{"gene":"SLC31A1","run_date":"2026-06-10T07:46:33","timeline":{"discoveries":[{"year":1997,"finding":"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.","method":"Yeast complementation, atomic absorption spectroscopy, functional rescue assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution in yeast with multiple orthogonal readouts (growth, iron transport, SOD1, copper levels), foundational paper replicated by subsequent work","pmids":["9207117"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Baculovirus expression, copper uptake assay, FLAG epitope accessibility, tryptic digestion, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (transport assay, epitope topology, mutagenesis, proteolytic mapping) in single rigorous study","pmids":["12034741"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Immunofluorescence, biosynthetic labeling, Western blot, endocytosis inhibition","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell fractionation, imaging, and pharmacological manipulation in single lab with multiple methods","pmids":["12023893"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Western blot, confocal microscopy, clathrin inhibitors, transferrin co-localization, surface protein assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal localization, pathway inhibition, and quantitative surface loss in same study; later partially contradicted but mechanism of copper-stimulated internalization confirmed independently","pmids":["12501239"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Yeast two-hybrid, glycosylation-site insertion/deletion mapping, indirect immunofluorescence","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — topology confirmed by two orthogonal methods; self-interaction by yeast two-hybrid (single method), single lab","pmids":["12466020"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Western blot, confocal microscopy, siRNA knockdown, copper uptake assay, membrane fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods in single lab; contradicts copper-stimulated internalization finding, lower confidence due to conflicting evidence","pmids":["15634665"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Site-directed mutagenesis, glycosidase treatment, CHO glycosylation-deficient cell expression, copper uptake assay, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis plus glycosylation-deficient cell model plus functional transport assay, multiple orthogonal approaches in single rigorous study","pmids":["17525160"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Cell surface biotinylation, confocal microscopy, copper influx measurement, immunohistochemistry, hCTR1 overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical and imaging approaches, multiple polarized cell lines, consistent with in vivo mouse intestinal sections","pmids":["17627945"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Electron crystallography, Cu(I) binding assay, site-directed mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination plus mutagenesis plus metal-binding biochemistry in single study","pmids":["19240214"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Cell surface biotinylation, reversible biotinylation assay, isotopic copper uptake, cycloheximide chase","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays in single lab, demonstrates recycling not seen in earlier study; endogenous hCTR1 showed cell-specific response","pmids":["19740744"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Western blot, confocal microscopy, 64Cu uptake assay","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (Western, imaging, functional uptake) in single lab with quantitative functional readout","pmids":["15475465"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Solution NMR, site-directed mutagenesis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structural approach with mutagenesis, but truncated construct in micelles, single lab","pmids":["17959139"],"is_preprint":false},{"year":2011,"finding":"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.","method":"shRNA knockdown, radioisotope/ICP-based metal uptake measurement","journal":"Biological trace element research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific quantitative metal transport readouts, single lab","pmids":["22068728"],"is_preprint":false},{"year":2013,"finding":"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).","method":"Metal binding thermodynamics (ITC/spectroscopy), peptide biochemistry","journal":"Chemical communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous biophysical measurement but focused on isolated N-terminal domain peptide, single lab","pmids":["23962988"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Copper/platinum uptake assays, CTR1 knockout MEFs, overexpression mutants, endocytosis assays","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell systems and orthogonal assays; contradicts prior claims about cisplatin transport by hCTR1, single lab","pmids":["23543413"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Reporter assay, Western blot, copper transport competition assay","journal":"Journal of biological inorganic chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (Sp1 as regulator) supported by multiple metal treatments and reporter assays, single lab","pmids":["24132751"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Stable mutant cell lines, ICP-MS metal accumulation, cytotoxicity assays","journal":"Metallomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function mutagenesis with quantitative metal accumulation, single lab","pmids":["22552365"],"is_preprint":false},{"year":2015,"finding":"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.","method":"NMR, circular dichroism, isothermal titration calorimetry, electrophoresis","journal":"The journal of physical chemistry B","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — multiple biophysical methods on isolated TMD2 peptide; functional inference for intact protein is indirect","pmids":["26061257"],"is_preprint":false},{"year":2017,"finding":"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.","method":"In vitro platinum transfer assay, mass spectrometry, biophysical characterization","journal":"Metallomics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution of platinum transfer, single lab, using peptide domains rather than full-length protein","pmids":["28383086"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Biophysical assays, live cell imaging, membrane interaction assay","journal":"Chemical communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conformational change and membrane interaction shown in vitro and in living cells, single lab","pmids":["31461100"],"is_preprint":false},{"year":2021,"finding":"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.","method":"ChIP