S39AE_HUMAN
ID S39AE_HUMAN Reviewed; 492 AA.
AC Q15043; A6NH98; B4DIW3; B6EU88; D3DSR4; Q6ZME8; Q96BB3;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 30-NOV-2010, sequence version 3.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=Metal cation symporter ZIP14 {ECO:0000305|PubMed:18270315};
DE AltName: Full=LIV-1 subfamily of ZIP zinc transporter 4 {ECO:0000303|PubMed:12659941};
DE Short=LZT-Hs4 {ECO:0000303|PubMed:12659941};
DE AltName: Full=Solute carrier family 39 member 14 {ECO:0000312|HGNC:HGNC:20858};
DE AltName: Full=Zrt- and Irt-like protein 14 {ECO:0000303|PubMed:15642354};
DE Short=ZIP-14 {ECO:0000303|PubMed:15642354};
DE Flags: Precursor;
GN Name=SLC39A14 {ECO:0000312|HGNC:HGNC:20858};
GN Synonyms=KIAA0062 {ECO:0000312|EMBL:BAA06685.1},
GN ZIP14 {ECO:0000303|PubMed:15642354};
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 [LARGE SCALE MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Bone marrow;
RX PubMed=7584044; DOI=10.1093/dnares/1.5.223;
RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S., Seki N.,
RA Kawarabayasi Y., Ishikawa K., Tabata S.;
RT "Prediction of the coding sequences of unidentified human genes. II. The
RT coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of
RT cDNA clones from human cell line KG-1.";
RL DNA Res. 1:223-229(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Hippocampus;
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].
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 GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANT PRO-33.
RC TISSUE=Colon;
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 [6]
RP SUBUNIT, AND MOTIF.
RX PubMed=12659941; DOI=10.1016/s0005-2736(03)00048-8;
RA Taylor K.M., Nicholson R.I.;
RT "The LZT proteins; the LIV-1 subfamily of zinc transporters.";
RL Biochim. Biophys. Acta 1611:16-30(2003).
RN [7]
RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=15642354; DOI=10.1016/j.febslet.2004.12.006;
RA Taylor K.M., Morgan H.E., Johnson A., Nicholson R.I.;
RT "Structure-function analysis of a novel member of the LIV-1 subfamily of
RT zinc transporters, ZIP14.";
RL FEBS Lett. 579:427-432(2005).
RN [8]
RP ALTERNATIVE SPLICING (ISOFORMS 1 AND 2).
RX PubMed=18270315; DOI=10.1124/mol.107.043588;
RA Girijashanker K., He L., Soleimani M., Reed J.M., Li H., Liu Z., Wang B.,
RA Dalton T.P., Nebert D.W.;
RT "Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities
RT to the ZIP8 transporter.";
RL Mol. Pharmacol. 73:1413-1423(2008).
RN [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-77.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [10]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-77 AND ASN-102.
RC TISSUE=Leukemic T-cell;
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-linked
RT cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=20682781; DOI=10.1074/jbc.m110.143248;
RA Zhao N., Gao J., Enns C.A., Knutson M.D.;
RT "ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron
RT from transferrin.";
RL J. Biol. Chem. 285:32141-32150(2010).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP FUNCTION, INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=23052185; DOI=10.1007/s00011-012-0559-y;
RA Sayadi A., Nguyen A.T., Bard F.A., Bard-Chapeau E.A.;
RT "Zip14 expression induced by lipopolysaccharides in macrophages attenuates
RT inflammatory response.";
RL Inflamm. Res. 62:133-143(2013).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [15]
RP INDUCTION BY IRON, UBIQUITINATION, MUTAGENESIS OF ASN-77; ASN-87 AND
RP ASN-102, AND GLYCOSYLATION AT ASN-77; ASN-87 AND ASN-102.
RX PubMed=24927598; DOI=10.1073/pnas.1405355111;
RA Zhao N., Zhang A.S., Worthen C., Knutson M.D., Enns C.A.;
RT "An iron-regulated and glycosylation-dependent proteasomal degradation
RT pathway for the plasma membrane metal transporter ZIP14.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:9175-9180(2014).
RN [16]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=27703010; DOI=10.1074/jbc.m116.748632;
RA Aydemir T.B., Troche C., Kim M.H., Cousins R.J.;
RT "Hepatic ZIP14-mediated Zinc Transport Contributes to Endosomal Insulin
RT Receptor Trafficking and Glucose Metabolism.";
RL J. Biol. Chem. 291:23939-23951(2016).
