S39A4_HUMAN
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 03-AUG-2022, entry version 153.
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; 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), AND VARIANTS
RP THR-58; THR-114; 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).
CC -!- FUNCTION: Plays an important role in cellular zinc homeostasis as a
CC zinc transporter. Regulated in response to zinc availability (By
CC similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14612438};
CC Multi-pass membrane protein {ECO:0000269|PubMed:14612438}. Recycling
CC endosome membrane {ECO:0000269|PubMed:14612438}; Multi-pass membrane
CC protein {ECO:0000269|PubMed:14612438}. Note=Colocalized with TFRC in
CC the recycling endosomes. Cycles between endosomal compartments and the
CC plasma membrane in response to zinc availability.
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 -!- 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}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC 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};
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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 GlyGen; Q6P5W5; 1 site.
DR iPTMnet; Q6P5W5; -.
DR PhosphoSitePlus; Q6P5W5; -.
DR BioMuta; SLC39A4; -.
DR DMDM; 296452970; -.
DR jPOST; Q6P5W5; -.
DR MassIVE; Q6P5W5; -.
DR PaxDb; Q6P5W5; -.
DR PeptideAtlas; Q6P5W5; -.
DR PRIDE; Q6P5W5; -.
DR ProteomicsDB; 67007; -. [Q6P5W5-1]
DR ProteomicsDB; 67008; -. [Q6P5W5-2]
DR Antibodypedia; 28508; 228 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 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; IFFLFES; -.
DR OrthoDB; 657777at2759; -.
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; 19 hits in 1078 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 95 other tissues.
DR ExpressionAtlas; Q6P5W5; baseline and differential.
DR Genevisible; Q6P5W5; HS.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0055038; C:recycling endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:CACAO.
DR GO; GO:0034224; P:cellular response to zinc ion starvation; IEA:Ensembl.
DR GO; GO:0006882; P:cellular zinc ion homeostasis; IBA:GO_Central.
DR GO; GO:0071578; P:zinc ion import across plasma membrane; IBA:GO_Central.
DR GO; GO:0071577; P:zinc ion transmembrane transport; TAS:Reactome.
DR DisProt; DP02554; -.
DR InterPro; IPR003689; ZIP.
DR InterPro; IPR041137; ZIP4_N.
DR Pfam; PF02535; Zip; 1.
DR Pfam; PF18292; ZIP4_domain; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Disease variant; Endosome;
KW Glycoprotein; Ion transport; Membrane; Reference proteome; Signal;
KW Transmembrane; Transmembrane helix; Transport; 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:0000255"
FT TRANSMEM 328..348
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 349..359
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 360..380
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 381..402
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 403..423
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 424..558
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 559..579
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 580..586
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 587..607
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 608..617
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 618..638
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 639..647
FT /note="Extracellular"
FT /evidence="ECO:0000255"
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 COMPBIAS 236..250
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 261
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
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; dbSNP:rs121434292)"
FT /evidence="ECO:0000269|PubMed:12787121"
FT /id="VAR_023629"
FT VARIANT 106
FT /note="N -> K (in AEZ; dbSNP:rs121434290)"
FT /evidence="ECO:0000269|PubMed:12032886"
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; dbSNP:rs121434287)"
FT /evidence="ECO:0000269|PubMed:12068297"
FT /id="VAR_023632"
FT VARIANT 251
FT /note="R -> W (in AEZ; unknown pathological 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; dbSNP:rs121434293)"
FT /evidence="ECO:0000269|PubMed:12787121"
FT /id="VAR_023634"
FT VARIANT 309
FT /note="C -> Y (in AEZ; unknown pathological significance;
FT dbSNP:rs782110796)"
FT /evidence="ECO:0000269|PubMed:12032886,
FT ECO:0000269|PubMed:14702039"
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; unknown pathological 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"
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