assay, CAPTURE approach, Co-IP, luciferase reporter assay, siRNA knockdown","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, co-IP, and reporter assays establish epigenetic mechanism; multiple orthogonal methods, single lab","pmids":["34521054"],"is_preprint":false},{"year":2020,"finding":"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.","method":"RNA immunoprecipitation, dual-luciferase reporter, RNA stability assay, transcriptome sequencing, in vivo xenograft","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal RNA-level methods establishing post-transcriptional regulation, single lab","pmids":["32207235"],"is_preprint":false},{"year":2022,"finding":"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.","method":"EPR spectroscopy, UV-vis spectroscopy, all-atom molecular dynamics simulation","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple biophysical methods plus simulation for full-length protein, single lab","pmids":["35202609"],"is_preprint":false},{"year":2022,"finding":"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.","method":"RT-qPCR, immunohistochemistry, mouse model of Menkes disease","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo localization and expression data with functional interpretation, single lab, mouse model","pmids":["36232742"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Transgenic mouse model, enzymatic activity assays, Western blot","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo rescue by hCTR1 overexpression with functional enzyme activity readouts, single lab","pmids":["29906423"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Luciferase reporter assay, ChIP, siRNA knockdown, in vivo mouse AKI model","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct transcription factor binding; functional knockdown in vivo and in vitro, single lab","pmids":["38462020"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Transcription factor overexpression, Western blot, bioinformatics prediction validated experimentally","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression experiment validates predicted transcription factor binding, but no direct ChIP confirmation of promoter binding, single lab","pmids":["36675183"],"is_preprint":false},{"year":2025,"finding":"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.","method":"AAV9 shRNA in vivo, ChIP, co-IP, Western blot, respirometry, inductively coupled plasma mass spectrometry","journal":"European heart journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including in vivo rescue and functional mitochondrial readouts, single lab","pmids":["40048660"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Transcription factor overexpression, RNA sequencing, bioinformatics prediction validated by overexpression","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression experiment supports prediction but no direct ChIP of SRF on SLC31A1 promoter reported, single lab","pmids":["39930648"],"is_preprint":false},{"year":2025,"finding":"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.","method":"m6A RNA immunoprecipitation, RNA immunoprecipitation (METTL3 and YTHDF2 interactions), Western blot, functional cell assays, in vivo PE rat model","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirms METTL3 and YTHDF2 binding to SLC31A1 mRNA with functional rescue, single lab","pmids":["40088504"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Distance electron paramagnetic resonance (EPR) in vitro and in cells","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — EPR in both reconstituted and native membranes reveals structural gating dynamics, single lab, single method","pmids":["39858521"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Luciferase reporter assay, ChIP-PCR, lentivirus knockdown, H3K18la ChIP, in vitro and in vivo models","journal":"Journal of assisted reproduction and genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm Grhl2-SLC31A1 promoter binding; epigenetic histone modification confirmed by ChIP-PCR, single lab","pmids":["39287710"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Direct binding assay, cellular copper uptake assay, ternary complex characterization","journal":"Inorganic chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding and functional inhibition, single lab, no structural resolution","pmids":["41494012"],"is_preprint":false},{"year":2025,"finding":"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.","method":"RNA sequencing, Western blot, high-resolution respirometry in patient fibroblasts","journal":"Brain communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mitochondrial studies in patient-derived cells linked to genetic variants; multi-family study with 13 cases","pmids":["41040850"],"is_preprint":false}],"current_model":"SLC31A1 (hCTR1) is a homotrimeric plasma membrane copper transporter that mediates high-affinity Cu(I) uptake through a central pore lined by TM2, with the extracellular N-terminus binding multiple Cu(I) ions via Met-rich motifs to initiate a conformational change that gates copper transfer to intracellular metallochaperones (e.g., Atox1); its expression is regulated transcriptionally by Sp1, ATF3, SPI1, ELF3, SRF, and ZNF711/JHDM2A, post-transcriptionally by miR-522-3p/PTBP1 and METTL3/YTHDF2-mediated m6A modification, and post-translationally by copper-stimulated clathrin-dependent endocytosis and recycling, O-linked glycosylation at Thr-27 that protects against proteolytic cleavage, and N-linked glycosylation at Asn-15; in polarized epithelial cells hCTR1 localizes to the basolateral membrane to supply copper from blood, and loss-of-function causes mitochondrial copper deficiency, impaired cuproenzyme activity, and in humans causes developmental and epileptic encephalopathy."