SLC31A1

Summary

SLC31A1 (solute carrier family 31 member 1, HGNC:11016) is a protein-coding gene on chromosome 9q32, encoding High affinity copper uptake protein 1 (O15431). Uniporter that mediates the transport of copper(1+) from the extracellular space to the cytoplasm, across the plasma membrane and delivers directly copper(1+) to specific chaperone such as ATOX1, via a copper(1+)- mediated transient interaction between the C-terminal domain and…. It is a selective cancer dependency (DepMap: 12.7% of cell lines).

The protein encoded by this gene is a high-affinity copper transporter found in the cell membrane. The encoded protein functions as a homotrimer to effect the uptake of dietary copper.

Source: NCBI Gene 1317 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegeneration and seizures due to copper transport defect (Moderate, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 28 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 12.7% of screened cell lines
• MANE Select transcript: NM_001859

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11016
Approved symbol	SLC31A1
Name	solute carrier family 31 member 1
Location	9q32
Locus type	gene with protein product
Status	Approved
Aliases	hCTR1, CTR1
Ensembl gene	ENSG00000136868
Ensembl biotype	protein_coding
OMIM	603085
Entrez	1317

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000374212, ENST00000496650, ENST00000902243, ENST00000937550, ENST00000937551, ENST00000937552

RefSeq mRNA: 1 — MANE Select: NM_001859 NM_001859

CCDS: CCDS6789

Canonical transcript exons

ENST00000374212 — 5 exons

Exon	Start	End
ENSE00000806205	113258694	113258862
ENSE00000806206	113257113	113257185
ENSE00001462793	113260272	113264492
ENSE00001462795	113256114	113256277
ENSE00001547338	113221544	113221678

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 95.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.9457 / max 236.7882, expressed in 1806 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98077	24.4714	1806
98079	0.4743	242

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	95.60	gold quality
jejunal mucosa	UBERON:0000399	95.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.84	gold quality
duodenum	UBERON:0002114	93.34	gold quality
nasal cavity mucosa	UBERON:0001826	93.10	gold quality
liver	UBERON:0002107	92.39	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.78	gold quality
right lobe of liver	UBERON:0001114	91.61	gold quality
nasal cavity epithelium	UBERON:0005384	91.60	gold quality
adrenal tissue	UBERON:0018303	91.56	gold quality
cartilage tissue	UBERON:0002418	91.29	gold quality
amniotic fluid	UBERON:0000173	91.01	gold quality
nipple	UBERON:0002030	90.92	gold quality
bronchial epithelial cell	CL:0002328	90.27	gold quality
monocyte	CL:0000576	90.09	gold quality
islet of Langerhans	UBERON:0000006	89.83	gold quality
endothelial cell	CL:0000115	89.74	gold quality
esophagus squamous epithelium	UBERON:0006920	89.74	gold quality
tibia	UBERON:0000979	89.66	gold quality
nephron tubule	UBERON:0001231	89.42	gold quality
stromal cell of endometrium	CL:0002255	89.33	gold quality
mononuclear cell	CL:0000842	89.25	gold quality
cervix squamous epithelium	UBERON:0006922	88.93	silver quality
choroid plexus epithelium	UBERON:0003911	88.83	gold quality
leukocyte	CL:0000738	88.79	gold quality
palpebral conjunctiva	UBERON:0001812	88.76	gold quality
epithelium of bronchus	UBERON:0002031	88.56	gold quality
bronchus	UBERON:0002185	88.52	gold quality
saliva-secreting gland	UBERON:0001044	88.30	gold quality
gingival epithelium	UBERON:0001949	87.93	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	46.39
E-ANND-3	yes	10.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, MTF1, NFE2L2, NFKB, NRF1, SP1, SPI1, TP53, WT1

miRNA regulators (miRDB)