RN [17]
RP INDUCTION.
RX PubMed=28673968; DOI=10.1073/pnas.1704012114;
RA Kim M.H., Aydemir T.B., Kim J., Cousins R.J.;
RT "Hepatic ZIP14-mediated zinc transport is required for adaptation to
RT endoplasmic reticulum stress.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:E5805-E5814(2017).
RN [18]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=31028174; DOI=10.1074/jbc.ra119.008762;
RA Scheiber I.F., Wu Y., Morgan S.E., Zhao N.;
RT "The intestinal metal transporter ZIP14 maintains systemic manganese
RT homeostasis.";
RL J. Biol. Chem. 294:9147-9160(2019).
RN [19]
RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=31699897; DOI=10.1074/jbc.ra119.009371;
RA Steimle B.L., Smith F.M., Kosman D.J.;
RT "The solute carriers ZIP8 and ZIP14 regulate manganese accumulation in
RT brain microvascular endothelial cells and control brain manganese levels.";
RL J. Biol. Chem. 294:19197-19208(2019).
RN [20]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY (ISOFORM 2), INVOLVEMENT
RP IN HMNDYT2, MOTIF, VARIANTS HMNDYT2 VAL-98; ARG-383 AND LYS-469, AND
RP CHARACTERIZATION OF VARIANTS HMNDYT2 VAL-98; ARG-383 AND LYS-469.
RX PubMed=27231142; DOI=10.1038/ncomms11601;
RA Tuschl K., Meyer E., Valdivia L.E., Zhao N., Dadswell C., Abdul-Sada A.,
RA Hung C.Y., Simpson M.A., Chong W.K., Jacques T.S., Woltjer R.L., Eaton S.,
RA Gregory A., Sanford L., Kara E., Houlden H., Cuno S.M., Prokisch H.,
RA Valletta L., Tiranti V., Younis R., Maher E.R., Spencer J.,
RA Straatman-Iwanowska A., Gissen P., Selim L.A., Pintos-Morell G.,
RA Coroleu-Lletget W., Mohammad S.S., Yoganathan S., Dale R.C., Thomas M.,
RA Rihel J., Bodamer O.A., Enns C.A., Hayflick S.J., Clayton P.T., Mills P.B.,
RA Kurian M.A., Wilson S.W.;
RT "Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-
RT onset parkinsonism-dystonia.";
RL Nat. Commun. 7:11601-11601(2016).
RN [21]
RP INVOLVEMENT IN HCIN, VARIANT HCIN ARG-441, CHARACTERIZATION OF VARIANT HCIN
RP ARG-441, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=29621230; DOI=10.1371/journal.pgen.1007321;
RA Hendrickx G., Borra V.M., Steenackers E., Yorgan T.A., Hermans C.,
RA Boudin E., Waterval J.J., Jansen I.D.C., Aydemir T.B., Kamerling N.,
RA Behets G.J., Plumeyer C., D'Haese P.C., Busse B., Everts V., Lammens M.,
RA Mortier G., Cousins R.J., Schinke T., Stokroos R.J., Manni J.J.,
RA Van Hul W.;
RT "Conditional mouse models support the role of SLC39A14 (ZIP14) in
RT Hyperostosis Cranialis Interna and in bone homeostasis.";
RL PLoS Genet. 14:E1007321-E1007321(2018).
CC -!- FUNCTION: Electroneutral transporter of the plasma membrane mediating
CC the cellular uptake of the divalent metal cations zinc, manganese and
CC iron that are important for tissue homeostasis, metabolism, development
CC and immunity (PubMed:15642354, PubMed:27231142, PubMed:29621230).