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1997,"claim":"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","pmids":["9207117"],"confidence":"High","gaps":["Did not resolve transporter topology or oligomeric architecture","No direct measurement of transport mechanism in human cells"]},{"year":2002,"claim":"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","pmids":["12034741"],"confidence":"High","gaps":["Oligomeric state inferred but not structurally resolved","Role of cytoplasmic loop cleavage in vivo unclear"]},{"year":2002,"claim":"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","pmids":["12023893"],"confidence":"Medium","gaps":["Determinants of differential localization not identified","Functional consequence of the perinuclear pool not established"]},{"year":2002,"claim":"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","pmids":["12501239"],"confidence":"High","gaps":["Whether internalization is required for transport vs. regulatory only was unresolved","Conflicting with later endogenous-protein findings"]},{"year":2003,"claim":"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","pmids":["12466020"],"confidence":"Medium","gaps":["Self-interaction shown by single method (Y2H)","Trimeric stoichiometry inferred, not directly measured"]},{"year":2004,"claim":"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","pmids":["15475465"],"confidence":"Medium","gaps":["Mechanism of cisplatin-induced loss not defined","Whether hCTR1 directly transports cisplatin left open"]},{"year":2005,"claim":"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","pmids":["15634665"],"confidence":"Medium","gaps":["Conflicts with overexpression-based internalization data","Cell-type dependence of endocytic response unresolved"]},{"year":2007,"claim":"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","pmids":["17525160"],"confidence":"High","gaps":["Identity of the responsible protease not determined","Regulatory cues controlling cleavage in vivo unknown"]},{"year":2007,"claim":"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","pmids":["17627945"],"confidence":"High","gaps":["Basolateral targeting signals not mapped","Apical copper entry route in intestine left to other transporters"]},{"year":2007,"claim":"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","pmids":["17959139"],"confidence":"Medium","gaps":["Truncated construct in micelles, not full-length protein","Relevance to trimeric assembly of the intact transporter unclear"]},{"year":2009,"claim":"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","pmids":["19240214"],"confidence":"High","gaps":["Resolution insufficient for side-chain detail","Conformational states during transport not captured"]},{"year":2009,"claim":"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","pmids":["19740744"],"confidence":"Medium","gaps":["Shown for overexpressed not endogenous protein","Trafficking machinery mediating recycling not identified"]},{"year":2011,"claim":"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","pmids":["22068728"],"confidence":"Medium","gaps":["Direct vs. indirect effect on Fe/Zn not distinguished","No reconstitution of multi-metal transport"]},{"year":2012,"claim":"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","pmids":["22552365"],"confidence":"Medium","gaps":["Mechanistic basis for differential Cu/cisplatin handling unresolved","Single-lab mutant panel"]},{"year":2013,"claim":"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","pmids":["23962988"],"confidence":"Medium","gaps":["Isolated peptide, not full-length transporter","Coupling of binding to transport not demonstrated"]},{"year":2013,"claim":"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","pmids":["23543413"],"confidence":"Medium","gaps":["Contradicts earlier cisplatin-transport claims","Single-lab reassessment"]},{"year":2013,"claim":"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","pmids":["24132751"],"confidence":"Medium","gaps":["Direct Sp1 promoter occupancy not shown here","Generality across cell types untested"]},{"year":2017,"claim":"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","pmids":["28383086"],"confidence":"Medium","gaps":["Peptide domain rather than full-length protein","Physiological copper (vs. platinum) handoff inferred"]},{"year":2018,"claim":"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","pmids":["29906423"],"confidence":"Medium","gaps":["Disease-modifying significance beyond enzyme rescue unclear","Single model system"]},{"year":2019,"claim":"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","pmids":["31461100"],"confidence":"Medium","gaps":["Membrane interaction characterized for isolated domain","Coupling to pore-mediated translocation not resolved"]},{"year":2020,"claim":"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","pmids":["32207235"],"confidence":"Medium","gaps":["Binding site on mRNA not mapped","Single-lab dataset"]},{"year":2021,"claim":"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","pmids":["34521054"],"confidence":"Medium","gaps":["Direct ZNF711 DNA contact vs. cofactor recruitment not fully separated","Single-lab mechanism"]},{"year":2022,"claim":"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","pmids":["35202609"],"confidence":"Medium","gaps":["Simulation-dependent interpretation","Direct structural snapshots of gating absent"]},{"year":2022,"claim":"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","pmids":["36232742"],"confidence":"Medium","gaps":["Trafficking trigger for relocalization not defined","Mouse-model specific"]},{"year":2023,"claim":"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","pmids":["36675183"],"confidence":"Low","gaps":["No direct ChIP confirmation of promoter binding","Overexpression-only validation, single lab"]},{"year":2024,"claim":"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","pmids":["38462020"],"confidence":"Medium","gaps":["Interplay with other SLC31A1 transcription factors unresolved","Single-lab mechanism"]},{"year":2024,"claim":"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","pmids":["39287710"],"confidence":"Medium","gaps":["Generalizability beyond trophoblast context untested","Single-lab study"]},{"year":2025,"claim":"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","pmids":["40088504"],"confidence":"Medium","gaps":["Specific m6A sites not mapped","Single-lab dataset"]},{"year":2025,"claim":"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","pmids":["40048660"],"confidence":"Medium","gaps":["Hierarchy among the many SLC31A1 regulators unclear","Single-lab mechanism"]},{"year":2025,"claim":"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","pmids":["39930648"],"confidence":"Low","gaps":["No direct ChIP of SRF on the SLC31A1 promoter","Overexpression-only evidence, single lab"]},{"year":2025,"claim":"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","pmids":["39858521"],"confidence":"Medium","gaps":["Single biophysical method","Lipid dependence not mapped to defined species"]},{"year":2025,"claim":"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","pmids":["41040850"],"confidence":"Medium","gaps":["Tissue-specific copper deficiency mechanism in brain not detailed","Genotype-phenotype range across variants incomplete"]},{"year":2026,"claim":"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","pmids":["41494012"],"confidence":"Medium","gaps":["No structural resolution of the ternary complex","Selectivity and in vivo efficacy untested"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,7,12,16]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[13,18,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,5,7]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,9,23]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[24,27,33]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,9]}],"complexes":["hCTR1 