208 targeting SLC31A1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• fundamentally conserved mechanism for high affinity copper uptake through the Ctr proteins in yeast and humans (PMID:11983704)
• biochemical characterization and subcellular localization (PMID:12023893)
• observations demonstrate that, although Ctr1 is critical for both cellular copper uptake and embryonic development, mammals possess additional biochemically distinct functional copper transport activities (PMID:12177073)
• Results suggest that human copper transporter 1 (CTR1) spans the membrane at least six times, permitting formation of a channel, which is consistent with its proposed role as a copper transporter. (PMID:12466020)
• hCtr1-mediated copper uptake into mammalian cells is regulated by a post-translational mechanism involving copper-stimulated endocytosis and degradation of the transporter (PMID:12501239)
• there are common biochemical mechanisms regulate both transport and trafficking functions of hCtr1 (PMID:14976198)
• there is a direct interaction between cisplatin and the hCtr1 protein; cisplatin and copper have distinct biochemical consequences on this transporter (PMID:15326162)
• Internalization of endogenous human Ctr1 in response to elevated extracellular copper levels does not play a significant regulatory role in copper homeostasis. (PMID:15634665)
• Hormones have a role in the formation of the active hCTR1 protein in human placental cells. (PMID:16356544)
• formation of a putative pore for metal ions at the interface of three identical subunits deviates from the structural design of typical primary and secondary active transporters (PMID:16501047)
• hCTR1 plays a key role in the physiologically important delivery of copper from blood to intracellular proteins, whereas its role in the initial apical uptake of dietary copper is indirect. (PMID:17627945)
• The results of NMR methods and site-directed mutagenesis of the two cysteine residues demonstrate that Cys-189 but not Cys-161 is essential for both dimer formation and proper folding of the protein. (PMID:17959139)
• Downregulation of Ctr1 suppresses cisplatin nephrotoxicity, including cell death by both apoptosis and necrosis. (PMID:19144690)
• Proteasomal inhibition prevents cisplatin-induced down-regulation of hCTR1 in ovarian cancer cells and enhanced drug uptake and cell killing in a synergistic manner (PMID:19147760)
• structure of the human CTR1 protein solved by electron crystallography to an in plane resolution of 7 A (PMID:19240214)
• Results demonstrate that co-exposure of tumor cells to emodin or DRB with cisplatin inhibits platinum drug uptake by impacting the hCtr1 transporter. (PMID:19529937)
• Results describe the interactions of a peptide corresponding to the N-terminal domain of the human copper transporter 1 with cisplatin and its analogues, at the molecular level. (PMID:19669174)
• Data indicate that human copper transporter 1 cleavage occurs in a late endosomal, Rab9-positive compartment prior to delivery of the transporter to the plasma membrane. (PMID:19684018)
• Copper-dependent internalization and recycling of hCTR1 provides an acute and reversible mechanism for the regulation of cellular copper entry. (PMID:19740744)
• findings reveal a high level of conservation between the mammalian and insect Ctr1-type copper importers (PMID:19856191)
• Sequence analysis demonstrated SLC31A1 on chromosome 9 was rearranged with breaks occurring within its intron. SLC31A1 lies close to BSPRY which is a candidate for cleft lip/palate involvement. (PMID:19929093)
• Identified as dominant hinge regions, CTR1’s MxxxM and GxxxG motifs were shown to have significant roles in functional movements characterized by the two slowest modes of motion. (PMID:20534491)
• Ctr1 is an important transport protein in the accumulation of silver in mammalian cells. (PMID:20569931)
• Data show apical localization of Ctr1 in intestinal epithelia and suggest that increased Ctr1 apical localization in response to dietary copper limitation may represent an adaptive response to modulate Ctr1 availability at the site of copper absorption. (PMID:20699218)
• Compared the binding interactions between cisplatin, carboplatin and oxaliplatin with synthetic peptides corresponding to hCtr1 Mets motifs. (PMID:21072377)
• Cisplatin induces drug resistant phenotype by decreasing the protein level of CTR1 in human esophageal squamous carcinoma cell line EC109. (PMID:21602128)
• Data show that both shRNA-DMT1 and shRNA-hCTR1 cells had lower apical Fe uptake, Cu uptake, and Zn content compared to control cells. (PMID:22068728)
• There was little difference in rates/kinetics of uptake of copper in the Ctr1+/+ and -/- cells. Endocytosis was not involved. (PMID:22354499)
• CTR1 plays an essential role in cisplatin toxicity and could be considered as a predictor for pretreatment evaluation in lung cancer patients. (PMID:22516052)
• The cells expressing the hCTR1 mutants of histidine-rich motifs in the N-terminus (H22-24A, NHA) resulted in a higher basal copper level in the steady state compared to those expressing wild-type protein. (PMID:22552365)
• Structure of CTR1 confirms that two triads of methionine residues delineate the intramembranous region of the transporter, and further identifies two additional methionine triads that are located in the extracellular N-terminal part of the transporter. (PMID:22569840)
• basal expression of Ctr1 is regulated by HIF2alpha; however, the induction by hypoxia is a HIF2alpha-independent event (PMID:22684009)
• genetic association study in Han population in China: Data suggest that SNPs in SLC31A1 (rs7851395; rs12686377) are associated with resistance to platinum compounds as antineoplastics and survival outcomes in non-small cell lung carcinoma patients. (PMID:22725681)
• This review explains how modulating cellular copper availability could influence treatment efficacy in platinum-based cancer chemotherapy through hCtr1 regulation[review] (PMID:22962276)
• Our findings imply that reduced CTR1 expression accounts for decreased cisplatin accumulation and represents one of the determinants of cisplatin resistance in A2780cis cell line (PMID:23010323)
• Depletion of glutathione decreases cellular copper uptake mediated by human copper transporter 1. (PMID:23426973)
• Results show that hCTR1 elements on the intracellular side of the hCTR1 pore, including the carboxyl tail, are not essential for permeation, but serve to regulate the rate of copper entry. (PMID:23658018)
• The patients with tumors showing high expression levels of at least one of OATP1B3 and CTR1 had potentially longer disease-free survival. (PMID:23782748)
• This study demonistrated that Inhibition of human high-affinity copper importer Ctr1 orthologous in the nervous system of Drosophila ameliorates Abeta42-induced Alzheimer’s disease-like symptoms. (PMID:23827522)
• Duodenal CTR1 mRNA and protein expression was decreased in Wilson’s disease patients, while ATP7A mRNA and protein production was increased. This can be a defense mechanism against systemic copper overload resulting from functional impairment of ATP7B. (PMID:23963605)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc31a1	ENSDARG00000013961
mus_musculus	Slc31a1	ENSMUSG00000066150
rattus_norvegicus	Slc31a1	ENSRNOG00000014475
caenorhabditis_elegans		WBGENE00010274
caenorhabditis_elegans	K12C11.3	WBGENE00019674
caenorhabditis_elegans		WBGENE00044107
caenorhabditis_elegans	K12C11.6	WBGENE00045052

