SLC31A1
Domain
The C-terminal domain mediates copper(1+) binding (PubMed:26745413) and is involved in the copper(1+)-dependent-ATOX1 interaction (PubMed:24837030, PubMed:26745413). 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 (PubMed:23658018). The N-terminal domain can collect copper(2+) from copper(2+) carriers in blood (PubMed:30489586). 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 (PubMed:35601835).
Function
High affinity copper uptake protein 1
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).
Truncated CTR1 form
Mobilizes copper(1+) out of the endosomal compartment, making copper(1+) available for export out of the cells.
Involvement in disease
Neurodegeneration and seizures due to copper transport defect
NSCT
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.
None
The disease may be caused by variants affecting the gene represented in this entry.
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 (PubMed:24167251) and initiated preferentially by CTSL and to a minor extend by CTSB in endolysosomal compartments (PubMed:24167251, PubMed:27143361). In vitro, is cleaved by CTSL/cathepsin L between residues 8 and 9 from the amino terminus (PubMed:27143361). A post-CTSL/cathepsin L processing occurs to yield to the fully truncated form (PubMed:27143361).
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.
Sequence Similarities
Belongs to the copper transporter (Ctr) (TC 1.A.56) family. SLC31A subfamily.
Cellular localization
- Cell membrane
- Multi-pass membrane protein
- Early endosome membrane
- Multi-pass membrane protein
- Recycling endosome membrane
- Multi-pass membrane protein
- Apical cell membrane
- Multi-pass membrane protein
- Late endosome membrane
- Multi-pass membrane protein
- Basolateral cell membrane
- Multi-pass membrane protein
- The localization is controlled by the intra and extra-cellular copper concentration (PubMed:15326162, PubMed:19740744, PubMed:23658018, PubMed:26205368, PubMed:26945057). Under conditions of elevated extracellular copper concentrations, it is rapidly internalized by endocytosis from the plasma membrane by a clathrin- and dynamin-mediated process and degradated in order to prevent intracellular copper accumulation and to reduce the transport of the copper across the membrane (PubMed:15326162, PubMed:19740744, PubMed:23658018, PubMed:26205368, PubMed:26945057). The internalized SLC31A1 is then localized in early endosomes, and, upon a low extracellular copper concentrations, it is transported back to the plasma membrane in a RAB11A-dependent recycling pathway (PubMed:26945057). Localizes to the apical membrane in intestinal epithelial cells (By similarity). Mainly localized on the basolateral side of renal tubular cells (By similarity). Localizes to the neuronal cell body plasma membranes (By similarity).
Alternative names
COPT1, CTR1, SLC31A1, High affinity copper uptake protein 1, Copper transporter 1, Solute carrier family 31 member 1, hCTR1