ID S39A4_HUMAN Reviewed; 647 AA. AC Q6P5W5; Q7L5S5; Q9H6T8; Q9NXC4; DT 25-OCT-2005, integrated into UniProtKB/Swiss-Prot. DT 12-APR-2017, sequence version 4. DT 27-MAR-2024, entry version 162. DE RecName: Full=Zinc transporter ZIP4; DE AltName: Full=Solute carrier family 39 member 4; DE AltName: Full=Zrt- and Irt-like protein 4; DE Short=ZIP-4; DE Flags: Precursor; GN Name=SLC39A4 {ECO:0000312|HGNC:HGNC:17129}; Synonyms=ZIP4; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, AND RP VARIANTS AEZ LEU-200; ARG-374 AND ARG-526. RX PubMed=12068297; DOI=10.1038/ng913; RA Kuery S., Dreno B., Bezieau S., Giraudet S., Kharfi M., Kamoun R., RA Moisan J.-P.; RT "Identification of SLC39A4, a gene involved in acrodermatitis RT enteropathica."; RL Nat. Genet. 31:239-240(2002). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), VARIANTS THR-58 RP AND THR-114, AND VARIANTS AEZ TYR-309 AND ALA-357. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT TRP-251. RX PubMed=16421571; DOI=10.1038/nature04406; RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., RA Platzer M., Shimizu N., Lander E.S.; RT "DNA sequence and analysis of human chromosome 8."; RL Nature 439:331-335(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS THR-58 AND RP THR-114. RC TISSUE=Lung, and Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP TISSUE SPECIFICITY, VARIANTS THR-58; LEU-84; THR-114 AND ALA-357, AND RP VARIANTS AEZ LYS-106; TRP-251; TYR-309; ASP-330; PRO-372; PRO-410 AND RP ARG-630. RX PubMed=12032886; DOI=10.1086/341125; RA Wang K., Zhou B., Kuo Y.-M., Zemansky J., Gitschier J.; RT "A novel member of a zinc transporter family is defective in acrodermatitis RT enteropathica."; RL Am. J. Hum. Genet. 71:66-73(2002). RN [6] RP SUBCELLULAR LOCATION. RX PubMed=14612438; DOI=10.1074/jbc.m310799200; RA Kim B.-E., Wang F., Dufner-Beattie J., Andrews G.K., Eide D.J., RA Petris M.J.; RT "Zn2+-stimulated endocytosis of the mZIP4 zinc transporter regulates its RT location at the plasma membrane."; RL J. Biol. Chem. 279:4523-4530(2004). RN [7] RP VARIANTS AEZ CYS-95 AND HIS-303. RX PubMed=12787121; DOI=10.1046/j.1523-1747.2003.12243.x; RA Nakano A., Nakano H., Nomura K., Toyomaki Y., Hanada K.; RT "Novel SLC39A4 mutations in acrodermatitis enteropathica."; RL J. Invest. Dermatol. 120:963-966(2003). RN [8] RP FUNCTION, TRANSPORTER ACTIVITY, UBIQUITINATION, AND GLYCOSYLATION. RX PubMed=17202136; DOI=10.1074/jbc.m610552200; RA Mao X., Kim B.E., Wang F., Eide D.J., Petris M.J.; RT "A histidine-rich cluster mediates the ubiquitination and degradation of RT the human zinc transporter, hZIP4, and protects against zinc RT cytotoxicity."; RL J. Biol. Chem. 282:6992-7000(2007). RN [9] RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND RP SUBSTRATE SPECIFICITY. RX PubMed=22242765; DOI=10.1021/bi201553p; RA Antala S., Dempski R.E.; RT "The human ZIP4 transporter has two distinct binding affinities and RT mediates transport of multiple transition metals."; RL Biochemistry 51:963-973(2012). RN [10] RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, DOMAIN, RP MUTAGENESIS OF PRO-202; TRP-266; ASP-275 AND GLN-303, AND GLYCOSYLATION. RX PubMed=27321477; DOI=10.1038/ncomms11979; RA Zhang T., Sui D., Hu J.; RT "Structural insights of ZIP4 extracellular domain critical for optimal zinc RT transport."; RL Nat. Commun. 