Paralogs (1): SLC31A2 (ENSG00000136867)

Protein

Protein identifiers

High affinity copper uptake protein 1 — O15431 (reviewed: O15431)

Alternative names: Copper transporter 1, Solute carrier family 31 member 1

All UniProt accessions (1): O15431

UniProt curated annotations — full annotation on UniProt →

Function. Uniporter that mediates the transport of copper(1+) from the extracellular space to the cytoplasm, across the plasma membrane 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. May function in copper(1+) import from the apical membrane thus may drive intestinal copper absorption. The copper(1+) transport mechanism is sodium-independent, saturable and of high-affinity. Also mediates the uptake of silver(1+). May function in the influx of the platinum-containing chemotherapeutic agents. The platinum-containing chemotherapeutic agents uptake is saturable. In vitro, mediates the transport of cadmium(2+) into cells. 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. 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. The SLC31A1-KDR complex is then co-internalized to early endosomes, driving a sustained VEGFR2 signaling. Mobilizes copper(1+) out of the endosomal compartment, making copper(1+) available for export out of the cells.

Subunit / interactions. Homotrimer; is stabilized by cisplatin via interactions between cisplatin and the methionine-rich clusters, and could be crucial for the copper(2+) reduction process and copper(1+) stabilization. Heterotrimer between SLC31A1, CCS and SOD1; this heterotrimer is copper(1+)-mediated and its maintenance is regulated through SOD1 activation. Interacts with KDR; this interaction is induced upon VEGFA stimulation leading to SLC31A1 and KDR subsequent co-internalization to early endosomes, thereby activating KDR downstream signaling in endothelial cells. Interacts (via C-terminal domain) with ATOX1 (via dimer form); this interaction improves ATOX1 stability and controls intracellular copper(1+) levels. Interacts with SLC31A2; this interaction stabilizes SLC31A2 and protects its from ubiquitination and degradation. Interacts (via C-terminal domain) with CCS; this interaction is copper(1+)-mediated.

Subcellular location. Cell membrane. Early endosome membrane. Recycling endosome membrane. Apical cell membrane. Late endosome membrane. Basolateral cell membrane.

