ID PDE8B_HUMAN Reviewed; 885 AA. AC O95263; Q5J7V7; Q86XK8; Q8IUJ7; Q8IUJ8; Q8IUJ9; Q8IUK0; Q8N3T2; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 22-AUG-2003, sequence version 2. DT 28-JAN-2026, entry version 215. DE RecName: Full=High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B; DE Short=HsPDE8B; DE EC=3.1.4.53 {ECO:0000269|PubMed:12681444}; DE AltName: Full=Cell proliferation-inducing gene 22 protein; GN Name=PDE8B; ORFNames=PIG22; 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 [GENOMIC DNA / MRNA] (ISOFORMS 1; 2 AND 6), AND TISSUE RP SPECIFICITY. RX PubMed=12372422; DOI=10.1016/s0006-291x(02)02371-9; RA Hayashi M., Shimada Y., Nishimura Y., Hama T., Tanaka T.; RT "Genomic organization, chromosomal localization, and alternative splicing RT of the human phosphodiesterase 8B gene."; RL Biochem. Biophys. Res. Commun. 297:1253-1258(2002). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), CATALYTIC ACTIVITY, RP ACTIVITY REGULATION, AND TISSUE SPECIFICITY. RC TISSUE=Thyroid; RX PubMed=12681444; DOI=10.1016/s0898-6568(02)00146-8; RA Gamanuma M., Yuasa K., Sasaki T., Sakurai N., Kotera J., Omori K.; RT "Comparison of enzymatic characterization and gene organization of cyclic RT nucleotide phosphodiesterase 8 family in humans."; RL Cell. Signal. 15:565-574(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RA Kim J.W.; RT "Identification of a human proliferation-inducing gene."; RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases. 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RC TISSUE=Testis; 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 NUCLEOTIDE SEQUENCE [MRNA] OF 227-885 (ISOFORM 1). RX PubMed=9784418; DOI=10.1006/bbrc.1998.9379; RA Hayashi M., Matsushima K., Ohashi H., Tsunoda H., Murase S., Kawarada Y., RA Tanaka T.; RT "Molecular cloning and characterization of human PDE8B, a novel thyroid- RT specific isozyme of 3',5'-cyclic nucleotide phosphodiesterase."; RL Biochem. Biophys. Res. Commun. 250:751-756(1998). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 43-885 (ISOFORM 1). RC TISSUE=Amygdala; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-517, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [9] RP INVOLVEMENT IN ADSD1. RX PubMed=20085714; DOI=10.1016/j.ajhg.2009.12.003; RA Appenzeller S., Schirmacher A., Halfter H., Baumer S., Pendziwiat M., RA Timmerman V., De Jonghe P., Fekete K., Stogbauer F., Ludemann P., Hund M., RA Quabius E.S., Ringelstein E.B., Kuhlenbaumer G.; RT "Autosomal-dominant striatal degeneration is caused by a mutation in the RT phosphodiesterase 8B gene."; RL Am. J. Hum. Genet. 86:83-87(2010). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-517, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-517, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [12] RP VARIANT PPNAD3 PRO-305, AND CHARACTERIZATION OF VARIANT PPNAD3 PRO-305. RX PubMed=18431404; DOI=10.1038/ejhg.2008.85; RA Horvath A., Giatzakis C., Tsang K., Greene E., Osorio P., Boikos S., RA Libe R., Patronas Y., Robinson-White A., Remmers E., Bertherat J., RA Nesterova M., Stratakis C.A.; RT "A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal RT hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B RT isoform in human adrenal cortex."; RL Eur. J. Hum. Genet. 16:1245-1253(2008). CC -!- FUNCTION: Hydrolyzes the second messenger cAMP, which is a key CC regulator of many important physiological processes. May be involved in CC specific signaling in the thyroid gland. CC -!- CATALYTIC ACTIVITY: CC Reaction=3',5'-cyclic AMP + H2O = AMP + H(+); Xref=Rhea:RHEA:25277, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:58165, CC ChEBI:CHEBI:456215; EC=3.1.4.53; CC Evidence={ECO:0000269|PubMed:12681444}; CC -!- COFACTOR: CC Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240; CC Evidence={ECO:0000250}; CC Note=Binds 2 divalent metal cations per subunit. Site 1 may CC preferentially bind zinc ions, while site 2 has a preference for CC magnesium and/or manganese ions. {ECO:0000250}; CC -!- ACTIVITY REGULATION: Inhibited by dipyridimole. Insensitive to CC selective PDE inhibitors including rolipram and milrinone as well as to CC the non-selective inhibitor, IBMX. Unaffected by cGMP. CC {ECO:0000269|PubMed:12681444}. CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic AMP degradation; AMP from CC 3',5'-cyclic AMP: step 1/1. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; Synonyms=PDE8B1; CC IsoId=O95263-1; Sequence=Displayed; CC Name=2; Synonyms=PDE8B2, PDE8B3; CC IsoId=O95263-2; Sequence=VSP_008084; CC Name=3; Synonyms=PDE8B3; CC IsoId=O95263-3; Sequence=VSP_008085; CC Name=4; Synonyms=PDE8B4; CC IsoId=O95263-4; Sequence=VSP_008082; CC Name=5; CC IsoId=O95263-5; Sequence=VSP_008081; CC Name=6; Synonyms=PDE8B2; CC IsoId=O95263-6; Sequence=VSP_008083; CC -!- TISSUE SPECIFICITY: Abundantly expressed in the thyroid. Also very CC weakly expressed in brain, spinal cord and placenta. In the thyroid CC isoform 1 predominates, and isoforms 2 and 6 are also highly expressed. CC In the placenta isoforms 1 and 2 are expressed equally. In the brain CC isoform 2 predominates. {ECO:0000269|PubMed:12372422, CC ECO:0000269|PubMed:12681444}. CC -!