7:11979-11979(2016). RN [11] RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND RP MUTAGENESIS OF ASP-375; HIS-379; HIS-507; ASN-508; ASP-511; HIS-536; RP GLU-537 AND HIS-540. RX PubMed=28875161; DOI=10.1126/sciadv.1700344; RA Zhang T., Liu J., Fellner M., Zhang C., Sui D., Hu J.; RT "Crystal structures of a ZIP zinc transporter reveal a binuclear metal RT center in the transport pathway."; RL Sci. Adv. 3:e1700344-e1700344(2017). RN [12] RP SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=30874431; DOI=10.1021/acs.biochem.9b00131; RA Ahern M.E., Bafaro E.M., Cowan A., Dempski R.E.; RT "Quantifying the Oligomeric State of hZIP4 on the Surface of Cells."; RL Biochemistry 58:1705-1708(2019). RN [13] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, ZINC-BINDING, RP BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF HIS-238; HIS-241; HIS-243 RP AND HIS-245. RX PubMed=31164399; DOI=10.1042/bcj20190108; RA Zhang T., Kuliyev E., Sui D., Hu J.; RT "The histidine-rich loop in the extracellular domain of ZIP4 binds zinc and RT plays a role in zinc transport."; RL Biochem. J. 476:1791-1803(2019). RN [14] RP FUNCTION, TRANSPORTER ACTIVITY, SUBSTRATE SPECIFICITY, AND MUTAGENESIS OF RP HIS-507; ASN-508; HIS-536; GLU-537 AND HIS-540. RX PubMed=31914589; DOI=10.1096/fj.201902043r; RA Zhang T., Sui D., Zhang C., Cole L., Hu J.; RT "Asymmetric functions of a binuclear metal center within the transport RT pathway of a human zinc transporter ZIP4."; RL FASEB J. 34:237-247(2020). RN [15] RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF HIS-388; HIS-390; RP 452-LEU--LEU-454; LEU-452; GLN-453; LEU-454; LYS-463; LEU-481; LEU-482; RP ASP-511; HIS-540 AND LYS-611. RX PubMed=32348750; DOI=10.1016/j.celrep.2020.107582; RA Zhang C., Sui D., Zhang T., Hu J.; RT "Molecular Basis of Zinc-Dependent Endocytosis of Human ZIP4 Transceptor."; RL Cell Rep. 31:107582-107582(2020). RN [16] RP FUNCTION, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=31979155; DOI=10.3390/ijms21030734; RA Hoch E., Levy M., Hershfinkel M., Sekler I.; RT "Elucidating the H+ Coupled Zn2+ Transport Mechanism of ZIP4; Implications RT in Acrodermatitis Enteropathica."; RL Int. J. Mol. Sci. 21:0-0(2020). RN [17] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, MUTAGENESIS OF RP CYS-62; ALA-99 AND ASN-261, CHARACTERIZATION OF VARIANTS AEZ ARG-95; RP ASN-106; PRO-200; GLN-303 AND CYS-309, AND GLYCOSYLATION AT ASN-261. RX PubMed=33837739; DOI=10.1016/j.jbc.2021.100269; RA Kuliyev E., Zhang C., Sui D., Hu J.; RT "Zinc transporter mutations linked to acrodermatitis enteropathica disrupt RT function and cause mistrafficking."; RL J. Biol. Chem. 296:100269-100269(2021). RN [18] RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND RP SUBCELLULAR LOCATION. RX PubMed=36473915; DOI=10.1038/s41598-022-24782-6; RA Liu Y., Bafaro E.M., Cowan A.E., Dempski R.E.; RT "The transmembrane domains mediate oligomerization of the human ZIP4 RT transporter in vivo."; RL Sci. Rep. 12:21083-21083(2022). CC -!- FUNCTION: Selective transporter that mediates the uptake of Zn(2+) CC (PubMed:17202136, PubMed:22242765, PubMed:27321477, PubMed:28875161, CC PubMed:31164399, PubMed:31914589, PubMed:31979155, PubMed:33837739, CC PubMed:36473915). Plays an essential role for dietary zinc uptake from CC small intestine (By similarity). The Zn(2+) uniporter activity is CC regulated by zinc availability (PubMed:32348750, PubMed:17202136). CC Exhibits also polyspecific binding and transport of Cu(2+), Cd(2+) and CC possibly Ni(2+) but at higher concentrations (PubMed:22242765, CC PubMed:31914589). {ECO:0000250|UniProtKB:Q78IQ7, CC ECO:0000269|PubMed:17202136, ECO:0000269|PubMed:22242765, CC ECO:0000269|PubMed:27321477, ECO:0000269|PubMed:28875161, CC ECO:0000269|PubMed:31164399, ECO:0000269|PubMed:31914589, CC ECO:0000269|PubMed:31979155, ECO:0000269|PubMed:32348750, CC ECO:0000269|PubMed:33837739, ECO:0000269|PubMed:36473915}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Zn(2+)(in) = Zn(2+)(out); Xref=Rhea:RHEA:29351, CC ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:17202136, CC ECO:0000269|PubMed:22242765, ECO:0000269|PubMed:27321477, CC ECO:0000269|PubMed:28875161, ECO:0000269|PubMed:31164399, CC ECO:0000269|PubMed:31914589, ECO:0000269|PubMed:31979155, CC ECO:0000269|PubMed:33837739, ECO:0000269|PubMed:36473915}; CC -!