CC Functions as an energy-dependent symporter, transporting through the
CC membranes an electroneutral complex composed of a divalent metal cation
CC and two bicarbonate anions (By similarity). Beside these endogenous
CC cellular substrates, can also import cadmium a non-essential metal
CC which is cytotoxic and carcinogenic (By similarity). Controls the
CC cellular uptake by the intestinal epithelium of systemic zinc, which is
CC in turn required to maintain tight junctions and the intestinal
CC permeability (By similarity). Modifies the activity of zinc-dependent
CC phosphodiesterases, thereby indirectly regulating G protein-coupled
CC receptor signaling pathways important for gluconeogenesis and
CC chondrocyte differentiation (By similarity). Regulates insulin receptor
CC signaling, glucose uptake, glycogen synthesis and gluconeogenesis in
CC hepatocytes through the zinc-dependent intracellular catabolism of
CC insulin (PubMed:27703010). Through zinc cellular uptake also plays a
CC role in the adaptation of cells to endoplasmic reticulum stress (By
CC similarity). Major manganese transporter of the basolateral membrane of
CC intestinal epithelial cells, it plays a central role in manganese
CC systemic homeostasis through intestinal manganese uptake
CC (PubMed:31028174). Also involved in manganese extracellular uptake by
CC cells of the blood-brain barrier (PubMed:31699897). May also play a
CC role in manganese and zinc homeostasis participating in their
CC elimination from the blood through the hepatobiliary excretion (By
CC similarity). Also functions in the extracellular uptake of free iron.
CC May also function intracellularly and mediate the transport from
CC endosomes to cytosol of iron endocytosed by transferrin
CC (PubMed:20682781). Plays a role in innate immunity by regulating the
CC expression of cytokines by activated macrophages (PubMed:23052185).
CC {ECO:0000250|UniProtKB:Q75N73, ECO:0000269|PubMed:15642354,
CC ECO:0000269|PubMed:20682781, ECO:0000269|PubMed:23052185,
CC ECO:0000269|PubMed:27231142, ECO:0000269|PubMed:27703010,
CC ECO:0000269|PubMed:29621230, ECO:0000269|PubMed:31028174,
CC ECO:0000269|PubMed:31699897}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 hydrogencarbonate(out) + Zn(2+)(out) = 2
CC hydrogencarbonate(in) + Zn(2+)(in); Xref=Rhea:RHEA:62252,
CC ChEBI:CHEBI:17544, ChEBI:CHEBI:29105;
CC Evidence={ECO:0000305|PubMed:15642354};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62253;
CC Evidence={ECO:0000269|PubMed:15642354};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 hydrogencarbonate(out) + Mn(2+)(out) = 2
CC hydrogencarbonate(in) + Mn(2+)(in); Xref=Rhea:RHEA:62260,
CC ChEBI:CHEBI:17544, ChEBI:CHEBI:29035;
CC Evidence={ECO:0000305|PubMed:31699897};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62261;
CC Evidence={ECO:0000269|PubMed:31699897};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Fe(2+)(out) + 2 hydrogencarbonate(out) = Fe(2+)(in) + 2
CC hydrogencarbonate(in); Xref=Rhea:RHEA:62368, ChEBI:CHEBI:17544,
CC ChEBI:CHEBI:29033; Evidence={ECO:0000250|UniProtKB:Q75N73};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62369;
CC Evidence={ECO:0000250|UniProtKB:Q75N73};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Cd(2+)(out) + 2 hydrogencarbonate(out) = Cd(2+)(in) + 2
CC hydrogencarbonate(in); Xref=Rhea:RHEA:62256, ChEBI:CHEBI:17544,
CC ChEBI:CHEBI:48775; Evidence={ECO:0000250|UniProtKB:Q75N73};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62257;
CC Evidence={ECO:0000250|UniProtKB:Q75N73};
CC -!- SUBUNIT: Homotrimer. {ECO:0000269|PubMed:12659941}.