homotrimer"],"partners":["ATOX1","SP1","PTBP1","METTL3","YTHDF2","ZNF711","ELF3","SRF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15431","full_name":"High affinity copper uptake protein 1","aliases":["Copper transporter 1","hCTR1","Solute carrier family 31 member 1"],"length_aa":190,"mass_kda":21.1,"function":"Uniporter that mediates the transport of copper(1+) from the extracellular space to the cytoplasm, across the plasma membrane (PubMed:11734551, PubMed:16135512, PubMed:17525160, PubMed:19740744, PubMed:20451502, PubMed:20569931, PubMed:23658018) and delivers directly copper(1+) to specific chaperone such as ATOX1, via a copper(1+)- mediated transient interaction between the C-terminal domain and a copper(1+) chaperone, thus controlling intracellular copper(1+) levels (PubMed:11734551, PubMed:16135512, PubMed:17525160, PubMed:19740744, PubMed:20451502, PubMed:20569931, PubMed:23658018, PubMed:26745413). May function in copper(1+) import from the apical membrane thus may drive intestinal copper absorption (By similarity). The copper(1+) transport mechanism is sodium-independent, saturable and of high-affinity (PubMed:11734551). Also mediates the uptake of silver(1+) (PubMed:20569931). May function in the influx of the platinum-containing chemotherapeutic agents (PubMed:20451502, PubMed:20569931). The platinum-containing chemotherapeutic agents uptake is saturable (By similarity). In vitro, mediates the transport of cadmium(2+) into cells (PubMed:33294387). Also participates in the first step of copper(2+) acquisition by cells through a direct transfer of copper(2+) from copper(2+) carriers in blood, such as ALB to the N-terminal domain of SLC31A1, leading to copper(2+) reduction and probably followed by copper(1+) stabilization (PubMed:30489586). In addition, functions as a redox sensor to promote angiogenesis in endothelial cells, in a copper(1+) transport independent manner, by transmitting the VEGF-induced ROS signal through a sulfenylation at Cys-189 leadin g to a subsequent disulfide bond formation between SLC31A1 and KDR (PubMed:35027734). The SLC31A1-KDR complex is then co-internalized to early endosomes, driving a sustained VEGFR2 signaling (PubMed:35027734) Mobilizes copper(1+) out of the endosomal compartment, making copper(1+) available for export out of the cells","subcellular_location":"Cell membrane; Early endosome membrane; Recycling endosome membrane; Apical cell membrane; Late endosome membrane; Basolateral cell membrane","url":"https://www.uniprot.org/uniprotkb/O15431/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC31A1","classification":"Not Classified","n_dependent_lines":207,"n_total_lines":1208,"dependency_fraction":0.17135761589403972},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000136868","cell_line_id":"CID001331","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"LAMTOR5","stoichiometry":10.0},{"gene":"WASF2","stoichiometry":4.0},{"gene":"SNX9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001331","total_profiled":1310},"omim":[{"mim_id":"620306","title":"NEURODEGENERATION AND SEIZURES DUE TO COPPER TRANSPORT DEFECT; NSCT","url":"https://www.omim.org/entry/620306"},{"mim_id":"603085","title":"SOLUTE CARRIER FAMILY 31 (COPPER TRANSPORTER), MEMBER 1; SLC31A1","url":"https://www.omim.org/entry/603085"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":100.5}],"url":"https://www.proteinatlas.org/search/SLC31A1"},"hgnc":{"alias_symbol":["hCTR1","CTR1"],"prev_symbol":["COPT1"]},"alphafold":{"accession":"O15431","domains":[{"cath_id":"1.20.1440","chopping":"53-101_129-187","consensus_level":"high","plddt":84.1726,"start":53,"end":187}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15431","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15431-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15431-F1-predicted_aligned_error_v6.png","plddt_mean":70.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC31A1","jax_strain_url":"https://www.jax.org/strain/search?query=SLC31A1"},"sequence":{"accession":"O15431","fasta_url":"https://rest.uniprot.org/uniprotkb/O15431.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15431/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15431"}},"corpus_meta":[{"pmid":"9207117","id":"PMC_9207117","title":"hCTR1: 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atomic absorption spectroscopy, functional rescue assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution in yeast with multiple orthogonal readouts (growth, iron transport, SOD1, copper levels), foundational paper replicated by subsequent work\",\n      \"pmids\": [\"9207117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Baculovirus expression, copper uptake assay, FLAG epitope accessibility, tryptic digestion, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (transport assay, epitope topology, mutagenesis, proteolytic mapping) in single rigorous study\",\n      \"pmids\": [\"12034741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence, biosynthetic labeling, Western blot, endocytosis inhibition\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell fractionation, imaging, and pharmacological manipulation in single lab with multiple methods\",\n      \"pmids\": [\"12023893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Western blot, confocal microscopy, clathrin inhibitors, transferrin co-localization, surface protein assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal localization, pathway inhibition, and quantitative surface loss in same study; later partially contradicted but mechanism of copper-stimulated internalization confirmed independently\",\n      \"pmids\": [\"12501239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, glycosylation-site insertion/deletion mapping, indirect immunofluorescence\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — topology confirmed by two orthogonal methods; self-interaction by yeast two-hybrid (single method), single lab\",\n      \"pmids\": [\"12466020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Western blot, confocal microscopy, siRNA knockdown, copper uptake assay, membrane fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods in single lab; contradicts copper-stimulated internalization finding, lower confidence due to conflicting evidence\",\n      \"pmids\": [\"15634665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis, glycosidase treatment, CHO glycosylation-deficient cell expression, copper uptake assay, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis plus glycosylation-deficient cell model plus functional transport assay, multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"17525160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Cell