- DOMAIN: Composed of a C-terminal catalytic domain containing two CC putative divalent metal sites and an N-terminal regulatory domain. CC -!- DISEASE: Striatal degeneration, autosomal dominant 1 (ADSD1) CC [MIM:609161]: A movement disorder affecting the striatal part of the CC basal ganglia and characterized by bradykinesia, dysarthria and muscle CC rigidity. These symptoms resemble idiopathic Parkinson disease, but CC tremor is not present. {ECO:0000269|PubMed:20085714}. Note=The disease CC is caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Primary pigmented nodular adrenocortical disease 3 (PPNAD3) CC [MIM:614190]: A rare bilateral adrenal defect causing ACTH-independent CC Cushing syndrome. Macroscopic appearance of the adrenals is CC characteristic with small pigmented micronodules observed in the CC cortex. Adrenal glands show overall normal size and weight, and CC multiple small yellow-to-dark brown nodules surrounded by a cortex with CC a uniform appearance. Microscopically, there are moderate diffuse CC cortical hyperplasia with mostly nonpigmented nodules, multiple CC capsular deficits and massive circumscribed and infiltrating extra- CC adrenal cortical excrescences with micronodules. Clinical CC manifestations of Cushing syndrome include facial and truncal obesity, CC abdominal striae, muscular weakness, osteoporosis, arterial CC hypertension, diabetes. {ECO:0000269|PubMed:18431404}. Note=The disease CC is caused by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 1]: Major isoform. CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family. CC PDE8 subfamily. {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; AY129948; AAN71723.1; -; mRNA. DR EMBL; AY129949; AAN71724.1; -; mRNA. DR EMBL; AY129950; AAN71725.1; -; Genomic_DNA. DR EMBL; AY129950; AAN71726.1; -; Genomic_DNA. DR EMBL; AY129950; AAN71727.1; -; Genomic_DNA. DR EMBL; AB085824; BAC53762.1; -; mRNA. DR EMBL; AB085825; BAC53763.1; -; mRNA. DR EMBL; AB085826; BAC53764.1; -; mRNA. DR EMBL; AB085827; BAC53765.1; -; mRNA. DR EMBL; AY423729; AAS00492.1; -; mRNA. DR EMBL; CH471084; EAW95803.1; -; Genomic_DNA. DR EMBL; BC043209; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AF079529; AAC69564.2; -; mRNA. DR EMBL; AL831924; CAD38584.1; -; mRNA. DR CCDS; CCDS34190.1; -. [O95263-3] DR CCDS; CCDS34191.1; -. [O95263-6] DR CCDS; CCDS34192.1; -. [O95263-2] DR CCDS; CCDS34193.1; -. [O95263-4] DR CCDS; CCDS4037.1; -. [O95263-1] DR PIR; JE0293; JE0293. DR RefSeq; NP_001025022.1; NM_001029851.4. [O95263-2] DR RefSeq; NP_001025023.1; NM_001029852.4. [O95263-3] DR RefSeq; NP_001025024.1; NM_001029853.4. [O95263-4] DR RefSeq; NP_001025025.1; NM_001029854.4. [O95263-6] DR RefSeq; NP_003710.1; NM_003719.5. [O95263-1] DR AlphaFoldDB; O95263; -. DR SMR; O95263; -. DR BioGRID; 114177; 12. DR CORUM; O95263; -. DR FunCoup; O95263; 217. DR IntAct; O95263; 4. DR MINT; O95263; -. DR STRING; 9606.ENSP00000264917; -. DR BindingDB; O95263; -. DR ChEMBL; CHEMBL4408; -. DR DrugBank; DB00201; Caffeine. DR DrugBank; DB09283; Trapidil. DR DrugCentral; O95263; -. DR GuidetoPHARMACOLOGY; 1308; -. DR iPTMnet; O95263; -. DR PhosphoSitePlus; O95263; -. DR BioMuta; PDE8B; -. DR jPOST; O95263; -. DR MassIVE; O95263; -. DR PaxDb; 9606-ENSP00000264917; -. DR PeptideAtlas; O95263; -. DR ProteomicsDB; 50759; -. [O95263-1] DR ProteomicsDB; 50760; -. [O95263-2] DR ProteomicsDB; 50761; -. [O95263-3] DR ProteomicsDB; 50762; -. [O95263-4] DR ProteomicsDB; 50763; -. [O95263-5] DR ProteomicsDB; 50764; -. [O95263-6] DR Pumba; O95263; -. DR Antibodypedia; 12495; 151 antibodies from 26 providers. DR DNASU; 8622; -. DR Ensembl; ENST00000264917.10; ENSP00000264917.6; ENSG00000113231.14. [O95263-1] DR Ensembl; ENST00000333194.8; ENSP00000331336.4; ENSG00000113231.14. [O95263-3] DR Ensembl; ENST00000340978.7; ENSP00000345446.3; ENSG00000113231.14. [O95263-6] DR Ensembl; ENST00000342343.8; ENSP00000345646.4; ENSG00000113231.14. [O95263-4] DR Ensembl; ENST00000346042.7; ENSP00000330428.3; ENSG00000113231.14. [O95263-2] DR Ensembl; ENST00000505283.1; ENSP00000423461.1; ENSG00000113231.14. [O95263-5] DR GeneID; 8622; -. DR KEGG; hsa:8622; -. DR MANE-Select; ENST00000264917.10; ENSP00000264917.6; NM_003719.5; NP_003710.1. DR UCSC; uc003kfa.4; human. [O95263-1] DR AGR; HGNC:8794; -. DR ClinPGx; PA33142; -. DR CTD; 8622; -. DR DisGeNET; 8622; -. DR GeneCards; PDE8B; -. DR HGNC; HGNC:8794; PDE8B. DR HPA; ENSG00000113231; Tissue enriched (thyroid). DR MalaCards; PDE8B; -. DR MIM; 603390; gene. DR MIM; 609161; phenotype. DR MIM; 614190; phenotype. DR OpenTargets; ENSG00000113231; -. DR Orphanet; 228169; Autosomal dominant striatal neurodegeneration. DR Orphanet; 647782; Isolated micronodular adrenocortical disease. DR VEuPathDB; HostDB:ENSG00000113231; -. DR eggNOG; KOG1229; Eukaryota. DR GeneTree; ENSGT00940000157817; -. DR HOGENOM; CLU_005940_4_2_1; -. DR InParanoid; O95263; -. DR OMA; RWCCGGS; -. DR OrthoDB; 189220at2759; -. DR PAN-GO; O95263; 2 GO annotations based on evolutionary models. DR PhylomeDB; O95263; -. DR BRENDA; 3.1.4.53; 2681. DR PathwayCommons; O95263; -. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR SignaLink; O95263; -. DR UniPathway; UPA00762; UER00747. DR Agora; ENSG00000113231; -. DR BioGRID-ORCS; 8622; 19 hits in 1161 CRISPR screens. DR ChiTaRS; PDE8B; human. DR GeneWiki; PDE8B; -. DR GenomeRNAi; 8622; -. DR Pharos; O95263; Tclin. DR PRO; PR:O95263; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; O95263; protein. DR Bgee; ENSG00000113231; Expressed in left lobe of thyroid gland and 104 other cell types or tissues. DR ExpressionAtlas; O95263; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IMP:UniProtKB. DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IBA:GO_Central. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0001662; P:behavioral fear response; IEA:Ensembl. DR GO; GO:0006198; P:cAMP catabolic process; IEA:UniProtKB-UniPathway. DR GO; GO:0141162; P:negative regulation of cAMP/PKA signal transduction; IBA:GO_Central. DR GO; GO:0061179; P:negative regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0090032; P:negative regulation of steroid hormone biosynthetic process; IEA:Ensembl. DR GO; GO:0050885; P:neuromuscular process controlling balance; IEA:Ensembl. DR GO; GO:0035106; P:operant conditioning; IEA:Ensembl. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IBA:GO_Central. DR GO; GO:0007165; P:signal transduction; IEA:InterPro. DR GO; GO:0008542; P:visual learning; IEA:Ensembl. DR CDD; cd00077; HDc; 1. DR CDD; cd00130; PAS; 1. DR FunFam; 1.10.1300.10:FF:000002; Phosphodiesterase; 1. DR FunFam; 3.30.450.20:FF:000023; Phosphodiesterase; 1. DR Gene3D; 1.10.1300.10; 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain; 1. DR Gene3D; 3.30.450.20; PAS domain; 1. DR InterPro; IPR003607; HD/PDEase_dom. DR InterPro; IPR000014; PAS. DR InterPro; IPR035965; PAS-like_dom_sf. DR InterPro; IPR057304; PDE8-like_REC_N. DR InterPro; IPR023088; PDEase. DR InterPro; IPR002073; PDEase_catalytic_dom. DR InterPro; IPR036971; PDEase_catalytic_dom_sf. DR InterPro; IPR023174; PDEase_CS. DR NCBIfam; TIGR00229; sensory_box; 1. DR PANTHER; PTHR11347; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; 1. DR Pfam; PF13426; PAS_9; 1. DR Pfam; PF08629; PDE8; 1. DR Pfam; PF23198; PDE8A_N; 1. DR Pfam; PF00233; PDEase_I; 1. DR PRINTS; PR00387; PDIESTERASE1. DR SMART; SM00471; HDc; 1. DR SMART; SM00091; PAS; 1. DR SUPFAM; SSF109604; HD-domain/PDEase-like; 1. DR SUPFAM; SSF55785; PYP-like sensor domain (PAS domain); 1. DR PROSITE; PS50112; PAS; 1. DR PROSITE; PS00126; PDEASE_I_1; 1. DR PROSITE; PS51845; PDEASE_I_2; 1. PE 1: Evidence at protein level; KW Alternative splicing; cAMP; Cushing syndrome; Disease variant; Hydrolase; KW Metal-binding; Phosphoprotein; Proteomics identification; KW Reference proteome. FT CHAIN 1..885 FT /note="High affinity cAMP-specific and IBMX-insensitive FT 3',5'-cyclic phosphodiesterase 8B" FT /id="PRO_0000198840" FT DOMAIN 267..338 FT /note="PAS" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 539..875 FT /note="PDEase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192" FT REGION 18..41 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 72..95 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 393..436 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 23..34 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 75..90 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 422..436 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 615 FT /note="Proton donor" FT /evidence="ECO:0000250|UniProtKB:O76083" FT BINDING 619 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 655 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 656 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 656 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:O60658" FT BINDING 781 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:O60658" FT MOD_RES 517 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 754 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q4S1" FT VAR_SEQ 1..535 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.3" FT /id="VSP_008081" FT VAR_SEQ 114..133 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:12681444" FT /id="VSP_008082" FT VAR_SEQ 293..389 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:12372422, FT ECO:0000303|PubMed:12681444" FT /id="VSP_008084" FT VAR_SEQ 293..339 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|PubMed:12372422" FT /id="VSP_008083" FT VAR_SEQ 456..510 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:12681444" FT /id="VSP_008085" FT VARIANT 305 FT /note="H -> P (in PPNAD3; shows significantly higher cyclic FT AMP levels after transfection with the mutant protein than FT after transfection with the wild-type, indicating an FT impaired ability of the mutant protein to degrade cAMP; FT dbSNP:rs121918360)" FT /evidence="ECO:0000269|PubMed:18431404" FT /id="VAR_066503" FT CONFLICT 147 FT /note="G -> R (in Ref. 7; CAD38584)" FT /evidence="ECO:0000305" SQ SEQUENCE 885 AA; 98979 MW; DB4F763E51F745A3 CRC64; MGCAPSIHVS QSGVIYCRDS DESSSPRQTT SVSQGPAAPL PGLFVQTDAA DAIPPSRASG PPSVARVRRA RTELGSGSSA GSAAPAATTS RGRRRHCCSS AEAETQTCYT SVKQVSSAEV RIGPMRLTQD PIQVLLIFAK EDSQSDGFWW ACDRAGYRCN IARTPESALE CFLDKHHEII VIDHRQTQNF DAEAVCRSIR ATNPSEHTVI LAVVSRVSDD HEEASVLPLL HAGFNRRFME NSSIIACYNE LIQIEHGEVR SQFKLRACNS VFTALDHCHE AIEITSDDHV IQYVNPAFER MMGYHKGELL GKELADLPKS DKNRADLLDT INTCIKKGKE WQGVYYARRK SGDSIQQHVK ITPVIGQGGK IRHFVSLKKL CCTTDNNKQI HKIHRDSGDN SQTEPHSFRY KNRRKESIDV KSISSRGSDA PSLQNRRYPS MARIHSMTIE APITKVINII NAAQENSPVT VAEALDRVLE ILRTTELYSP QLGTKDEDPH TSDLVGGLMT DGLRRLSGNE YVFTKNVHQS HSHLAMPITI NDVPPCISQL LDNEESWDFN IFELEAITHK RPLVYLGLKV FSRFGVCEFL NCSETTLRAW FQVIEANYHS SNAYHNSTHA ADVLHATAFF LGKERVKGSL DQLDEVAALI AATVHDVDHP GRTNSFLCNA GSELAVLYND TAVLESHHTA LAFQLTVKDT KCNIFKNIDR NHYRTLRQAI IDMVLATEMT KHFEHVNKFV NSINKPMAAE IEGSDCECNP AGKNFPENQI LIKRMMIKCA DVANPCRPLD LCIEWAGRIS EEYFAQTDEE KRQGLPVVMP VFDRNTCSIP KSQISFIDYF ITDMFDAWDA FAHLPALMQH LADNYKHWKT LDDLKCKSLR LPSDS // 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 28-JAN-2026, entry version 178. 