Post-translational modifications. O-Glycosylation at Thr-27 protects from proteolytic cleavage in the N-terminal extracellular domain. Proteolytic cleavage, leading to a truncated form, is facilitated by SLC31A2 and initiated preferentially by CTSL and to a minor extend by CTSB in endolysosomal compartments. In vitro, is cleaved by CTSL/cathepsin L between residues 8 and 9 from the amino terminus. A post-CTSL/cathepsin L processing occurs to yield to the fully truncated form. Sulfenylated at Cys-189 after stimulation with VEGFA, which induces SLC31A1-KDR disulfide bond formation and their co-internalization to early endosomes, driving to a sustained VEGFR2 signaling.

Disease relevance. Neurodegeneration and seizures due to copper transport defect (NSCT) [MIM:620306] An autosomal recessive disorder of copper metabolism characterized by global developmental delay, seizures, cortical and cerebellar atrophy, and axial hypotonia. Death in infancy may occur. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. Copper(1+) transport is stimulated by extracellular acidic pH and high potassium ions concentrations. Copper(1+) import is regulated by a copper(1+)-dependent recycling of SLC31A1.

Domain organisation. The C-terminal domain mediates copper(1+) binding and is involved in the copper(1+)-dependent-ATOX1 interaction. The C-terminal domain appears to act to limit transport through the pore by regulating the rate of exit of copper ions at the intracellular side. The N-terminal domain can collect copper(2+) from copper(2+) carriers in blood. The N-terminal domain, in the trimeric arrangement, tunes its reactivity with copper, promoting copper(2+) reduction and copper(1+) stabilization thanks to the presence of histidine (His) and methionine (Met) motifs (PubMed:32914794, Ref.24). The bis-His motif directly coordinate to copper(2+), whereas the Mets motif is involved in copper(1+) binding (Ref.24). The ligand switching between the bis-His motif and the Mets motif is regulated by pH.

Similarity. Belongs to the copper transporter (Ctr) (TC 1.A.56) family. SLC31A subfamily.

RefSeq proteins (1): NP_001850* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007274	Cop_transporter	Family

Pfam: PF04145

Enzyme classification (BRENDA):

• EC 7.2.2.8 — P-type Cu+ transporter (BRENDA: 25 organisms, 32 substrates, 20 inhibitors, 14 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.11–0.5	5
CU+[SIDE 1]	0.0019–0.19	3
CU+	0.0004–0.0015	2
4-NITROPHENYL PHOSPHATE	9	1

Catalyzed reactions (Rhea), 2 shown:

• Ag(+)(out) = Ag(+)(in) (RHEA:75207)
• Cu(+)(out) = Cu(+)(in) (RHEA:75211)

UniProt features (51 total): mutagenesis site 22, topological domain 4, helix 4, sequence variant 3, transmembrane region 3, chain 2, short sequence motif 2, modified residue 2, glycosylation site 2, compositionally biased region 1, site 1, disulfide bond 1, sequence conflict 1, turn 1, strand 1, region of interest 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2LS2	SOLUTION NMR
2LS3	SOLUTION NMR
2LS4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15431-F1	70.54	0.21

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 42–43 (cleavage)

Post-translational modifications (2): 114, 189

Disulfide bonds (1): 189

Glycosylation sites (2): 15, 27

Mutagenesis-validated functional residues (22):