- ACTIVITY REGULATION: The Zn(2+) uniporter activity is regulated by zinc CC availability (PubMed:32348750, PubMed:17202136). Extracellular CC acidification stimulated SLC39A4-dependent Zn(2+) uptake CC (PubMed:31979155). {ECO:0000269|PubMed:17202136, CC ECO:0000269|PubMed:31979155, ECO:0000269|PubMed:32348750}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.9 uM for Zn(2+) {ECO:0000269|PubMed:28875161}; CC KM=2.2 uM for Zn(2+) {ECO:0000269|PubMed:27321477}; CC KM=3.14 uM for Zn(2+) {ECO:0000269|PubMed:36473915}; CC KM=2.5 uM for Zn(2+) {ECO:0000269|PubMed:31914589}; CC KM=1.1 nM for Ni(2+) {ECO:0000269|PubMed:22242765}; CC pH dependence: CC Optimum pH is 5. {ECO:0000269|PubMed:31979155}; CC -!- SUBUNIT: Homodimer; homodimerization is mediated by the transmembrane CC domain. {ECO:0000269|PubMed:30874431, ECO:0000269|PubMed:36473915}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14612438, CC ECO:0000269|PubMed:17202136, ECO:0000269|PubMed:30874431, CC ECO:0000269|PubMed:31164399, ECO:0000269|PubMed:32348750, CC ECO:0000269|PubMed:36473915}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:A0A0H3LM39}. Recycling endosome membrane CC {ECO:0000269|PubMed:14612438}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:A0A0H3LM39}. Apical cell membrane CC {ECO:0000250|UniProtKB:Q78IQ7}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:A0A0H3LM39}. Note=Colocalized with TFRC in the CC recycling endosomes. Cycles between endosomal compartments and the CC plasma membrane in response to Zn(2+) availability. Zn(2+) deficiency CC promotes accumulation of SLC39A4 on the surface membrane, whereas high CC extracellular Zn(2+) levels induce internalization of SLC39A4, but also CC trigger drastic removal of cellular SLC39A4 via proteasomal and CC lysosomal degradation pathways. {ECO:0000250|UniProtKB:Q78IQ7, CC ECO:0000269|PubMed:17202136, ECO:0000269|PubMed:32348750}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q6P5W5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q6P5W5-2; Sequence=VSP_015911, VSP_015912; CC -!- TISSUE SPECIFICITY: Highly expressed in kidney, small intestine, CC stomach, colon, jejunum and duodenum. {ECO:0000269|PubMed:12032886, CC ECO:0000269|PubMed:12068297}. CC -!- DOMAIN: The N-terminal extracellular domain is required for high CC efficient zinc transport. {ECO:0000269|PubMed:27321477}. CC -!- DOMAIN: The two metal binding sites M1 and M2 that are halfway through CC the membrane form a binuclear metal center. M1 is essential to Zn(2+) CC transport, while the other, M2 appears to have an auxiliary role CC presumably by acting as an additional transport site that can modulate CC the properties of the primary transport site (PubMed:28875161, CC PubMed:31914589). The binuclear metal center plays a key role in Zn(2+) CC sensing (PubMed:32348750). {ECO:0000269|PubMed:28875161, CC ECO:0000269|PubMed:31914589, ECO:0000269|PubMed:32348750}. CC -!- PTM: The extracellular N-terminal ectodomain is cleaved when cells are CC Zn(2+) deficient, N-terminally cleaved SLC39A4 is internalized at a CC faster rate. {ECO:0000250|UniProtKB:Q78IQ7}. CC -!- PTM: Under excess Zn(2+) conditions, SLC39A4 on the cell surface is CC rapidly endocytosed, ubiquitinated and degraded. CC {ECO:0000269|PubMed:17202136}. CC -!- PTM: Glycosylated. {ECO:0000269|PubMed:17202136, CC ECO:0000269|PubMed:27321477, ECO:0000269|PubMed:33837739}. CC -!