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=Zn(2+)(out) + 2 hydrogencarbonate(out) = Zn(2+)(in) + 2 CC hydrogencarbonate(in); Xref=Rhea:RHEA:62252, ChEBI:CHEBI:17544, CC ChEBI:CHEBI:29105; 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=Mn(2+)(out) + 2 hydrogencarbonate(out) = Mn(2+)(in) + 2 CC hydrogencarbonate(in); Xref=Rhea:RHEA:62260, ChEBI:CHEBI:17544, CC ChEBI:CHEBI:29035; 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:15642354, PubMed:20682781, CC PubMed:7584044). 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}; 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; 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_001128431.4. [Q15043-1] DR RefSeq; NP_001128625.1; NM_001135153.3. [Q15043-1] DR RefSeq; NP_001128626.1; NM_001135154.3. [Q15043-2] DR RefSeq; NP_001338584.1; NM_001351655.2. [Q15043-1] DR RefSeq; NP_001338585.1; NM_001351656.2. [Q15043-1] DR RefSeq; NP_001338589.1; NM_001351660.2. [Q15043-1] DR RefSeq; NP_056174.2; NM_015359.6. [Q15043-3] DR RefSeq; XP_006716387.1; XM_006716324.4. [Q15043-1] DR RefSeq; XP_047277610.1; XM_047421654.1. [Q15043-1] DR RefSeq; XP_047277611.1; XM_047421655.1. [Q15043-1] DR AlphaFoldDB; Q15043; -. DR SMR; Q15043; -. DR BioGRID; 117063; 343. DR FunCoup; Q15043; 631. DR IntAct; Q15043; 255. DR MINT; Q15043; -. DR STRING; 9606.ENSP00000370635; -. DR DrugBank; DB06757; Manganese cation. 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 GlyCosmos; Q15043; 3 sites, No reported glycans. DR GlyGen; Q15043; 4 sites, 21 N-linked glycans (3 sites), 1 O-linked glycan (1 site). DR iPTMnet; Q15043; -. DR PhosphoSitePlus; Q15043; -. DR SwissPalm; Q15043; -. DR BioMuta; SLC39A14; -. DR DMDM; 313104191; -. DR jPOST; Q15043; -. DR MassIVE; Q15043; -. DR PaxDb; 9606-ENSP00000352779; -. DR PeptideAtlas; Q15043; -. DR ProteomicsDB; 60392; -. [Q15043-1] DR ProteomicsDB; 60393; -. [Q15043-2] DR ProteomicsDB; 60394; -. [Q15043-3] DR Pumba; Q15043; -. DR Antibodypedia; 9517; 193 antibodies from 27 providers. DR DNASU; 23516; -. DR Ensembl; ENST00000240095.10; ENSP00000240095.6; ENSG00000104635.16. [Q15043-2] DR Ensembl; ENST00000289952.9; ENSP00000289952.5; ENSG00000104635.16. [Q15043-1] DR Ensembl; ENST00000359741.10; ENSP00000352779.5; ENSG00000104635.16. [Q15043-3] DR Ensembl; ENST00000381237.6; ENSP00000370635.1; ENSG00000104635.16. [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 AGR; HGNC:20858; -. DR ClinPGx; PA134863701; -. 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 OpenTargets; ENSG00000104635; -. DR Orphanet; 521406; Dystonia-parkinsonism-hypermanganesemia syndrome. DR VEuPathDB; HostDB:ENSG00000104635; -. DR eggNOG; KOG2693; Eukaryota. DR GeneTree; ENSGT00940000157986; -. DR InParanoid; Q15043; -. DR OMA; ADHYSTP; -. DR OrthoDB; 200954at2759; -. DR PAN-GO; Q15043; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q15043; -. DR PathwayCommons; Q15043; -. DR Reactome; R-HSA-442380; Zinc influx into cells by the SLC39 gene family. DR SignaLink; Q15043; -. DR Agora; ENSG00000104635; -. DR BioGRID-ORCS; 23516; 16 hits in 1166 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 199 other cell types or tissues. DR ExpressionAtlas; Q15043; baseline and differential. 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:0031902; C:late endosome membrane; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; IDA: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:0015296; F:monoatomic anion:monoatomic cation symporter activity; ISS:UniProtKB. DR GO; GO:0140410; F:monoatomic cation:bicarbonate symporter 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: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:0030003; P:intracellular monoatomic cation homeostasis; IBA:GO_Central. DR GO; GO:0006882; P:intracellular zinc ion homeostasis; IDA:BHF-UCL. 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: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 InterPro; IPR050799; ZIP_Transporter. DR PANTHER; PTHR12191:SF5; METAL CATION SYMPORTER ZIP14; 1. DR PANTHER; PTHR12191; SOLUTE CARRIER FAMILY 39; 1. 