CC -!- INTERACTION:
CC Q15043-2; Q9BRK4: LZTS2; NbExp=3; IntAct=EBI-12176399, EBI-741037;
CC Q15043-2; Q9UH03: SEPTIN3; NbExp=3; IntAct=EBI-12176399, EBI-727037;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15642354,
CC ECO:0000269|PubMed:27231142, ECO:0000269|PubMed:27703010,
CC ECO:0000269|PubMed:29621230}; Multi-pass membrane protein
CC {ECO:0000255}. Apical cell membrane {ECO:0000269|PubMed:31699897};
CC Multi-pass membrane protein {ECO:0000255}. Basolateral cell membrane
CC {ECO:0000269|PubMed:31028174, ECO:0000269|PubMed:31699897}; Multi-pass
CC membrane protein {ECO:0000255}. Early endosome membrane
CC {ECO:0000269|PubMed:20682781, ECO:0000269|PubMed:27703010}; Multi-pass
CC membrane protein {ECO:0000255}. Late endosome membrane
CC {ECO:0000269|PubMed:27703010}; Multi-pass membrane protein
CC {ECO:0000255}. Lysosome membrane {ECO:0000269|PubMed:20682781}; Multi-
CC pass membrane protein {ECO:0000255}. Note=Localized and functional at
CC both apical and basolateral membranes of microvascular capillary
CC endothelial cells that constitute the blood-brain barrier
CC (PubMed:31699897). Localized at the basolateral membrane of enterocytes
CC (PubMed:31028174). Enriched at the plasma membrane upon glucose uptake
CC (PubMed:27703010). {ECO:0000269|PubMed:27703010,
CC ECO:0000269|PubMed:31028174, ECO:0000269|PubMed:31699897}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1 {ECO:0000303|PubMed:27231142}; Synonyms=ZIP14B
CC {ECO:0000303|PubMed:18270315};
CC IsoId=Q15043-1; Sequence=Displayed;
CC Name=3;
CC IsoId=Q15043-2; Sequence=VSP_029728;
CC Name=2 {ECO:0000303|PubMed:27231142}; Synonyms=ZIP14A
CC {ECO:0000303|PubMed:18270315};
CC IsoId=Q15043-3; Sequence=VSP_040139;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with higher expression in
CC liver, pancreas, fetal liver, thyroid gland, left and right ventricle,
CC right atrium and fetal heart (PubMed:7584044, PubMed:15642354,
CC PubMed:20682781). Weakly expressed in spleen, thymus, and peripheral
CC blood leukocytes (PubMed:7584044). Expressed in liver and in brain by
CC large neurons in the globus pallidus, the insular cortex and the
CC dentate nucleus and to a lower extent in the putamen and the caudate
CC nucleus (at protein level) (PubMed:27231142). Expressed in osteoblasts
CC and giant osteoclast-like cells, but not in osteocytes found
CC osteoblastoma and giant cell tumors (at protein level)
CC (PubMed:29621230). Expressed by microvascular capillary endothelial
CC cells that constitute the blood-brain barrier (at protein level)
CC (PubMed:31699897). Expressed by macrophages (PubMed:23052185).
CC {ECO:0000269|PubMed:15642354, ECO:0000269|PubMed:20682781,
CC ECO:0000269|PubMed:23052185, ECO:0000269|PubMed:31699897,
CC ECO:0000269|PubMed:7584044}.
CC -!- TISSUE SPECIFICITY: [Isoform 2]: Widely expressed but not detected in
CC brain, heart, skeletal muscle, placenta and fetal skin.
CC {ECO:0000269|PubMed:27231142}.
CC -!- INDUCTION: Up-regulated by iron (at protein level) (PubMed:24927598).
CC Down-regulation upon iron depletion occurs through proteasomal
CC degradation of the intracellular pool (PubMed:24927598). Up-regulated
CC by tunicamycin, a drug inducing endoplasmic reticulum stress (at
CC protein level) (PubMed:28673968). Up-regulated by
CC lipopolysaccharide/LPS (PubMed:23052185). {ECO:0000269|PubMed:23052185,
CC ECO:0000269|PubMed:24927598, ECO:0000269|PubMed:28673968}.
CC -!- PTM: Ubiquitinated. Ubiquitination occurs upon iron depletion. The
CC ubiquitinated form undergoes proteasomal degradation.
CC {ECO:0000269|PubMed:24927598}.
CC -!- PTM: N-glycosylated. N-glycosylation at Asn-102 is required for iron-
CC regulated extraction of the transporter from membranes and subsequent
CC proteasomal degradation. {ECO:0000269|PubMed:24927598}.
CC -!- DISEASE: Hypermanganesemia with dystonia 2 (HMNDYT2) [MIM:617013]: A
CC metabolic autosomal recessive disorder characterized by increased blood
CC manganese levels, neurodegeneration, and rapidly progressive
CC parkinsonism and dystonia. Affected individuals present with loss of
CC developmental milestones, progressive dystonia and bulbar dysfunction
CC in infancy or early childhood. Towards the end of the first decade,
CC they manifest severe generalized pharmacoresistant dystonia,
CC spasticity, limb contractures and scoliosis, and loss of independent
CC ambulation. Cognition may be impaired, but is better preserved than
CC motor function. {ECO:0000269|PubMed:27231142}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: Hyperostosis cranialis interna (HCIN) [MIM:144755]: An
CC autosomal dominant bone disorder characterized by endosteal
CC hyperostosis and osteosclerosis of the calvaria and the skull base. The
CC progressive bone overgrowth causes entrapment and dysfunction of
CC cranial nerves I, II, V, VII, and VIII, its first symptoms often
CC presenting during the second decade of life.