Position	Phenotype
3	decreases affinity towards copper(1+).
5	affects copper(2+) binding. increases the efficiency of the reduction.
6	increases the efficiency of the reduction.
7–12	affects homotrimer formation; when associated with 40-a–a-45. does not affect localization at the plasma membrane; when
40–45	affects homotrimer formation; when associated with 7-a–a-12. does not affect localization at the plasma membrane; when
139	decreases of about 40% the copper(1+) transport activity.
139	dramatically decreases copper(1+) affinity. reduces copper(1+) uptake; when associated with l-150 and l-154. does not af
150	reduces of about 30% the copper(1+) transport activity; when associated with i-154. does not affect copper(1+) affinity;
150	reduces copper(1+) uptake; when associated with l-154. reduces copper(1+) uptake; when associated with l-154 and r-139.
154	inhibits copper(1+)-induced mapk activation. loss of copper(1+)-induced endothelil cell (ec) migration and capillary for
154	reduces of about 30% the copper(1+) transport activity; when associated with i-150. does not affect copper(1+) affinity;
154	reduces copper(1+) uptake; when associated with l-150. reduces copper(1+) uptake; when associated with l-150 and r-139.
156	dramatically affects copper(1+) transport activity.
161	markedly decreases the copper(1+) transport activity; when associated with s-189.
179–190	does not affect expression. does not affect cell membrane localization. significantly reduces copper(1+) transport activ
180–190	increases copper(1+) uptake. reduces affinity for copper(1+).
184–190	increases copper(1+) uptake.
185–190	does not affect expression. does not affect cell membrane localization. moderately affects copper(1+) transport activity
188–190	increases copper(1+) uptake. reduces affinity for copper(1+). reduces copper(1+) uptake; when associated with l-150 and
188–190	decreases of 45-fold copper(1+) affinity.
189	does not affect copper(1+)-induced mapk activation. does not affect copper(1+)-induced endothelial cells migration and c
189	markedly decreases the copper(1+) transport activity; when associated with s-161.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-425410	Metal ion SLC transporters

MSigDB gene sets: 388 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, SHEPARD_BMYB_MORPHOLINO_UP, MULLIGHAN_NPM1_SIGNATURE_3_UP, ACTACCT_MIR196A_MIR196B, GOBP_TRANSITION_METAL_ION_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, CREBP1_Q2, TGACCTY_ERR1_Q2, ATGCAGT_MIR217, IIZUKA_LIVER_CANCER_PROGRESSION_L1_G1_UP, GOBP_COPPER_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (12): angiogenesis (GO:0001525), copper ion transport (GO:0006825), intracellular copper ion homeostasis (GO:0006878), copper ion import (GO:0015677), plasma membrane copper ion transport (GO:0015679), vascular endothelial growth factor receptor-2 signaling pathway (GO:0036324), xenobiotic transport (GO:0042908), protein complex oligomerization (GO:0051259), establishment of localization in cell (GO:0051649), silver ion transmembrane transport (GO:1902601), monoatomic ion transport (GO:0006811), copper ion transmembrane transport (GO:0035434)

GO Molecular Function (6): copper ion transmembrane transporter activity (GO:0005375), copper ion binding (GO:0005507), silver ion transmembrane transporter activity (GO:0015080), identical protein binding (GO:0042802), xenobiotic transmembrane transporter activity (GO:0042910), protein binding (GO:0005515)

GO Cellular Component (11): plasma membrane (GO:0005886), intercalated disc (GO:0014704), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), recycling endosome membrane (GO:0055038), endosome (GO:0005768), late endosome (GO:0005770), membrane (GO:0016020), recycling endosome (GO:0055037)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
SLC-mediated transmembrane transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endosome membrane	3
copper ion transport	2
copper ion transmembrane transport	2
transport	2
monoatomic cation transmembrane transport	2
transition metal ion transmembrane transporter activity	2
plasma membrane region	2
endosome	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
transition metal ion transport	1
intracellular monoatomic cation homeostasis	1
copper ion homeostasis	1
vascular endothelial growth factor receptor signaling pathway	1
protein-containing complex assembly	1
establishment of localization	1
cellular localization	1
silver ion transport	1
transition metal ion binding	1
silver ion transmembrane transport	1
protein binding	1
transmembrane transporter activity	1
xenobiotic transport	1
binding	1
membrane	1
cell periphery	1
cell-cell contact zone	1
basal plasma membrane	1
apical part of cell	1
early endosome	1
late endosome	1
recycling endosome	1
endomembrane system	1
cytoplasmic vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1166 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC31A1	ATP7B	P35670	938
SLC31A1	ATP7A	Q04656	934
SLC31A1	ATOX1	O00244	883
SLC31A1	COX17	Q14061	770
SLC31A1	CCS	O14618	732
SLC31A1	SLC22A2	O15244	706
SLC31A1	SLC11A2	P49281	664
SLC31A1	SLC22A1	O15245	631
SLC31A1	CP	P00450	602
SLC31A1	SLC30A1	Q9Y6M5	573
SLC31A1	COX11	Q9Y6N1	555
SLC31A1	H3BSS0	H3BSS0	547
SLC31A1	SLC47A1	Q96FL8	514
SLC31A1	SOD1	P00441	513
SLC31A1	SLC28A3	Q9HAS3	504