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; Proteomics identification; Reference proteome; Signal; KW Transmembrane; Transmembrane helix; Transport; Ubl conjugation; Zinc; KW 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 // ID ZNT10_HUMAN Reviewed; 485 AA. AC Q6XR72; Q49AL9; Q9NPW0; DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 2. DT 28-JAN-2026, entry version 156. DE RecName: Full=Calcium/manganese antiporter SLC30A10 {ECO:0000305|PubMed:30755481}; DE AltName: Full=Solute carrier family 30 member 10 {ECO:0000312|HGNC:HGNC:25355}; DE AltName: Full=Zinc transporter 10; DE Short=ZnT-10; GN Name=SLC30A10 {ECO:0000312|HGNC:HGNC:25355}; GN Synonyms=ZNT10 {ECO:0000303|PubMed:22706290}, ZNT8 {ECO:0000303|Ref.1}; 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] (ISOFORM 1). RA Huang L., Zhou B., Gitschier J.; RT "Characterization of a novel mammalian zinc transporter, ZNT8."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 90-485 (ISOFORM 3). RC TISSUE=Brain; 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. RX PubMed=15154973; DOI=10.1186/1471-2164-5-32; RA Seve M., Chimienti F., Devergnas S., Favier A.; RT "In silico identification and expression of SLC30 family genes: an RT expressed sequence tag data mining strategy for the characterization of RT zinc transporters' tissue expression."; RL BMC Genomics 5:32-32(2004). RN [6] RP FUNCTION, INVOLVEMENT IN HMNDYT1, VARIANTS HMNDYT1 PRO-89; 105-ALA--PRO-107 RP DEL; VAL-256 DEL AND PRO-349, AND CHARACTERIZATION OF VARIANTS HMNDYT1 RP PRO-89. RX PubMed=22341972; DOI=10.1016/j.ajhg.2012.01.018; RA Tuschl K., Clayton P.T., Gospe S.M. Jr., Gulab S., Ibrahim S., Singhi P., RA Aulakh R., Ribeiro R.T., Barsottini O.G., Zaki M.S., Del Rosario M.L., RA Dyack S., Price V., Rideout A., Gordon K., Wevers R.A., Chong W.K., RA Mills P.B.; RT "Syndrome of hepatic cirrhosis, dystonia, polycythemia, and RT hypermanganesemia caused by mutations in SLC30A10, a manganese transporter RT in man."; RL Am. J. Hum. Genet. 90:457-466(2012). RN [7] RP INVOLVEMENT IN HMNDYT1, VARIANT SER-167, INDUCTION BY MANGANESE, AND TISSUE RP SPECIFICITY. RX PubMed=22341971; DOI=10.1016/j.ajhg.2012.01.017; RA Quadri M., Federico A., Zhao T., Breedveld G.J., Battisti C., Delnooz C., RA Severijnen L.A., Di Toro Mammarella L., Mignarri A., Monti L., Sanna A., RA Lu P., Punzo F., Cossu G., Willemsen R., Rasi F., Oostra B.A., RA van de Warrenburg B.P., Bonifati V.; RT "Mutations in SLC30A10 cause parkinsonism and dystonia with RT hypermanganesemia, polycythemia, and chronic liver disease."; RL Am. J. Hum. Genet. 90:467-477(2012). RN [8] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=22706290; DOI=10.1039/c2mt20088k; RA Bosomworth H.J., Thornton J.K., Coneyworth L.J., Ford D., Valentine R.A.; RT "Efflux function, tissue-specific expression and intracellular trafficking RT of the Zn transporter ZnT10 indicate roles in adult Zn homeostasis."; RL Metallomics 4:771-779(2012). RN [9] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH RP SLC30A3, AND INDUCTION. RX PubMed=22427991; DOI=10.1371/journal.pone.0033211; RA Patrushev N., Seidel-Rogol B., Salazar G.; RT "Angiotensin II requires zinc and downregulation of the zinc transporters RT ZnT3 and ZnT10 to induce senescence of vascular smooth muscle cells."; RL PLoS ONE 7:E33211-E33211(2012). RN [10] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, MUTAGENESIS OF RP THR-196, AND CHARACTERIZATION OF VARIANTS HMNDYT1 PRO-89 AND RP 105-ALA--PRO-107 DEL. RX PubMed=25319704; DOI=10.1523/jneurosci.2329-14.2014; RA Leyva-Illades D., Chen P., Zogzas C.E., Hutchens S., Mercado J.M., RA Swaim C.D., Morrisett R.A., Bowman A.B., Aschner M., Mukhopadhyay S.; RT "SLC30A10 is a cell surface-localized manganese efflux transporter, and RT parkinsonism-causing mutations block its intracellular trafficking and RT efflux activity."; RL J. Neurosci. 34:14079-14095(2014). RN [11] RP INDUCTION. RX PubMed=25582195; DOI=10.1128/mcb.01298-14; RA Ogo O.A., Tyson J., Cockell S.J., Howard A., Valentine R.A., Ford D.; RT "The zinc finger protein ZNF658 regulates the transcription of genes RT involved in zinc homeostasis and affects ribosome biogenesis through the RT zinc transcriptional regulatory element."; RL Mol. Cell. Biol. 35:977-987(2015). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP ASN-43; CYS-52 AND LEU-242. RX PubMed=27226609; DOI=10.1074/jbc.m116.728014; RA Nishito Y., Tsuji N., Fujishiro H., Takeda T.A., Yamazaki T., Teranishi F., RA Okazaki F., Matsunaga A., Tuschl K., Rao R., Kono S., Miyajima H., RA Narita H., Himeno S., Kambe T.; RT "Direct comparison of manganese detoxification/efflux proteins and RT molecular characterization of ZnT10 protein as a manganese transporter."; RL J. Biol. Chem. 291:14773-14787(2016). RN [13] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP GLU-25; ASP-40; ASN-43; ASP-47; ASN-127; HIS-244; ASP-248; HIS-333 AND RP HIS-350. RX PubMed=27307044; DOI=10.1074/jbc.m116.726935; RA Zogzas C.E., Aschner M., Mukhopadhyay S.; RT "Structural elements in the transmembrane and cytoplasmic domains of the RT metal transporter SLC30A10 are required for its manganese efflux RT activity."; RL J. Biol. Chem. 291:15940-15957(2016). RN [14] RP FUNCTION, TRANSPORTER ACTIVITY, SUBUNIT, INTERACTION WITH SLC30A2; SLC30A3 RP AND SLC30A4, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TYR-4. RX PubMed=26728129; DOI=10.1111/tra.12371; RA Zhao Y., Feresin R.G., Falcon-Perez J.M., Salazar G.; RT "Differential targeting of SLC30A10/ZnT10 heterodimers to endolysosomal RT compartments modulates EGF-induced MEK/ERK1/2 activity."; RL Traffic 17:267-288(2016). RN [15] RP FUNCTION, TRANSPORTER ACTIVITY, MUTAGENESIS OF ASN-43; ASP-47; HIS-244 AND RP ASP-248, AND SITE. RX PubMed=30755481; DOI=10.1074/jbc.ra118.006816; RA Levy M., Elkoshi N., Barber-Zucker S., Hoch E., Zarivach R., RA Hershfinkel M., Sekler I.; RT "Zinc transporter 10 (ZnT10)-dependent extrusion of cellular Mn2+ is driven RT by an active Ca2+-coupled exchange."; RL J. Biol. Chem. 294:5879-5889(2019). CC -!