surface biotinylation, confocal microscopy, copper influx measurement, immunohistochemistry, hCTR1 overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical and imaging approaches, multiple polarized cell lines, consistent with in vivo mouse intestinal sections\",\n      \"pmids\": [\"17627945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Electron crystallography, Cu(I) binding assay, site-directed mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination plus mutagenesis plus metal-binding biochemistry in single study\",\n      \"pmids\": [\"19240214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Cell surface biotinylation, reversible biotinylation assay, isotopic copper uptake, cycloheximide chase\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays in single lab, demonstrates recycling not seen in earlier study; endogenous hCTR1 showed cell-specific response\",\n      \"pmids\": [\"19740744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Western blot, confocal microscopy, 64Cu uptake assay\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (Western, imaging, functional uptake) in single lab with quantitative functional readout\",\n      \"pmids\": [\"15475465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Solution NMR, site-directed mutagenesis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structural approach with mutagenesis, but truncated construct in micelles, single lab\",\n      \"pmids\": [\"17959139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown, radioisotope/ICP-based metal uptake measurement\",\n      \"journal\": \"Biological trace element research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific quantitative metal transport readouts, single lab\",\n      \"pmids\": [\"22068728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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).\",\n      \"method\": \"Metal binding thermodynamics (ITC/spectroscopy), peptide biochemistry\",\n      \"journal\": \"Chemical communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous biophysical measurement but focused on isolated N-terminal domain peptide, single lab\",\n      \"pmids\": [\"23962988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Copper/platinum uptake assays, CTR1 knockout MEFs, overexpression mutants, endocytosis assays\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell systems and orthogonal assays; contradicts prior claims about cisplatin transport by hCTR1, single lab\",\n      \"pmids\": [\"23543413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Reporter assay, Western blot, copper transport competition assay\",\n      \"journal\": \"Journal of biological inorganic chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (Sp1 as regulator) supported by multiple metal treatments and reporter assays, single lab\",\n      \"pmids\": [\"24132751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Stable mutant cell lines, ICP-MS metal accumulation, cytotoxicity assays\",\n      \"journal\": \"Metallomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function mutagenesis with quantitative metal accumulation, single lab\",\n      \"pmids\": [\"22552365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"NMR, circular dichroism, isothermal titration calorimetry, electrophoresis\",\n      \"journal\": \"The journal of physical chemistry B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — multiple biophysical methods on isolated TMD2 peptide; functional inference for intact protein is indirect\",\n      \"pmids\": [\"26061257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro platinum transfer assay, mass spectrometry, biophysical characterization\",\n      \"journal\": \"Metallomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution of platinum transfer, single lab, using peptide domains rather than full-length protein\",\n      \"pmids\": [\"28383086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Biophysical assays, live cell imaging, membrane interaction assay\",\n      \"journal\": \"Chemical communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conformational change and membrane interaction shown in vitro and in living cells, single lab\",\n      \"pmids\": [\"31461100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay, CAPTURE approach, Co-IP, luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-IP, and reporter assays establish epigenetic mechanism; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34521054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"RNA immunoprecipitation, dual-luciferase reporter, RNA stability assay, transcriptome sequencing, in vivo xenograft\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal RNA-level methods establishing post-transcriptional regulation, single lab\",\n      \"pmids\": [\"32207235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"EPR spectroscopy, UV-vis spectroscopy, all-atom molecular dynamics simulation\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical methods plus simulation for full-length protein, single lab\",\n      \"pmids\": [\"35202609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"RT-qPCR, immunohistochemistry, mouse model of Menkes disease\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo localization and expression data with functional interpretation, single lab, mouse model\",\n      \"pmids\": [\"36232742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Transgenic mouse model, enzymatic activity assays, Western blot\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo rescue by hCTR1 overexpression with functional enzyme activity readouts, single lab\",\n      \"pmids\": [\"29906423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay, ChIP, siRNA knockdown, in vivo mouse AKI model\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct transcription factor binding; functional knockdown in vivo and in vitro, single lab\",\n      \"pmids\": [\"38462020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Transcription factor overexpression, Western blot, bioinformatics prediction validated experimentally\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression experiment validates predicted transcription factor binding, but no direct ChIP confirmation of promoter binding, single lab\",\n      \"pmids\": [\"36675183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"AAV9 shRNA in vivo, ChIP, co-IP, Western blot, respirometry, inductively coupled plasma mass spectrometry\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including in vivo rescue and functional mitochondrial readouts, single lab\",\n      \"pmids\": [\"40048660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Transcription factor overexpression, RNA sequencing, bioinformatics prediction validated