IntAct

32 interactions, top by confidence:

A	B	Type	Score
SLC31A1	SLC31A1	psi-mi:“MI:0407”(direct interaction)	0.750
STX7	SNAP23	psi-mi:“MI:0914”(association)	0.640
NCR3LG1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
PLXDC2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ERBB3	SLC31A1	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC31A1	PRORP	psi-mi:“MI:0914”(association)	0.530
CD70	GXYLT2	psi-mi:“MI:0914”(association)	0.350
LGALS8	SLC22A23	psi-mi:“MI:0914”(association)	0.350
STX7	TYW5	psi-mi:“MI:0914”(association)	0.350
TMPRSS11B		psi-mi:“MI:0914”(association)	0.350
CD81	STX3	psi-mi:“MI:0914”(association)	0.350
CD81	PVR	psi-mi:“MI:0914”(association)	0.350
M	TM9SF1	psi-mi:“MI:0914”(association)	0.350
SLC31A1	LAMTOR5	psi-mi:“MI:0914”(association)	0.350
TMPRSS11B	ADAM10	psi-mi:“MI:0914”(association)	0.350
TM4SF5	PLSCR1	psi-mi:“MI:0914”(association)	0.350
SLC5A6	SLC31A1	psi-mi:“MI:0914”(association)	0.350
SLC31A2	SLC31A1	psi-mi:“MI:0914”(association)	0.350

BioGRID (301): SLC31A1 (Affinity Capture-RNA), SLC31A1 (Affinity Capture-RNA), SLC31A1 (Affinity Capture-MS), SLC31A1 (Affinity Capture-MS), SLC31A1 (Affinity Capture-MS), SLC31A1 (Affinity Capture-MS), SLC31A1 (Affinity Capture-MS), SLC31A1 (Affinity Capture-MS), SLC31A1 (Affinity Capture-MS), SLC31A1 (Affinity Capture-MS), SLC31A1 (Affinity Capture-MS), SLC31A1 (Affinity Capture-MS), SLC31A1 (Affinity Capture-RNA), SLC31A1 (Affinity Capture-RNA), SLC31A1 (Two-hybrid)

ESM2 similar proteins: A0JNC1, A2VE61, A6QL84, A7YY49, B2RZ37, O15260, O15431, O57590, O95674, P31064, Q00765, Q06400, Q0VCK9, Q0X0A5, Q3KNM2, Q3T126, Q3ZC24, Q5M7T4, Q5R705, Q5R7B1, Q5R9I4, Q5R9M4, Q5RBJ7, Q5RE33, Q5ZJ41, Q5ZKJ0, Q64310, Q6DD32, Q6GM44, Q6P360, Q6P3N5, Q7SZQ7, Q800K9, Q8BG21, Q8C407, Q8R1Z9, Q91ZQ0, Q940S0, Q96GC9, Q96KA5

Diamond homologs: O15431, O15432, P38865, Q4WHY8, Q4WX45, Q5RAS6, Q8K211, Q8WNR0, Q9CPU9, Q9JK41, Q9STG2, Q7XTF8, Q60EN8, Q9USV7, Q7YXD4, Q10KT6, Q39065, Q5ZD08, Q69P80, Q8GWP3, Q8SAA5, Q93VM8, Q94EE4, Q9FGU8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

28 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	18
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2446405	NM_001859.4(SLC31A1):c.284G>A (p.Arg95His)	Pathogenic
1722767	NM_001859.4(SLC31A1):c.236T>C (p.Leu79Pro)	Likely pathogenic

SpliceAI

1010 predictions. Top by Δscore:

Variant	Effect	Δscore
9:113221679:G:GA	donor_loss	1.0000
9:113243543:A:G	donor_gain	1.0000
9:113256274:GATG:G	donor_gain	1.0000
9:113257107:T:A	acceptor_gain	1.0000
9:113257111:A:AG	acceptor_gain	1.0000
9:113257112:G:GG	acceptor_gain	1.0000
9:113257112:GC:G	acceptor_gain	1.0000
9:113257112:GCC:G	acceptor_gain	1.0000
9:113257112:GCCT:G	acceptor_gain	1.0000
9:113257112:GCCTA:G	acceptor_gain	1.0000
9:113257184:AGGT:A	donor_loss	1.0000
9:113257185:GGTG:G	donor_loss	1.0000
9:113257187:TGAG:T	donor_loss	1.0000
9:113258687:T:G	acceptor_gain	1.0000
9:113221679:G:GG	donor_gain	0.9900
9:113243540:GAGA:G	donor_gain	0.9900
9:113255388:T:G	donor_gain	0.9900
9:113255388:T:TG	donor_gain	0.9900
9:113256109:A:AG	acceptor_gain	0.9900
9:113256111:A:AG	acceptor_gain	0.9900
9:113256112:A:G	acceptor_gain	0.9900
9:113256113:G:GG	acceptor_gain	0.9900
9:113256113:GA:G	acceptor_gain	0.9900
9:113256141:T:A	acceptor_gain	0.9900
9:113256276:TGG:T	donor_loss	0.9900
9:113256277:GGTGA:G	donor_loss	0.9900
9:113256279:TGAGT:T	donor_loss	0.9900
9:113256280:GAGT:G	donor_loss	0.9900
9:113257099:T:TA	acceptor_gain	0.9900
9:113257108:G:A	acceptor_gain	0.9900

AlphaMissense

1276 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:113258752:G:C	K87N	1.000
9:113258752:G:T	K87N	1.000
9:113260336:A:C	S146R	1.000
9:113260338:C:A	S146R	1.000
9:113260338:C:G	S146R	1.000
9:113260349:T:C	M150T	1.000
9:113260350:G:A	M150I	1.000
9:113260350:G:C	M150I	1.000
9:113260350:G:T	M150I	1.000
9:113260352:T:C	L151P	1.000
9:113260362:G:A	M154I	1.000
9:113260362:G:C	M154I	1.000
9:113260362:G:T	M154I	1.000
9:113260381:T:C	C161R	1.000
9:113260399:G:A	G167R	1.000
9:113260399:G:C	G167R	1.000
9:113260399:G:T	G167W	1.000
9:113260400:G:A	G167E	1.000
9:113260406:G:A	G169D	1.000
9:113260411:G:A	G171R	1.000
9:113260411:G:C	G171R	1.000
9:113260412:G:A	G171E	1.000
9:113258730:C:A	A80E	0.999
9:113258741:G:A	E84K	0.999
9:113258742:A:C	E84A	0.999
9:113258742:A:T	E84V	0.999
9:113258743:A:C	E84D	0.999
9:113258743:A:T	E84D	0.999
9:113258744:G:A	G85R	0.999
9:113258744:G:C	G85R	0.999

dbSNP variants (sampled 300 via entrez): RS1000035617 (9:113245673 C>G), RS1000200372 (9:113227262 T>C), RS1000299158 (9:113252324 C>T), RS1000414234 (9:113226939 T>C), RS1000534020 (9:113253573 G>T), RS1000582404 (9:113240701 G>A), RS1000612369 (9:113256179 T>A), RS1000653056 (9:113233972 A>G), RS1000711201 (9:113246765 T>C), RS1000954565 (9:113263799 T>C), RS1001184584 (9:113246988 G>A), RS1001270622 (9:113250542 G>A,C,T), RS1001321626 (9:113230450 G>A), RS1001325683 (9:113243825 T>C), RS1001397335 (9:113257615 A>G)

Disease associations

OMIM: gene MIM:603085 | disease phenotypes: MIM:620306

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration and seizures due to copper transport defect	Moderate	Autosomal recessive

Mondo (1): neurodegeneration and seizures due to copper transport defect (MONDO:0957211)

Orphanet (0):

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000474	Thickened nuchal skin fold
HP:0000807	Glanular hypospadias
HP:0001250	Seizure
HP:0001254	Lethargy
HP:0001272	Cerebellar atrophy
HP:0001347	Hyperreflexia
HP:0001640	Cardiomegaly
HP:0001762	Talipes equinovarus
HP:0002059	Cerebral atrophy
HP:0002089	Pulmonary hypoplasia
HP:0002098	Respiratory distress
HP:0002107	Pneumothorax
HP:0002119	Ventriculomegaly
HP:0002151	Increased circulating lactate concentration
HP:0002280	Enlarged cisterna magna
HP:0002384	Focal impaired awareness seizure
HP:0002490	Increased CSF lactate
HP:0002509	Limb hypertonia
HP:0003097	Short femur
HP:0003593	Infantile onset
HP:0005180	Tricuspid regurgitation
HP:0005736	Short tibia
HP:0005968	Temperature instability
HP:0008936	Axial hypotonia
HP:0010836	Abnormal circulating copper concentration
HP:0030674	Antenatal onset
HP:0032988	Persistent head lag
HP:0032989	Delayed ability to roll over
HP:0033144	Abnormal circulating ceruloplasmin concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001813_3	Hematology traits	8.000000e-06
GCST90002394_329	Monocyte percentage of white cells	5.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005128	albumin:globulin ratio measurement
EFO:0007989	monocyte percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724591 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