- FUNCTION: Calcium:manganese antiporter of the plasma membrane mediating CC the efflux of intracellular manganese coupled to an active CC extracellular calcium exchange (PubMed:30755481). Required for CC intracellular manganese homeostasis, an essential cation for the CC function of several enzymes, including some crucially important for the CC metabolism of neurotransmitters and other neuronal metabolic pathways. CC Manganese can also be cytotoxic and induce oxidative stress, CC mitochondrial dysfunction and apoptosis (PubMed:22341972, CC PubMed:25319704, PubMed:26728129, PubMed:27226609, PubMed:27307044). CC Could also have an intracellular zinc ion transporter activity, CC directly regulating intracellular zinc ion homeostasis and more CC indirectly various signaling pathway and biological processes CC (PubMed:22427991, PubMed:26728129). {ECO:0000269|PubMed:22341972, CC ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:25319704, CC ECO:0000269|PubMed:26728129, ECO:0000269|PubMed:27226609, CC ECO:0000269|PubMed:27307044, ECO:0000269|PubMed:30755481}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Mn(2+)(out) + Ca(2+)(in) = Mn(2+)(in) + Ca(2+)(out); CC Xref=Rhea:RHEA:73059, ChEBI:CHEBI:29035, ChEBI:CHEBI:29108; CC Evidence={ECO:0000269|PubMed:25319704, ECO:0000269|PubMed:27226609, CC ECO:0000269|PubMed:27307044, ECO:0000269|PubMed:30755481}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Zn(2+)(in) = Zn(2+)(out); Xref=Rhea:RHEA:29351, CC ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:26728129}; CC -!- SUBUNIT: Forms homodimers. Forms heterodimers and high-molecular weight CC oligomers with SLC30A3, SLC30A2 and SLC30A4; heterodimerization is CC mediated by covalent-bound tyrosine residues, occurs probably in a CC tissue-specific manner and could mediate the intracellular zinc CC transport activity into early endosomes and recycling endosomes. CC {ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:26728129}. CC -!- INTERACTION: CC Q6XR72; Q9BRI3: SLC30A2; NbExp=4; IntAct=EBI-13917996, EBI-8644112; CC Q6XR72; Q99726: SLC30A3; NbExp=3; IntAct=EBI-13917996, EBI-10294651; CC Q6XR72; O14863: SLC30A4; NbExp=2; IntAct=EBI-13917996, EBI-13918058; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:22706290, CC ECO:0000269|PubMed:25319704, ECO:0000269|PubMed:26728129, CC ECO:0000269|PubMed:27226609, ECO:0000269|PubMed:27307044}; Multi-pass CC membrane protein {ECO:0000255}. Golgi apparatus membrane CC {ECO:0000269|PubMed:22706290, ECO:0000269|PubMed:27226609}; Multi-pass CC membrane protein {ECO:0000255}. Recycling endosome membrane CC {ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:26728129}. Early CC endosome membrane {ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:26728129}; Multi-pass membrane protein CC {ECO:0000255}. Note=Localization to the Golgi and plasma membrane is CC regulated by zinc. {ECO:0000269|PubMed:22706290}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q6XR72-4; Sequence=Displayed; CC Name=2; CC IsoId=Q6XR72-2; Sequence=VSP_029863; CC Name=3; CC IsoId=Q6XR72-3; Sequence=VSP_029864, VSP_029865; CC -!- TISSUE SPECIFICITY: Specifically expressed in fetal liver and fetal CC brain (PubMed:15154973). Expressed in adult tissues with relative CC levels small intestine > liver > testes > brain > ovary > colon > CC cervix > prostate > placenta (PubMed:22706290). Expressed in liver and CC neurons of the nervous system (at protein level) (PubMed:22341971). CC {ECO:0000269|PubMed:15154973, ECO:0000269|PubMed:22341971, CC ECO:0000269|PubMed:22706290}. CC -!- INDUCTION: Down-regulated by zinc (PubMed:22427991, PubMed:22706290, CC PubMed:25582195). Down-regulated by angiotensin-2 (PubMed:22427991). CC Up-regulated by manganese (PubMed:22341971). CC {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:22706290, ECO:0000269|PubMed:25582195}. CC -!- DISEASE: Hypermanganesemia with dystonia 1 (HMNDYT1) [MIM:613280]: A CC metabolic autosomal recessive disorder characterized by dystonia, CC parkinsonism, extrapyramidal signs, severe hypermanganesemia, CC polycythemia, and chronic hepatic disease, including steatosis and CC cirrhosis. {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22341972, CC ECO:0000269|PubMed:25319704}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 2]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the cation diffusion facilitator (CDF) CC transporter (TC 2.A.4) family. SLC30A subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAP44332.