by overexpression\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression experiment supports prediction but no direct ChIP of SRF on SLC31A1 promoter reported, single lab\",\n      \"pmids\": [\"39930648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"m6A RNA immunoprecipitation, RNA immunoprecipitation (METTL3 and YTHDF2 interactions), Western blot, functional cell assays, in vivo PE rat model\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirms METTL3 and YTHDF2 binding to SLC31A1 mRNA with functional rescue, single lab\",\n      \"pmids\": [\"40088504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Distance electron paramagnetic resonance (EPR) in vitro and in cells\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — EPR in both reconstituted and native membranes reveals structural gating dynamics, single lab, single method\",\n      \"pmids\": [\"39858521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay, ChIP-PCR, lentivirus knockdown, H3K18la ChIP, in vitro and in vivo models\",\n      \"journal\": \"Journal of assisted reproduction and genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm Grhl2-SLC31A1 promoter binding; epigenetic histone modification confirmed by ChIP-PCR, single lab\",\n      \"pmids\": [\"39287710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Direct binding assay, cellular copper uptake assay, ternary complex characterization\",\n      \"journal\": \"Inorganic chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding and functional inhibition, single lab, no structural resolution\",\n      \"pmids\": [\"41494012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"RNA sequencing, Western blot, high-resolution respirometry in patient fibroblasts\",\n      \"journal\": \"Brain communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mitochondrial studies in patient-derived cells linked to genetic variants; multi-family study with 13 cases\",\n      \"pmids\": [\"41040850\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC31A1 (hCTR1) is a homotrimeric plasma membrane copper transporter that mediates high-affinity Cu(I) uptake through a central pore lined by TM2, with the extracellular N-terminus binding multiple Cu(I) ions via Met-rich motifs to initiate a conformational change that gates copper transfer to intracellular metallochaperones (e.g., Atox1); its expression is regulated transcriptionally by Sp1, ATF3, SPI1, ELF3, SRF, and ZNF711/JHDM2A, post-transcriptionally by miR-522-3p/PTBP1 and METTL3/YTHDF2-mediated m6A modification, and post-translationally by copper-stimulated clathrin-dependent endocytosis and recycling, O-linked glycosylation at Thr-27 that protects against proteolytic cleavage, and N-linked glycosylation at Asn-15; in polarized epithelial cells hCTR1 localizes to the basolateral membrane to supply copper from blood, and loss-of-function causes mitochondrial copper deficiency, impaired cuproenzyme activity, and in humans causes developmental and epileptic encephalopathy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0]. 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) [#1, #4, #8]. 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 [#13, #19], TM2 lines the central translocation pore [#8], 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 [#22, #30, #16, #18]. 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 [#6], and by copper-stimulated clathrin-dependent endocytosis with subsequent recycling that tunes surface transporter levels [#3, #9]. In polarized epithelia hCTR1 localizes to the basolateral membrane, where it dominates copper influx [#7]. Functionally, hCTR1 supplies copper to cuproenzymes: its overexpression restores SOD1 and ceruloplasmin activity in the CNS [#24], and its loss depletes mitochondrial copper and impairs respiration [#27, #33]. SLC31A1 expression is heavily regulated at multiple levels — transcriptionally through Sp1, ATF3/SPI1, ELF3, SRF, Grhl2, and ZNF711/JHDM2A-mediated H3K9me2 demethylation [#15, #25, #20, #31], and post-transcriptionally through PTBP1-mediated mRNA destabilization and METTL3/YTHDF2 m6A-dependent decay [#21, #29]. Bi-allelic loss-of-function variants in SLC31A1 cause early-onset epileptic encephalopathy with neurodevelopmental delay and impaired mitochondrial respiration in patient cells [#33].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that the human gene encodes a functional high-affinity copper uptake transporter, defining its core physiological activity.\",\n      \"evidence\": \"Functional complementation of a yeast ctr1 mutant with rescue of growth, iron transport, SOD1, and elevated copper by atomic absorption spectroscopy\",\n      \"pmids\": [\"9207117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve transporter topology or oligomeric architecture\", \"No direct measurement of transport mechanism in human cells\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined membrane topology and transport kinetics, showing an extracellular N-terminus, intracellular C-terminus, and saturable copper uptake.\",\n      \"evidence\": \"Baculovirus expression in Sf9 cells, FLAG epitope accessibility, copper uptake kinetics, tryptic mapping, and mutagenesis of Cys-161/Cys-189\",\n      \"pmids\": [\"12034741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Oligomeric state inferred but not structurally resolved\", \"Role of cytoplasmic loop cleavage in vivo unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Characterized hCTR1 maturation by glycosylation and revealed cell-type-dependent localization between plasma membrane and intracellular compartments.\",\n      \"evidence\": \"Immunofluorescence, biosynthetic labeling, Western blot, and endocytosis inhibition in HeLa cells\",\n      \"pmids\": [\"12023893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of differential localization not identified\", \"Functional consequence of the perinuclear pool not established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed copper itself triggers clathrin-dependent endocytosis and degradation of hCTR1, establishing a copper-responsive regulatory loop.\",\n      \"evidence\": \"Confocal microscopy, clathrin inhibitors, transferrin co-localization, and surface protein assays in HEK293 cells\",\n      \"pmids\": [\"12501239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether internalization is required for transport vs. regulatory only was unresolved\", \"Conflicting with later endogenous-protein findings\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated CTR1 self-association through N-terminal domains, supporting a homotrimeric channel model.