7 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10759637	Efficacy	3	Platinum compounds	Overall survival;Thrombocytopenia
rs10817464	Toxicity	3	Platinum compounds	Anemia;Leukopenia;Nausea;Neutropenia;Thrombocytopenia;Vomiting
rs10981694	Toxicity	3	cisplatin	Non-Small Cell Lung Carcinoma
rs2233914	Efficacy,Toxicity	3	Platinum compounds	Drug Toxicity;Overall survival
rs4978536	Toxicity	3	Platinum compounds	Thrombocytopenia
rs4979223	Efficacy,Toxicity	3	Platinum compounds	Overall survival;Thrombocytopenia
rs7851395	Efficacy	3	carboplatin;cisplatin	Non-Small Cell Lung Carcinoma

PharmGKB variants

9 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7851395	SLC31A1	3	2.25	1	carboplatin;cisplatin
rs10981694	FKBP15, SLC31A1	3	0.50	1	cisplatin
rs4979223	FKBP15, SLC31A1	3	5.75	1	Platinum compounds
rs4978536	FKBP15, SLC31A1	3	2.50	1	Platinum compounds
rs10817464	SLC31A1	3	1.75	1	Platinum compounds
rs10759637	SLC31A1	3	2.75	1	Platinum compounds
rs2233914	FKBP15, SLC31A1	3	5.50	1	Platinum compounds
rs10817465	SLC31A1		0.00	0
rs10513202	SLC31A1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC31 family of copper transporters

CTD chemical–gene interactions

82 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Copper	decreases abundance, affects expression, affects uptake, decreases response to substance, decreases reaction (+14 more)	32
Cisplatin	decreases import, decreases reaction, increases import, increases response to substance, affects uptake (+11 more)	21
Copper Sulfate	decreases reaction, increases expression, increases import, affects binding, decreases expression	4
tetrathiomolybdate	increases response to substance, affects binding, increases reaction, decreases expression, increases expression (+1 more)	3
Oxaliplatin	increases response to substance, increases uptake, decreases response to substance, increases expression, affects response to substance	3
Benzo(a)pyrene	decreases expression, decreases methylation	3
Platinum	affects response to substance, increases reaction, decreases degradation, increases uptake	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
sodium arsenite	increases abundance, increases expression	2
cobaltous chloride	increases expression, decreases expression, decreases reaction	2
cupric chloride	increases response to substance, decreases expression, increases abundance	2
epigallocatechin gallate	increases expression, decreases reaction, increases degradation, affects localization	2
Bortezomib	decreases reaction, increases uptake, decreases degradation, decreases expression	2
Paraquat	increases expression, decreases response to substance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Trientine	increases reaction, increases uptake, increases expression, decreases response to substance, increases response to substance	2
Carboplatin	increases expression, increases response to substance, increases uptake	2
Genistein	increases expression	2
GSK-J4	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
trichostatin A	affects expression	1
o,p’-DDT	increases expression	1
cadmium acetate	decreases expression	1
bathocuproine sulfonate	increases expression, increases reaction, decreases abundance	1
cupric oxide	increases expression	1
cisplatin-DNA adduct	affects abundance, affects uptake	1
di-n-butylphosphoric acid	affects expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5723785	Binding	RLU of HCTR1 at 1.0 µM in the Aequorin PRESTO-Tango GPCRome screen	Data for DCP probe T-10430

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D4LM	HCT116-SLC31A1-KO-c12	Cancer cell line	Male
CVCL_D4LN	HCT116-SLC31A1-KO-c35	Cancer cell line	Male
CVCL_TM97	HAP1 SLC31A1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.