- DISEASE: Acrodermatitis enteropathica, zinc-deficiency type (AEZ) CC [MIM:201100]: A rare autosomal recessive disease caused by the CC inability to absorb sufficient zinc. The clinical features are growth CC retardation, immune-system dysfunction, alopecia, severe dermatitis, CC diarrhea and occasionally mental disorders. CC {ECO:0000269|PubMed:12032886, ECO:0000269|PubMed:12068297, CC ECO:0000269|PubMed:12787121, ECO:0000269|PubMed:14702039, CC ECO:0000269|PubMed:33837739}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the ZIP transporter (TC 2.A.5) family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA91091.1; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK000334; BAA91091.1; ALT_FRAME; mRNA. DR EMBL; AK025537; BAB15164.1; -; mRNA. DR EMBL; AF205589; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC001688; AAH01688.2; -; mRNA. DR EMBL; BC062625; AAH62625.1; -; mRNA. DR CCDS; CCDS43782.1; -. [Q6P5W5-2] DR CCDS; CCDS6424.1; -. [Q6P5W5-1] DR RefSeq; NP_060237.2; NM_017767.2. [Q6P5W5-2] DR RefSeq; NP_570901.2; NM_130849.3. [Q6P5W5-1] DR AlphaFoldDB; Q6P5W5; -. DR SMR; Q6P5W5; -. DR BioGRID; 120769; 184. DR IntAct; Q6P5W5; 69. DR MINT; Q6P5W5; -. DR STRING; 9606.ENSP00000301305; -. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR TCDB; 2.A.5.4.1; the zinc (zn(2+))-iron (fe(2+)) permease (zip) family. DR GlyCosmos; Q6P5W5; 1 site, No reported glycans. DR GlyGen; Q6P5W5; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q6P5W5; -. DR PhosphoSitePlus; Q6P5W5; -. DR BioMuta; SLC39A4; -. DR DMDM; 296452970; -. DR jPOST; Q6P5W5; -. DR MassIVE; Q6P5W5; -. DR PaxDb; 9606-ENSP00000301305; -. DR PeptideAtlas; Q6P5W5; -. DR ProteomicsDB; 67007; -. [Q6P5W5-1] DR ProteomicsDB; 67008; -. [Q6P5W5-2] DR Antibodypedia; 28508; 259 antibodies from 32 providers. DR DNASU; 55630; -. DR Ensembl; ENST00000276833.9; ENSP00000276833.5; ENSG00000147804.10. [Q6P5W5-2] DR Ensembl; ENST00000301305.8; ENSP00000301305.4; ENSG00000147804.10. [Q6P5W5-1] DR GeneID; 55630; -. DR KEGG; hsa:55630; -. DR MANE-Select; ENST00000301305.8; ENSP00000301305.4; NM_130849.4; NP_570901.3. DR UCSC; uc003zcq.4; human. [Q6P5W5-1] DR AGR; HGNC:17129; -. DR CTD; 55630; -. DR DisGeNET; 55630; -. DR GeneCards; SLC39A4; -. DR HGNC; HGNC:17129; SLC39A4. DR HPA; ENSG00000147804; Tissue enriched (intestine). DR MalaCards; SLC39A4; -. DR MIM; 201100; phenotype. DR MIM; 607059; gene. DR neXtProt; NX_Q6P5W5; -. DR OpenTargets; ENSG00000147804; -. DR Orphanet; 37; Acrodermatitis enteropathica. DR PharmGKB; PA38204; -. DR VEuPathDB; HostDB:ENSG00000147804; -. DR eggNOG; KOG2693; Eukaryota. DR GeneTree; ENSGT00940000160042; -. DR HOGENOM; CLU_015114_12_0_1; -. DR InParanoid; Q6P5W5; -. DR OMA; HRSHTHI; -. DR OrthoDB; 5488029at2759; -. DR PhylomeDB; Q6P5W5; -. DR TreeFam; TF318470; -. DR PathwayCommons; Q6P5W5; -. DR Reactome; R-HSA-442380; Zinc influx into cells by the SLC39 gene family. DR Reactome; R-HSA-5619088; Defective SLC39A4 causes acrodermatitis enteropathica, zinc-deficiency type (AEZ). DR SignaLink; Q6P5W5; -. DR BioGRID-ORCS; 55630; 20 hits in 1161 CRISPR screens. DR ChiTaRS; SLC39A4; human. DR GenomeRNAi; 55630; -. DR Pharos; Q6P5W5; Tbio. DR PRO; PR:Q6P5W5; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; Q6P5W5; Protein. DR Bgee; ENSG00000147804; Expressed in duodenum and 97 other cell types or tissues. DR ExpressionAtlas; Q6P5W5; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB. DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0055038; C:recycling endosome membrane; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB. DR GO; GO:0046872; F:metal ion binding; EXP:DisProt. DR GO; GO:0140410; F:monoatomic cation:bicarbonate symporter activity; IBA:GO_Central. DR GO; GO:0008270; F:zinc ion binding; IMP:DisProt. DR GO; GO:0106219; F:zinc ion sensor activity; IMP:UniProtKB. DR GO; GO:0140486; F:zinc