\",\n      \"evidence\": \"Yeast two-hybrid across human/mouse/rat/yeast CTR1, glycosylation-site mapping, and immunofluorescence\",\n      \"pmids\": [\"12466020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Self-interaction shown by single method (Y2H)\", \"Trimeric stoichiometry inferred, not directly measured\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed that cisplatin rapidly down-regulates hCTR1 protein with functional loss of copper uptake, linking the transporter to platinum-drug pharmacology.\",\n      \"evidence\": \"Western blot, confocal microscopy, and 64Cu uptake in A2780 ovarian carcinoma cells\",\n      \"pmids\": [\"15475465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of cisplatin-induced loss not defined\", \"Whether hCTR1 directly transports cisplatin left open\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Challenged the obligatory-internalization model by showing endogenous hCTR1 remains stably at the plasma membrane and mediates uptake without copper-induced internalization.\",\n      \"evidence\": \"Western blot, confocal microscopy, siRNA knockdown, and copper uptake with membrane fractionation in HEK293 cells\",\n      \"pmids\": [\"15634665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conflicts with overexpression-based internalization data\", \"Cell-type dependence of endocytic response unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified O-glycosylation at Thr-27 as a protective modification preventing proteolytic cleavage that reduces transport activity, distinguishing it from dispensable N-glycosylation.\",\n      \"evidence\": \"Site-directed mutagenesis, glycosidase treatment, O-glycosylation-deficient CHO cells, and copper uptake assays\",\n      \"pmids\": [\"17525160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the responsible protease not determined\", \"Regulatory cues controlling cleavage in vivo unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that hCTR1 is basolaterally targeted in polarized epithelia, defining the direction of physiological copper acquisition from blood.\",\n      \"evidence\": \"Cell surface biotinylation, confocal microscopy, copper influx measurement in Caco2/T84/MDCK cells and mouse intestine\",\n      \"pmids\": [\"17627945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basolateral targeting signals not mapped\", \"Apical copper entry route in intestine left to other transporters\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Assigned a structural role to Cys-189 in folding and dimerization of the N-terminal region.\",\n      \"evidence\": \"Solution NMR and mutagenesis on a truncated residue 45–190 construct\",\n      \"pmids\": [\"17959139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Truncated construct in micelles, not full-length protein\", \"Relevance to trimeric assembly of the intact transporter unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided the first 3D architecture, confirming a homotrimeric pore with TM2 lining the central channel and direct Cu(I) coordination.\",\n      \"evidence\": \"Electron crystallography at 7 Å, Cu(I) binding assays, and mutagenesis\",\n      \"pmids\": [\"19240214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Resolution insufficient for side-chain detail\", \"Conformational states during transport not captured\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a reversible, acute regulatory cycle of copper-dependent internalization and recycling of overexpressed hCTR1.\",\n      \"evidence\": \"Surface biotinylation, reversible biotinylation, isotopic copper uptake, and cycloheximide chase in HEK293 cells\",\n      \"pmids\": [\"19740744\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shown for overexpressed not endogenous protein\", \"Trafficking machinery mediating recycling not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Indicated hCTR1 contributes to iron and zinc uptake in addition to copper, broadening its metal-handling role.\",\n      \"evidence\": \"shRNA knockdown in Caco-2 cells with radioisotope/ICP metal uptake measurement\",\n      \"pmids\": [\"22068728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect effect on Fe/Zn not distinguished\", \"No reconstitution of multi-metal transport\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped structure-function determinants of metal accumulation, establishing the C-terminal motif as essential and dissecting residues that differentially affect copper vs. cisplatin handling.\",\n      \"evidence\": \"Stable mutant cell lines (H139R, Y156A, C189S, ΔC), ICP-MS metal accumulation, and cytotoxicity assays\",\n      \"pmids\": [\"22552365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis for differential Cu/cisplatin handling unresolved\", \"Single-lab mutant panel\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Metal binding thermodynamics and peptide biochemistry on the isolated N-terminal domain\",\n      \"pmids\": [\"23962988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isolated peptide, not full-length transporter\", \"Coupling of binding to transport not demonstrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Refuted hCTR1 as the major platinum-drug entry route, redefining its relationship to cisplatin as regulatory rather than transport-mediating.\",\n      \"evidence\": \"Copper/platinum uptake assays in CTR1-knockout MEFs, overexpression mutants, and sensitive/resistant tumor cells\",\n      \"pmids\": [\"23543413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contradicts earlier cisplatin-transport claims\", \"Single-lab reassessment\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed cisplatin induces hCTR1 transcription indirectly by competing for copper and elevating the Sp1 activator, linking metal status to transporter expression.\",\n      \"evidence\": \"Reporter assays, Western blot, and copper transport competition with multiple metals in cells\",\n      \"pmids\": [\"24132751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Sp1 promoter occupancy not shown here\", \"Generality across cell types untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated metal transfer from the hCTR1 C-terminal motif to the chaperone Atox1, connecting the transporter to downstream copper distribution.\",\n      \"evidence\": \"In vitro platinum transfer assay with the C8 peptide, mass spectrometry, and biophysical characterization\",\n      \"pmids\": [\"28383086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peptide domain rather than full-length protein\", \"Physiological copper (vs. platinum) handoff inferred\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established in vivo that hCTR1 delivers copper to CNS cuproenzymes by rescuing SOD1 and ceruloplasmin activity.