CC {ECO:0000269|PubMed:29621230}. Note=The disease is caused by variants
CC affecting the gene represented in this entry. Conditional knockin mice
CC overexpressing Arg-438 variant, which is the mouse equivalent of human
CC variant Leu-441, in osteoblasts have a severe skeletal phenotype marked
CC by a drastic increase in cortical thickness due to an enhanced
CC endosteal bone formation, resembling the underlying pathology in HCI
CC patients. {ECO:0000269|PubMed:29621230}.
CC -!- SIMILARITY: Belongs to the ZIP transporter (TC 2.A.5) family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA06685.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; D31887; BAA06685.1; ALT_INIT; mRNA.
DR EMBL; AK172810; BAD18780.1; -; mRNA.
DR EMBL; AK295807; BAG58625.1; -; mRNA.
DR EMBL; AC087854; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC105910; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471080; EAW63681.1; -; Genomic_DNA.
DR EMBL; CH471080; EAW63682.1; -; Genomic_DNA.
DR EMBL; CH471080; EAW63683.1; -; Genomic_DNA.
DR EMBL; BC015770; AAH15770.1; -; mRNA.
DR CCDS; CCDS47822.1; -. [Q15043-2]
DR CCDS; CCDS47823.1; -. [Q15043-1]
DR CCDS; CCDS6030.1; -. [Q15043-3]
DR RefSeq; NP_001121903.1; NM_001128431.2. [Q15043-1]
DR RefSeq; NP_001128625.1; NM_001135153.1. [Q15043-1]
DR RefSeq; NP_056174.2; NM_015359.4. [Q15043-3]
DR RefSeq; XP_005273522.1; XM_005273465.2.
DR RefSeq; XP_005273523.1; XM_005273466.4. [Q15043-1]
DR RefSeq; XP_006716387.1; XM_006716324.2. [Q15043-1]
DR RefSeq; XP_011542780.1; XM_011544478.2. [Q15043-1]
DR RefSeq; XP_016868783.1; XM_017013294.1.
DR RefSeq; XP_016868784.1; XM_017013295.1.
DR AlphaFoldDB; Q15043; -.
DR SMR; Q15043; -.
DR BioGRID; 117063; 112.
DR IntAct; Q15043; 28.
DR MINT; Q15043; -.
DR STRING; 9606.ENSP00000352779; -.
DR DrugBank; DB14533; Zinc chloride.
DR DrugBank; DB14548; Zinc sulfate, unspecified form.
DR TCDB; 2.A.5.4.5; the zinc (zn(2+))-iron (fe(2+)) permease (zip) family.
DR GlyGen; Q15043; 3 sites.
DR iPTMnet; Q15043; -.
DR PhosphoSitePlus; Q15043; -.
DR SwissPalm; Q15043; -.
DR BioMuta; SLC39A14; -.
DR DMDM; 313104191; -.
DR EPD; Q15043; -.
DR jPOST; Q15043; -.
DR MassIVE; Q15043; -.
DR MaxQB; Q15043; -.
DR PaxDb; Q15043; -.
DR PeptideAtlas; Q15043; -.
DR PRIDE; Q15043; -.
DR ProteomicsDB; 60392; -. [Q15043-1]
DR ProteomicsDB; 60393; -. [Q15043-2]
DR ProteomicsDB; 60394; -. [Q15043-3]
DR Antibodypedia; 9517; 189 antibodies from 27 providers.
DR DNASU; 23516; -.
DR Ensembl; ENST00000240095.10; ENSP00000240095.6; ENSG00000104635.15. [Q15043-2]
DR Ensembl; ENST00000289952.9; ENSP00000289952.5; ENSG00000104635.15. [Q15043-1]
DR Ensembl; ENST00000359741.10; ENSP00000352779.5; ENSG00000104635.15. [Q15043-3]
DR Ensembl; ENST00000381237.6; ENSP00000370635.1; ENSG00000104635.15. [Q15043-1]
DR GeneID; 23516; -.
DR KEGG; hsa:23516; -.
DR MANE-Select; ENST00000381237.6; ENSP00000370635.1; NM_001128431.4; NP_001121903.1.
DR UCSC; uc003xbp.5; human. [Q15043-1]
DR CTD; 23516; -.
DR DisGeNET; 23516; -.