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in position 427.; 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; AY212919; AAP44332.1; ALT_SEQ; mRNA. DR EMBL; AL359609; CAB94880.1; -; mRNA. DR EMBL; AC093562; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC036078; AAH36078.1; -; mRNA. DR CCDS; CCDS31026.1; -. [Q6XR72-4] DR PIR; T50628; T50628. DR RefSeq; NP_061183.2; NM_018713.2. [Q6XR72-4] DR AlphaFoldDB; Q6XR72; -. DR SMR; Q6XR72; -. DR BioGRID; 120703; 181. DR ComplexPortal; CPX-8462; ZNT10 calcium-coupled manganese antiporter homodimer. DR ComplexPortal; CPX-8463; ZNT2-ZNT10 proton-coupled zinc antiporter complex. DR ComplexPortal; CPX-8464; ZNT3-ZNT10 proton-coupled zinc antiporter complex. DR ComplexPortal; CPX-8465; ZNT4-ZNT10 proton-coupled zinc antiporter complex. DR FunCoup; Q6XR72; 245. DR IntAct; Q6XR72; 179. DR STRING; 9606.ENSP00000355893; -. DR DrugBank; DB06757; Manganese cation. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR TCDB; 2.A.4.2.5; the cation diffusion facilitator (cdf) family. DR GlyGen; Q6XR72; 1 site. DR iPTMnet; Q6XR72; -. DR PhosphoSitePlus; Q6XR72; -. DR BioMuta; SLC30A10; -. DR DMDM; 311033506; -. DR jPOST; Q6XR72; -. DR MassIVE; Q6XR72; -. DR PaxDb; 9606-ENSP00000355893; -. DR PeptideAtlas; Q6XR72; -. DR ProteomicsDB; 67813; -. [Q6XR72-4] DR ProteomicsDB; 67814; -. [Q6XR72-2] DR ProteomicsDB; 67815; -. [Q6XR72-3] DR Antibodypedia; 3072; 116 antibodies from 18 providers. DR DNASU; 55532; -. DR Ensembl; ENST00000356609.2; ENSP00000349018.2; ENSG00000196660.13. [Q6XR72-3] DR Ensembl; ENST00000366926.4; ENSP00000355893.4; ENSG00000196660.13. [Q6XR72-4] DR GeneID; 55532; -. DR KEGG; hsa:55532; -. DR MANE-Select; ENST00000366926.4; ENSP00000355893.4; NM_018713.3; NP_061183.2. DR UCSC; uc001hlw.4; human. [Q6XR72-4] DR AGR; HGNC:25355; -. DR ClinPGx; PA142670903; -. DR CTD; 55532; -. DR DisGeNET; 55532; -. DR GeneCards; SLC30A10; -. DR GeneReviews; SLC30A10; -. DR HGNC; HGNC:25355; SLC30A10. DR HPA; ENSG00000196660; Group enriched (intestine, liver). DR MalaCards; SLC30A10; -. DR MIM; 611146; gene. DR MIM; 613280; phenotype. DR OpenTargets; ENSG00000196660; -. DR Orphanet; 309854; Cirrhosis-dystonia-polycythemia-hypermanganesemia syndrome. DR VEuPathDB; HostDB:ENSG00000196660; -. DR eggNOG; KOG1483; Eukaryota. DR GeneTree; ENSGT00940000159967; -. DR HOGENOM; CLU_1239780_0_0_1; -. DR InParanoid; Q6XR72; -. DR OMA; FQDCASW; -. DR OrthoDB; 29444at2759; -. DR PAN-GO; Q6XR72; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q6XR72; -. DR PathwayCommons; Q6XR72; -. DR Reactome; R-HSA-425410; Metal ion SLC transporters. DR SignaLink; Q6XR72; -. DR Agora; ENSG00000196660; -. DR BioGRID-ORCS; 55532; 11 hits in 1155 CRISPR screens. DR ChiTaRS; SLC30A10; human. DR GenomeRNAi; 55532; -. DR Pharos; Q6XR72; Tbio. DR PRO; PR:Q6XR72; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q6XR72; protein. DR Bgee; ENSG00000196660; Expressed in jejunal mucosa and 75 other cell types or tissues. DR GO; GO:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB. DR GO; GO:0055038; C:recycling endosome membrane; IDA:UniProtKB. DR GO; GO:0140983; F:calcium:manganese antiporter activity; IDA:UniProtKB. DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:1904385; P:cellular response to angiotensin; IDA:UniProtKB. DR GO; GO:0010312; P:detoxification of zinc ion; IBA:GO_Central. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0030026; P:intracellular manganese ion homeostasis; IDA:UniProtKB. DR GO; GO:0006882; P:intracellular zinc ion homeostasis; IDA:UniProtKB. DR GO; GO:0140048; P:manganese ion export across plasma membrane; IDA:UniProtKB. DR GO; GO:0006828; P:manganese ion transport; IMP:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0062111; P:zinc ion import into organelle; IDA:UniProtKB. DR GO; GO:0071577; P:zinc ion transmembrane transport; IBA:GO_Central. DR Gene3D; 1.20.1510.10; Cation efflux protein transmembrane domain; 1. DR InterPro; IPR002524; Cation_efflux. DR InterPro; IPR027470; Cation_efflux_CTD. DR InterPro; IPR058533; Cation_efflux_TM. DR InterPro; IPR027469; Cation_efflux_TMD_sf. DR NCBIfam; TIGR01297; CDF; 1. DR PANTHER; PTHR45820:SF3; CALCIUM_MANGANESE ANTIPORTER SLC30A10; 1. DR PANTHER; PTHR45820; FI23527P1; 1. DR Pfam; PF01545; Cation_efflux; 1. DR Pfam; PF16916; ZT_dimer; 1. DR SUPFAM; SSF161111; Cation efflux protein transmembrane domain-like; 1. PE 1: Evidence at protein level; KW Alternative splicing; Antiport; Cell membrane; Disease variant; Dystonia; KW Endosome; Golgi apparatus; Ion transport; Manganese; Membrane; KW Neurodegeneration; Parkinsonism; Proteomics identification; KW Reference proteome; Transmembrane; Transmembrane helix; Transport; Zinc; KW Zinc transport. FT CHAIN 1..485 FT /note="Calcium/manganese antiporter SLC30A10" FT /id="PRO_0000312580" FT TOPO_DOM 1..10 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 11..31 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 32..40 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 41..61 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 62..81 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 82..102 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 103..113 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 114..134 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 135..244 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 245..265 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 266..278 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 