\",\n      \"evidence\": \"hCTR1 overexpression in SOD1G37R ALS mice with enzymatic activity assays and Western blot\",\n      \"pmids\": [\"29906423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Disease-modifying significance beyond enzyme rescue unclear\", \"Single model system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the Cu(I)-induced conformational change of the N-terminal domain that engages the membrane as the initiating step of copper internalization.\",\n      \"evidence\": \"Biophysical assays, live cell imaging, and membrane interaction assays\",\n      \"pmids\": [\"31461100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Membrane interaction characterized for isolated domain\", \"Coupling to pore-mediated translocation not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed post-transcriptional control by PTBP1, which destabilizes SLC31A1 mRNA and modulates cisplatin sensitivity.\",\n      \"evidence\": \"RNA immunoprecipitation, dual-luciferase, RNA stability assays, transcriptome sequencing, and xenografts\",\n      \"pmids\": [\"32207235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on mRNA not mapped\", \"Single-lab dataset\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined an epigenetic activation mechanism in which ZNF711 recruits JHDM2A to demethylate H3K9me2 at the SLC31A1 promoter, controlling cisplatin influx.\",\n      \"evidence\": \"ChIP, CAPTURE, Co-IP, luciferase reporter, and siRNA knockdown\",\n      \"pmids\": [\"34521054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ZNF711 DNA contact vs. cofactor recruitment not fully separated\", \"Single-lab mechanism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"EPR and UV-vis spectroscopy with all-atom molecular dynamics on full-length protein\",\n      \"pmids\": [\"35202609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Simulation-dependent interpretation\", \"Direct structural snapshots of gating absent\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated physiological regulation of CTR1 localization in vivo, showing relocalization from apical membrane to cytoplasm protects against renal copper toxicity.\",\n      \"evidence\": \"RT-qPCR and immunohistochemistry in a Menkes disease mosaic mutant mouse model\",\n      \"pmids\": [\"36232742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking trigger for relocalization not defined\", \"Mouse-model specific\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Proposed ATF3 and SPI1 as transcriptional activators driving SLC31A1-dependent copper accumulation and cuproptosis in cardiomyocytes.\",\n      \"evidence\": \"Transcription factor overexpression, Western blot, and bioinformatic prediction validated experimentally\",\n      \"pmids\": [\"36675183\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct ChIP confirmation of promoter binding\", \"Overexpression-only validation, single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified ELF3 as a direct transcriptional activator of SLC31A1 driving renal copper accumulation and mitochondrial injury in cisplatin-induced AKI.\",\n      \"evidence\": \"Luciferase reporter, ChIP, siRNA knockdown, and an in vivo mouse AKI model\",\n      \"pmids\": [\"38462020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay with other SLC31A1 transcription factors unresolved\", \"Single-lab mechanism\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed Grhl2, induced via H3K18 lactylation, transcriptionally activates SLC31A1 to drive trophoblast cuproptosis in preeclampsia.\",\n      \"evidence\": \"Luciferase reporter, ChIP-PCR, lentivirus knockdown, H3K18la ChIP, and in vitro/in vivo models\",\n      \"pmids\": [\"39287710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability beyond trophoblast context untested\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked m6A modification by METTL3/YTHDF2 to destabilization of SLC31A1 mRNA, controlling trophoblast copper supply and migration.\",\n      \"evidence\": \"m6A and protein RNA immunoprecipitation, Western blot, functional cell assays, and an in vivo preeclampsia rat model\",\n      \"pmids\": [\"40088504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites not mapped\", \"Single-lab dataset\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected YTHDF1/MeCP2-driven promoter methylation to SLC31A1 suppression, with loss depleting mitochondrial copper and promoting cardiac fibrosis.\",\n      \"evidence\": \"AAV9 shRNA in vivo, ChIP, Co-IP, respirometry, and ICP-MS with SLC31A1 reconstitution rescue\",\n      \"pmids\": [\"40048660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy among the many SLC31A1 regulators unclear\", \"Single-lab mechanism\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed SRF as a transcription factor for SLC31A1 promoting copper accumulation and cuproptosis in NSCLC.\",\n      \"evidence\": \"Transcription factor overexpression and RNA sequencing with bioinformatic prediction\",\n      \"pmids\": [\"39930648\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct ChIP of SRF on the SLC31A1 promoter\", \"Overexpression-only evidence, single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Distance EPR in micelles and native cell membranes\",\n      \"pmids\": [\"39858521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single biophysical method\", \"Lipid dependence not mapped to defined species\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established SLC31A1 as a Mendelian disease gene, with bi-allelic loss-of-function causing epileptic encephalopathy and impaired mitochondrial respiration.\",\n      \"evidence\": \"Multi-family study with RNA sequencing, Western blot, and high-resolution respirometry in patient fibroblasts\",\n      \"pmids\": [\"41040850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific copper deficiency mechanism in brain not detailed\", \"Genotype-phenotype range across variants incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated pharmacological inhibition of hCTR1, with rosmarinic acid binding the N-terminal domain to lower copper affinity and block uptake.\",\n      \"evidence\": \"Direct binding assay, cellular copper uptake assay, and ternary complex characterization\",\n      \"pmids\": [\"41494012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural resolution of the ternary complex\", \"Selectivity and in vivo efficacy untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 7, 12, 16]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [13, 18, 22]},\n      {\"term_id\": \"GO:0046872\", \"supporting_discovery_ids\": [8, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 5, 7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 9, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [24, 27, 33]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"complexes\": [\"hCTR1 homotrimer\"],\n    \"partners\": [\"Atox1\", \"Sp1\", \"PTBP1\", \"METTL3\", \"YTHDF2\", \"ZNF711\", \"ELF3\", \"SRF\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}