DR GeneCards; SLC39A14; -.
DR GeneReviews; SLC39A14; -.
DR HGNC; HGNC:20858; SLC39A14.
DR HPA; ENSG00000104635; Tissue enhanced (liver, pancreas).
DR MalaCards; SLC39A14; -.
DR MIM; 144755; phenotype.
DR MIM; 608736; gene.
DR MIM; 617013; phenotype.
DR neXtProt; NX_Q15043; -.
DR OpenTargets; ENSG00000104635; -.
DR Orphanet; 521406; Dystonia-parkinsonism-hypermanganesemia syndrome.
DR PharmGKB; PA134863701; -.
DR VEuPathDB; HostDB:ENSG00000104635; -.
DR eggNOG; KOG2693; Eukaryota.
DR GeneTree; ENSGT00940000157986; -.
DR InParanoid; Q15043; -.
DR OMA; GHSHYSA; -.
DR PhylomeDB; Q15043; -.
DR TreeFam; TF318470; -.
DR PathwayCommons; Q15043; -.
DR Reactome; R-HSA-442380; Zinc influx into cells by the SLC39 gene family.
DR SignaLink; Q15043; -.
DR BioGRID-ORCS; 23516; 15 hits in 1086 CRISPR screens.
DR ChiTaRS; SLC39A14; human.
DR GenomeRNAi; 23516; -.
DR Pharos; Q15043; Tbio.
DR PRO; PR:Q15043; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q15043; protein.
DR Bgee; ENSG00000104635; Expressed in cartilage tissue and 197 other tissues.
DR ExpressionAtlas; Q15043; baseline and differential.
DR Genevisible; Q15043; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IDA:BHF-UCL.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0031902; C:late endosome membrane; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0015296; F:anion:cation symporter activity; ISS:UniProtKB.
DR GO; GO:0015086; F:cadmium ion transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0015093; F:ferrous iron transmembrane transporter activity; IEA:Ensembl.
DR GO; GO:0005381; F:iron ion transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0071333; P:cellular response to glucose stimulus; ISS:UniProtKB.
DR GO; GO:0032869; P:cellular response to insulin stimulus; ISS:UniProtKB.
DR GO; GO:0006882; P:cellular zinc ion homeostasis; IDA:BHF-UCL.
DR GO; GO:0002062; P:chondrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0006094; P:gluconeogenesis; ISS:UniProtKB.
DR GO; GO:0098739; P:import across plasma membrane; IMP:UniProtKB.
DR GO; GO:0098662; P:inorganic cation transmembrane transport; ISS:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0033212; P:iron import into cell; IMP:UniProtKB.
DR GO; GO:0034755; P:iron ion transmembrane transport; IMP:UniProtKB.
DR GO; GO:0055071; P:manganese ion homeostasis; ISS:UniProtKB.
DR GO; GO:0071421; P:manganese ion transmembrane transport; IMP:UniProtKB.
DR GO; GO:0051344; P:negative regulation of cyclic-nucleotide phosphodiesterase activity; ISS:UniProtKB.
DR GO; GO:0045745; P:positive regulation of G protein-coupled receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0010817; P:regulation of hormone levels; ISS:UniProtKB.
DR GO; GO:0071578; P:zinc ion import across plasma membrane; IDA:UniProtKB.
DR GO; GO:0071577; P:zinc ion transmembrane transport; IDA:BHF-UCL.
DR InterPro; IPR003689; ZIP.
DR Pfam; PF02535; Zip; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Disease variant; Dystonia; Endosome;
KW Glycoprotein; Ion transport; Lysosome; Membrane; Neurodegeneration;
KW Parkinsonism; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix; Transport; Ubl conjugation; Zinc; Zinc transport.
