that Interferes with Copper Transport Activity. Inorganic chemistry 0 41494012
2026 ZNF384-regulated SLC31A1 expression promotes tumor proliferation and invasion in breast cancer. Molecular and cellular biochemistry 0 41553436
2026 STAT1/SLC31A1 signaling promotes diabetic retinopathy progression by mediating cuproptosis-induced M1 polarization in microglial cells. Life sciences 0 41611203
2026 SLC31A1 exon 1 methylation reduces intracellular copper ion and promotes diabetic cardiac fibrosis. Cardiovascular diabetology 0 41776560
2026 The copper transporter protein SLC31A1-mediated copper metabolism imbalance drives cuproptosis through the SIRT1/HMGB1 pathway in heart failure. Chemico-biological interactions 0 41786017
2026 SLC31A1 knockdown mitigates post-MI heart failure via regulation of copper metabolism. Frontiers in immunology 0 41808820
2026 Nrf2 modulates the IRF7-SLC31A1 axis to suppress neuronal cuproptosis after traumatic brain injury. Experimental neurology 0 41903734
2026 ATF3/SLC31A1-Mediated Cuproptosis Contributes to Bortezomib-Induced Peripheral Neurotoxicity and Intervention by (-)-Epigallocatechin Gallate. International journal of molecular sciences 0 42074318
2026 Copper transporters promote the malignant progression of glioblastoma by regulating the immunosuppressive tumour microenvironment via the SLC31A1-WNT5A axis. Journal of translational medicine 0 42121271
2026 Implications of the Cuproptosis Protein SLC31A1 for the Immune Microenvironment and Temozolomide Sensitivity in Glioblastoma. Anticancer research 0 42203322
2026 Nitroxyl relieves acute kidney injury by suppressing SLC31A1-mediated cuproptosis in renal tubular epithelial cells. Life sciences 0 42214610
2026 Sunitinib enhances cuproptosis induced by copper ionophores via ROS-ATF3-SLC31A1 axis in thyroid Carcinoma. Cell death & disease 0 42225617
2026 Sodium butyrate induces cuproptosis by regulating the HDAC1-SLC31A1 axis in hepatocellular carcinoma. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 0 42235674
2024 Retraction Note: MiR-522-3p inhibits proliferation and activation by regulating the expression of SLC31A1 in T cells. Cytotechnology 0 39435414

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