SLC39A4
Domain
The N-terminal extracellular domain is required for high efficient zinc transport.
The two metal binding sites M1 and M2 that are halfway through the membrane form a binuclear metal center. M1 is essential to Zn(2+) transport, while the other, M2 appears to have an auxiliary role presumably by acting as an additional transport site that can modulate the properties of the primary transport site (PubMed:28875161, PubMed:31914589). The binuclear metal center plays a key role in Zn(2+) sensing (PubMed:32348750).
Function
Selective transporter that mediates the uptake of Zn(2+) (PubMed:17202136, PubMed:22242765, PubMed:27321477, PubMed:28875161, PubMed:31164399, PubMed:31914589, PubMed:31979155, PubMed:33837739, PubMed:36473915). Plays an essential role for dietary zinc uptake from small intestine (By similarity). The Zn(2+) uniporter activity is regulated by zinc availability (PubMed:17202136, PubMed:32348750). Exhibits also polyspecific binding and transport of Cu(2+), Cd(2+) and possibly Ni(2+) but at higher concentrations (PubMed:22242765, PubMed:31914589).
Involvement in disease
Acrodermatitis enteropathica, zinc-deficiency type
AEZ
A rare autosomal recessive disease caused by the inability to absorb sufficient zinc. The clinical features are growth retardation, immune-system dysfunction, alopecia, severe dermatitis, diarrhea and occasionally mental disorders.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
The extracellular N-terminal ectodomain is cleaved when cells are Zn(2+) deficient, N-terminally cleaved SLC39A4 is internalized at a faster rate.
Under excess Zn(2+) conditions, SLC39A4 on the cell surface is rapidly endocytosed, ubiquitinated and degraded.
Glycosylated.
Sequence Similarities
Belongs to the ZIP transporter (TC 2.A.5) family.
Tissue Specificity
Highly expressed in kidney, small intestine, stomach, colon, jejunum and duodenum.
Cellular localization
- Cell membrane
- Multi-pass membrane protein
- Recycling endosome membrane
- Multi-pass membrane protein
- Apical cell membrane
- Multi-pass membrane protein
- Colocalized with TFRC in the recycling endosomes. Cycles between endosomal compartments and the plasma membrane in response to Zn(2+) availability. Zn(2+) deficiency promotes accumulation of SLC39A4 on the surface membrane, whereas high extracellular Zn(2+) levels induce internalization of SLC39A4, but also trigger drastic removal of cellular SLC39A4 via proteasomal and lysosomal degradation pathways.
Alternative names
ZIP4, SLC39A4, Zinc transporter ZIP4, Solute carrier family 39 member 4, Zrt- and Irt-like protein 4, ZIP-4