FT SIGNAL 1..30
FT /evidence="ECO:0000255"
FT CHAIN 31..492
FT /note="Metal cation symporter ZIP14"
FT /id="PRO_0000312194"
FT TOPO_DOM 31..157
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 158..178
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 179..186
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 187..207
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 208..224
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 225..245
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 246..397
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 398..418
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 419..424
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 425..445
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 446..460
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 461..481
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 482..492
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT MOTIF 251..258
FT /note="HHHGHXHX-motif"
FT /evidence="ECO:0000305|PubMed:27231142"
FT MOTIF 376..381
FT /note="XEXPHE-motif"
FT /evidence="ECO:0000305|PubMed:12659941"
FT CARBOHYD 77
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218,
FT ECO:0000269|PubMed:19349973, ECO:0000269|PubMed:24927598"
FT CARBOHYD 87
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:24927598"
FT CARBOHYD 102
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973,
FT ECO:0000269|PubMed:24927598"
FT VAR_SEQ 156..199
FT /note="YGLLCVTVISLCSLLGASVVPFMKKTFYKRLLLYFIALAIGTLY -> FGFL
FT SVSLINLASLLGVLVLPCTEKAFFSRVLTYFIALSIGTLL (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_040139"
FT VAR_SEQ 445..492
FT /note="FPEMNEVCQEDERKGSILIPFIIQNLGLLTGFTIMVVLTMYSGQIQIG ->
FT MEFCSVAQAGVQWCHLSSLQPLPLGLKRLSCLSLPSN (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_029728"
FT VARIANT 33
FT /note="L -> P (in dbSNP:rs896378)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_037450"
FT VARIANT 98
FT /note="F -> V (in HMNDYT2; no effect on protein abundance;
FT no effect on subcellular localization at the plasma
FT membrane and within the cytoplasm; decreased manganese ion
FT transmembrane transporter activity; dbSNP:rs879253763)"
FT /evidence="ECO:0000269|PubMed:27231142"
FT /id="VAR_077004"
FT VARIANT 383
FT /note="G -> R (in HMNDYT2; no effect on protein abundance;
FT no effect on subcellular localization at the plasma
FT membrane and within the cytoplasm; decreased manganese ion
FT transmembrane transporter activity; dbSNP:rs879253766)"
FT /evidence="ECO:0000269|PubMed:27231142"
FT /id="VAR_077005"
FT VARIANT 441
FT /note="L -> R (in HCIN; loss of localization at the plasma
FT membrane; loss of Zn uptake activity; dbSNP:rs1554520924)"
FT /evidence="ECO:0000269|PubMed:29621230"
FT /id="VAR_080794"
FT VARIANT 469
FT /note="N -> K (in HMNDYT2; no effect on protein abundance;
FT no effect on subcellular localization at the plasma
FT membrane and within the cytoplasm; decreased manganese ion
FT transmembrane transporter activity; dbSNP:rs750281602)"
FT /evidence="ECO:0000269|PubMed:27231142"
FT /id="VAR_077006"
FT MUTAGEN 77
FT /note="N->A: Decreased N-glycosylation."
FT /evidence="ECO:0000269|PubMed:24927598"
FT MUTAGEN 87
FT /note="N->A: Decreased N-glycosylation."
FT /evidence="ECO:0000269|PubMed:24927598"
FT MUTAGEN 102
FT /note="N->A: Decreased N-glycosylation."
FT /evidence="ECO:0000269|PubMed:24927598"
FT CONFLICT 57
FT /note="L -> P (in Ref. 2; BAD18780)"
FT /evidence="ECO:0000305"
FT CONFLICT 314
FT /note="D -> G (in Ref. 2; BAG58625)"
FT /evidence="ECO:0000305"
FT CONFLICT 380
FT /note="H -> R (in Ref. 2; BAD18780)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 492 AA; 54212 MW; F2ACE1DA4656A5F0 CRC64;
MKLLLLHPAF QSCLLLTLLG LWRTTPEAHA SSLGAPAISA ASFLQDLIHR YGEGDSLTLQ
QLKALLNHLD VGVGRGNVTQ HVQGHRNLST CFSSGDLFTA HNFSEQSRIG SSELQEFCPT
ILQQLDSRAC TSENQENEEN EQTEEGRPSA VEVWGYGLLC VTVISLCSLL GASVVPFMKK
TFYKRLLLYF IALAIGTLYS NALFQLIPEA FGFNPLEDYY VSKSAVVFGG FYLFFFTEKI
LKILLKQKNE HHHGHSHYAS ESLPSKKDQE EGVMEKLQNG DLDHMIPQHC SSELDGKAPM
VDEKVIVGSL SVQDLQASQS ACYWLKGVRY SDIGTLAWMI TLSDGLHNFI DGLAIGASFT
VSVFQGISTS VAILCEEFPH ELGDFVILLN AGMSIQQALF FNFLSACCCY LGLAFGILAG
SHFSANWIFA LAGGMFLYIS LADMFPEMNE VCQEDERKGS ILIPFIIQNL GLLTGFTIMV
VLTMYSGQIQ IG