ion sequestering activity; IMP:DisProt. DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0034224; P:cellular response to zinc ion starvation; IEA:Ensembl. DR GO; GO:0006882; P:intracellular zinc ion homeostasis; ISS:UniProtKB. DR GO; GO:0071578; P:zinc ion import across plasma membrane; IBA:GO_Central. DR GO; GO:0071577; P:zinc ion transmembrane transport; IDA:UniProtKB. DR DisProt; DP02554; -. DR InterPro; IPR003689; ZIP. DR InterPro; IPR049406; ZIP4_12_EF-hand. DR InterPro; IPR041137; ZIP4_N. DR PANTHER; PTHR12191; SOLUTE CARRIER FAMILY 39; 1. DR PANTHER; PTHR12191:SF21; ZINC TRANSPORTER ZIP4; 1. DR Pfam; PF21116; EF-hand_Zip; 1. DR Pfam; PF02535; Zip; 1. DR Pfam; PF18292; ZIP4_domain; 1. DR Genevisible; Q6P5W5; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cadmium; Cell membrane; Disease variant; KW Disulfide bond; Endosome; Glycoprotein; Ion transport; Membrane; KW Metal-binding; Reference proteome; Signal; Transmembrane; KW Transmembrane helix; Transport; Ubl conjugation; Zinc; Zinc transport. FT SIGNAL 1..22 FT /evidence="ECO:0000255" FT CHAIN 23..647 FT /note="Zinc transporter ZIP4" FT /id="PRO_0000042620" FT TOPO_DOM 23..327 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 328..348 FT /note="Helical; Name=1" FT /evidence="ECO:0000250|UniProtKB:A0A0H3LM39" FT TOPO_DOM 349..359 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 360..380 FT /note="Helical; Name=2" FT /evidence="ECO:0000250|UniProtKB:A0A0H3LM39" FT TOPO_DOM 381..402 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 403..423 FT /note="Helical; Name=3" FT /evidence="ECO:0000250|UniProtKB:A0A0H3LM39" FT TOPO_DOM 424..498 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 499..518 FT /note="Helical; Name=4" FT /evidence="ECO:0000250|UniProtKB:A0A0H3LM39" FT TOPO_DOM 519..526 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 527..553 FT /note="Helical; Name=5" FT /evidence="ECO:0000250|UniProtKB:A0A0H3LM39" FT TOPO_DOM 554..558 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 559..579 FT /note="Helical; Name=6" FT /evidence="ECO:0000250|UniProtKB:A0A0H3LM39" FT TOPO_DOM 580..586 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 587..607 FT /note="Helical; Name=7" FT /evidence="ECO:0000250|UniProtKB:A0A0H3LM39" FT TOPO_DOM 608..617 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 618..638 FT /note="Helical; Name=8" FT /evidence="ECO:0000250|UniProtKB:A0A0H3LM39" FT TOPO_DOM 639..647 FT /note="Extracellular" FT /evidence="ECO:0000305" FT REGION 236..255 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 458..486 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 452..454 FT /note="Essential for SLC39A4 endocytosis" FT /evidence="ECO:0000269|PubMed:32348750" FT COMPBIAS 236..250 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 507 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /note="M1 metal binding site" FT /evidence="ECO:0000305|PubMed:28875161" FT BINDING 508 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /note="M2 metal binding site" FT /evidence="ECO:0000305|PubMed:28875161" FT BINDING 511 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /note="M1 metal binding site" FT /evidence="ECO:0000305|PubMed:28875161" FT BINDING 511 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /note="M2 metal binding site" FT /evidence="ECO:0000305|PubMed:28875161" FT BINDING 536 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /note="M1 metal binding site" FT /evidence="ECO:0000305|PubMed:28875161" FT BINDING 537 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /note="M2 metal binding site" FT /evidence="ECO:0000305|PubMed:28875161" FT BINDING 540 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /note="M1 metal binding site" FT /evidence="ECO:0000305|PubMed:28875161" FT SITE 511 FT /note="Essential role in Zn(2+) sensing" FT /evidence="ECO:0000269|PubMed:32348750" FT CARBOHYD 261 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:33837739" FT DISULFID 57..62 FT /evidence="ECO:0000250|UniProtKB:L5KLU7" FT DISULFID 65..111 FT /evidence="ECO:0000250|UniProtKB:L5KLU7" FT DISULFID 160..195 FT /evidence="ECO:0000250|UniProtKB:L5KLU7" FT DISULFID 270..309 FT /evidence="ECO:0000250|UniProtKB:L5KLU7" FT VAR_SEQ 1..25 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:12068297, FT ECO:0000303|PubMed:14702039" FT /id="VSP_015911" FT VAR_SEQ 26..64 FT /note="AGLLSLLTSGQGALDQEALGGLLNTLADRVHCANGPCGK -> MVDVVGLER FT ETGPRGSPWPGLPLPSLVGPAPLLTCLCPQ (in isoform 2)" FT /evidence="ECO:0000303|PubMed:12068297, FT ECO:0000303|PubMed:14702039" FT /id="VSP_015912" FT VARIANT 22 FT /note="A -> E (in dbSNP:rs2280839)" FT /id="VAR_060487" FT VARIANT 58 FT /note="A -> T (in dbSNP:rs2280838)" FT /evidence="ECO:0000269|PubMed:12032886, FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15489334" FT /id="VAR_023627" FT VARIANT 84 FT /note="P -> L (in dbSNP:rs117535951)" FT /evidence="ECO:0000269|PubMed:12032886" FT /id="VAR_023628" FT VARIANT 95 FT /note="R -> C (in AEZ; Loss of zinc transport activity. FT Decreases location at cell membrane; retained in the ER; FT dbSNP:rs121434292)" FT /evidence="ECO:0000269|PubMed:12787121, FT ECO:0000269|PubMed:33837739" FT /id="VAR_023629" FT VARIANT 106 FT /note="N -> K (in AEZ; Loss of zinc transport activity. FT Decreases location at cell membrane; retained in the ER.; FT dbSNP:rs121434290)" FT /evidence="ECO:0000269|PubMed:12032886, FT ECO:0000269|PubMed:33837739" FT /id="VAR_023630" FT VARIANT 114 FT /note="A -> T (in dbSNP:rs17855765)" FT /evidence="ECO:0000269|PubMed:12032886, FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15489334" FT /id="VAR_023631" FT VARIANT 158 FT /note="M -> T (in dbSNP:rs1871533)" FT /id="VAR_057481" FT VARIANT 200 FT /note="P -> L (in AEZ; Loss of zinc transport activity. FT Decreases location at cell membrane. Retained in the ER; FT dbSNP:rs121434287)" FT /evidence="ECO:0000269|PubMed:12068297, FT ECO:0000269|PubMed:33837739" FT /id="VAR_023632" FT VARIANT 251 FT /note="R -> W (in AEZ; uncertain significance; FT dbSNP:rs2977838)" FT /evidence="ECO:0000269|PubMed:12032886, FT ECO:0000269|PubMed:16421571" FT /id="VAR_023633" FT VARIANT 284 FT /note="E -> K (in dbSNP:rs7823979)" FT /id="VAR_057482" FT VARIANT 303 FT /note="Q -> H (in AEZ; uncertain significance; Loss of zinc FT transport activity. Decreases location at cell membrane. FT Retained in the ER; dbSNP:rs121434293)" FT /evidence="ECO:0000269|PubMed:12787121, FT ECO:0000269|PubMed:33837739" FT /id="VAR_023634" FT VARIANT 309 FT /note="C -> Y (in AEZ; Decreases location at cell membrane. FT Retained in the ER; dbSNP:rs782110796)" FT /evidence="ECO:0000269|PubMed:12032886, FT ECO:0000269|PubMed:33837739" FT /id="VAR_023635" FT VARIANT 330 FT /note="G -> D (in AEZ; dbSNP:rs121434291)" FT /evidence="ECO:0000269|PubMed:12032886" FT /id="VAR_023636" FT VARIANT 357 FT /note="T -> A (in dbSNP:rs2272662)" FT /evidence="ECO:0000269|PubMed:12032886, FT ECO:0000269|PubMed:14702039" FT /id="VAR_023637" FT VARIANT 372 FT /note="V -> L (in dbSNP:rs1871534)" FT /id="VAR_057483" FT VARIANT 372 FT /note="V -> P (in AEZ; requires 2 nucleotide FT substitutions)" FT /evidence="ECO:0000269|PubMed:12032886" FT /id="VAR_023638" FT VARIANT 374 FT /note="G -> R (in AEZ; dbSNP:rs121434289)" FT /evidence="ECO:0000269|PubMed:12068297" FT /id="VAR_023639" FT VARIANT 410 FT /note="L -> P (in AEZ; uncertain significance)" FT /evidence="ECO:0000269|PubMed:12032886" FT /id="VAR_023640" FT VARIANT 526 FT /note="G -> R (in AEZ; dbSNP:rs121434288)" FT /evidence="ECO:0000269|PubMed:12068297" FT /id="VAR_023641" FT VARIANT 630 FT /note="G -> R (in AEZ)" FT /evidence="ECO:0000269|PubMed:12032886" FT /id="VAR_023642" FT MUTAGEN 62 FT /note="C->R: Decreases location at cell membrane. Retained FT in the ER. Loss of zinc transport activity." FT /evidence="ECO:0000269|PubMed:33837739" FT MUTAGEN 99 FT /note="A->T: Loss of zinc transport activity." FT /evidence="ECO:0000269|PubMed:33837739" FT MUTAGEN 202 FT /note="P->A: Does not affect location at cell membrane. FT Does not affect zinc transport activity." FT /evidence="ECO:0000269|PubMed:27321477" FT MUTAGEN 238 FT /note="H->S: Decreases zinc transport activity; when FT associated with S-241; S-243; S-245. Decreases Vmax for FT Zn(2+) by 20% but does not affect the KM; when associated FT with S-241; S-243; S-245." FT /evidence="ECO:0000269|PubMed:31164399" FT MUTAGEN 241 FT /note="H->S: Decreases zinc transport activity; when FT associated with S-238; S-243 and S-245. Decreases Vmax for FT Zn(2+) by 20% does not affect the KM; when associated with FT S-238; S-243 and S-245." FT /evidence="ECO:0000269|PubMed:31164399" FT MUTAGEN 243 FT /note="H->S: Decreases zinc transport activity; when FT associated with S-238; S-241 and S-245. Decreases Vmax for FT Zn(2+) by 20% does not affect the KM; when associated with FT S-238; S-241 and S-245." FT /evidence="ECO:0000269|PubMed:31164399" FT MUTAGEN 245 FT /note="H->S: Decreases zinc transport activity; when FT associated with S-238; S-241 and S-243. Decreases Vmax for FT Zn(2+) by 20% but does not affect the KM; when associated FT with S-238; S-241 and S-243." FT /evidence="ECO:0000269|PubMed:31164399" FT MUTAGEN 261 FT /note="N->Q: Decreases location at cell membrane; retained FT in the ER." FT /evidence="ECO:0000269|PubMed:33837739" FT MUTAGEN 266 FT /note="W->A: No glycosylated. Very low cell surface FT expression. Decreases zinc uptake activity." FT /evidence="ECO:0000269|PubMed:27321477" FT MUTAGEN 275 FT /note="D->A: Decreases zinc uptake activity." FT /evidence="ECO:0000269|PubMed:27321477" FT MUTAGEN 303 FT /note="Q->A: Reduces glycosylation level. Reduces cell FT surface expression. Decreases zinc uptake activity." FT /evidence="ECO:0000269|PubMed:27321477" FT MUTAGEN 375 FT /note="D->A: Reduces zinc transport activity; when FT associated with A-379." FT /evidence="ECO:0000269|PubMed:28875161" FT MUTAGEN 379 FT /note="H->A: Reduces zinc transport activity; when FT associated with A-375." FT /evidence="ECO:0000269|PubMed:28875161" FT MUTAGEN 388 FT /note="H->A: Does not affect zinc sensing." FT /evidence="ECO:0000269|PubMed:32348750" FT MUTAGEN 390 FT /note="H->A: Does not affect zinc sensing." FT /evidence="ECO:0000269|PubMed:32348750" FT MUTAGEN 452..454 FT /note="LQL->AAA: Abrogates endocytosis of the A-511 mutant FT which undergoes zinc-independent endocytosis." FT /evidence="ECO:0000269|PubMed:32348750" FT MUTAGEN 452 FT /note="L->A: Abrogates endocytosis." FT /evidence="ECO:0000269|PubMed:32348750" FT MUTAGEN 453 FT /note="Q->A: Reduces endocytosis." FT /evidence="ECO:0000269|PubMed:32348750" FT MUTAGEN 454 FT /note="L->A: Abrogates endocytosis." FT /evidence="ECO:0000269|PubMed:32348750" FT MUTAGEN 463 FT /note="K->R: No effect on SLC39A4 endocytosis. No effect on FT SLC39A4 endocytosis; when associated with R-611." FT /evidence="ECO:0000269|PubMed:32348750" FT MUTAGEN 481 FT /note="L->A: No effect on SLC39A4 endocytosis. No effect on FT SLC39A4 endocytosis; when associated with A-482." FT /evidence="ECO:0000269|PubMed:32348750" FT MUTAGEN 482 FT /note="L->A: No effect on SLC39A4 endocytosis. No effect on FT SLC39A4 endocytosis; when associated with A-481." FT /evidence="ECO:0000269|PubMed:32348750" FT MUTAGEN 507 FT /note="H->A: Moderately reduces zinc transport activity. FT Completely abrogated zinc transport activity; when FT associated with A-536 and A-540." FT /evidence="ECO:0000269|PubMed:28875161, FT ECO:0000269|PubMed:31914589" FT MUTAGEN 507 FT /note="H->R: Abolishes zinc transport activity." FT /evidence="ECO:0000269|PubMed:28875161, FT ECO:0000269|PubMed:31914589" FT MUTAGEN 508 FT /note="N->A: Moderately Reduces zinc transport activity. FT Reduced zinc transmembrane transporter activity; when FT associated with A-537. Does not affect substrate FT specificity; when associated with A-537. Exhibits a zinc FT transport activity dependent on pH; when associated with FT A-537." FT /evidence="ECO:0000269|PubMed:28875161, FT ECO:0000269|PubMed:31914589" FT MUTAGEN 508 FT /note="N->R: Reduces zinc transport activity by 60%." FT /evidence="ECO:0000269|PubMed:28875161" FT MUTAGEN 508 FT /note="N->S: Strong reduction of zinc transport activity; FT when associated with K-537." FT /evidence="ECO:0000269|PubMed:31914589" FT MUTAGEN 511 FT /note="D->A: Strongly reduced zinc transport activity. Loss FT of zinc-sensing function; endocytosis of this mutant FT becomes a zinc-independent process." FT /evidence="ECO:0000269|PubMed:28875161, FT ECO:0000269|PubMed:32348750" FT MUTAGEN 536 FT /note="H->A: Moderately reduces zinc transport activity. FT Completely abrogates zinc transport activity; when FT associated with A-507 and A-540." FT /evidence="ECO:0000269|PubMed:28875161, FT ECO:0000269|PubMed:31914589" FT MUTAGEN 536 FT /note="H->R: Abolishes zinc transport activity." FT /evidence="ECO:0000269|PubMed:28875161, FT ECO:0000269|PubMed:31914589" FT MUTAGEN 537 FT /note="E->A: Moderately reduces zinc transport activity. FT Reduces zinc transmembrane transporter activity; when FT associated with A-508. Does not affect substrate FT specificity; when associated with A-508. Exhibits a zinc FT transport activity dependent on pH; when associated with FT A-508." FT /evidence="ECO:0000269|PubMed:28875161, FT ECO:0000269|PubMed:31914589" FT MUTAGEN 537 FT /note="E->K: Strong reduction of zinc transport activity; FT when associated with S-537." FT /evidence="ECO:0000269|PubMed:31914589" FT MUTAGEN 537 FT /note="E->R: Abolishes zinc transport activity." FT /evidence="ECO:0000269|PubMed:28875161" FT MUTAGEN 540 FT /note="H->A: Increases zinc transport activity. Reduces FT affinity toward zinc. No defect in endocytosis or zinc FT sensing. Completely abrogated zinc transport activity; when FT associated with A-507 and A-536." FT /evidence="ECO:0000269|PubMed:28875161, FT ECO:0000269|PubMed:31914589, ECO:0000269|PubMed:32348750" FT MUTAGEN 540 FT /note="H->R: Does not affect zinc transport activity." FT /evidence="ECO:0000269|PubMed:28875161" FT MUTAGEN 611 FT /note="K->R: No effect on SLC39A4 endocytosis. No effect on FT SLC39A4 endocytosis; when associated with R-463." FT /evidence="ECO:0000269|PubMed:32348750" SQ SEQUENCE 647 AA; 68408 MW; AB84735F4BEF434F CRC64; MASLVSLELG LLLAVLVVTA TASPPAGLLS LLTSGQGALD QEALGGLLNT LADRVHCANG PCGKCLSVED ALGLGEPEGS GLPPGPVLEA RYVARLSAAA VLYLSNPEGT CEDARAGLWA SHADHLLALL ESPKALTPGL SWLLQRMQAR AAGQTPKMAC VDIPQLLEEA VGAGAPGSAG GVLAALLDHV RSGSCFHALP SPQYFVDFVF QQHSSEVPMT LAELSALMQR LGVGREAHSD HSHRHRGASS RDPVPLISSS NSSSVWDTVC LSARDVMAAY GLSEQAGVTP EAWAQLSPAL LQQQLSGACT SQSRPPVQDQ LSQSERYLYG SLATLLICLC AVFGLLLLTC TGCRGVTHYI LQTFLSLAVG AVTGDAVLHL TPKVLGLHTH SEEGLSPQPT WRLLAMLAGL YAFFLFENLF NLLLPRDPED LEDGPCGHSS HSHGGHSHGV SLQLAPSELR QPKPPHEGSR ADLVAEESPE LLNPEPRRLS PELRLLPYMI TLGDAVHNFA DGLAVGAAFA SSWKTGLATS LAVFCHELPH ELGDFAALLH AGLSVRQALL LNLASALTAF AGLYVALAVG VSEESEAWIL AVATGLFLYV ALCDMLPAML KVRDPRPWLL FLLHNVGLLG GWTVLLLLSL YEDDITF //