279..299 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 300..485 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 167..196 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 308..485 FT /note="Required for plasma membrane localization" FT /evidence="ECO:0000269|PubMed:25319704" FT SITE 43 FT /note="Important for coupling of manganese to calcium FT transport" FT /evidence="ECO:0000269|PubMed:30755481" FT VAR_SEQ 1..245 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_029863" FT VAR_SEQ 214..223 FT /note="GDSFNTQNEP -> ELIHNTRFLL (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029864" FT VAR_SEQ 224..485 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029865" FT VARIANT 89 FT /note="L -> P (in HMNDYT1; loss of localization to the FT plasma membrane; retained in the endoplasmic reticulum; FT increased proteasomal degradation; loss of function in FT intracellular manganese ion homeostasis; FT dbSNP:rs281860284)" FT /evidence="ECO:0000269|PubMed:22341972, FT ECO:0000269|PubMed:25319704" FT /id="VAR_072573" FT VARIANT 105..107 FT /note="Missing (in HMNDYT1; loss of localization to the FT plasma membrane; retained in the endoplasmic reticulum; FT increased proteasomal degradation; decreased function in FT intracellular manganese ion homeostasis)" FT /evidence="ECO:0000269|PubMed:22341972, FT ECO:0000269|PubMed:25319704" FT /id="VAR_072574" FT VARIANT 167 FT /note="F -> S (in dbSNP:rs281860286)" FT /evidence="ECO:0000269|PubMed:22341971" FT /id="VAR_072575" FT VARIANT 256 FT /note="Missing (in HMNDYT1)" FT /evidence="ECO:0000269|PubMed:22341972" FT /id="VAR_072576" FT VARIANT 349 FT /note="L -> P (in HMNDYT1; dbSNP:rs281860291)" FT /evidence="ECO:0000269|PubMed:22341972" FT /id="VAR_072577" FT MUTAGEN 4 FT /note="Y->F: Decreased interaction with SLC30A3. No effect FT on self-association. Decreased zinc ion transmembrane FT transporter activity. Decreased EGF-induced ERK1/2 FT phosphorylation." FT /evidence="ECO:0000269|PubMed:26728129" FT MUTAGEN 25 FT /note="E->A: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 40 FT /note="D->A: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 43 FT /note="N->A: No effect on localization to the plasma FT membrane. Changed calcium:manganese antiporter activity. FT Enhanced coupling between manganese and calcium exchange." FT /evidence="ECO:0000269|PubMed:27307044, FT ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->D: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->H: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity. FT Loss of calcium:manganese antiporter activity and increased FT zinc ion transmembrane transporter activity; when FT associated with V-52 and F-242." FT /evidence="ECO:0000269|PubMed:27226609, FT ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->T: Loss of calcium:manganese antiporter activity. FT Uncoupling between manganese and calcium exchange." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 47 FT /note="D->A: No effect on localization to the plasma FT membrane. No effect on calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 47 FT /note="D->E: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 52 FT /note="C->V: Loss of calcium:manganese antiporter activity FT and increased zinc ion transmembrane transporter activity; FT when associated with H-43 and F-242." FT /evidence="ECO:0000269|PubMed:27226609" FT MUTAGEN 127 FT /note="N->A: No effect on localization to the plasma FT membrane. No effect on localization to the plasma membrane FT and decreased calcium:manganese antiporter activity; when FT associated with A-244." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 196 FT /note="T->P: Loss of localization to the plasma membrane." FT /evidence="ECO:0000269|PubMed:25319704" FT MUTAGEN 242 FT /note="L->F: Loss of calcium:manganese antiporter activity FT and increased zinc ion transmembrane transporter activity; FT when associated with H-43 and V-52." FT /evidence="ECO:0000269|PubMed:27226609" FT MUTAGEN 244 FT /note="H->A: No effect on localization to the plasma FT membrane. No effect on localization to the plasma membrane FT and decreased calcium:manganese antiporter activity; when FT associated with A-127." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 244 FT /note="H->D: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 248 FT /note="D->A: No effect on localization to the plasma FT membrane. Loss of manganese ion export across plasma FT membrane." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 333 FT /note="H->A: Decreased calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 350 FT /note="H->A: Decreased calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" SQ SEQUENCE 485 AA; 52684 MW; 96A3495EF026DE94 CRC64; MGRYSGKTCR LLFMLVLTVA FFVAELVSGY LGNSIALLSD SFNMLSDLIS LCVGLSAGYI ARRPTRGFSA TYGYARAEVV GALSNAVFLT ALCFTIFVEA VLRLARPERI DDPELVLIVG VLGLLVNVVG LLIFQDCAAW FACCLRGRSR RLQQRQQLAE GCVPGAFGGP QGAEDPRRAA DPTAPGSDSA VTLRGTSVER KREKGATVFA NVAGDSFNTQ NEPEDMMKKE KKSEALNIRG VLLHVMGDAL GSVVVVITAI IFYVLPLKSE DPCNWQCYID PSLTVLMVII ILSSAFPLIK ETAAILLQMV PKGVNMEELM SKLSAVPGIS SVHEVHIWEL VSGKIIATLH IKYPKDRGYQ DASTKIREIF HHAGIHNVTI QFENVDLKEP LEQKDLLLLC NSPCISKGCA KQLCCPPGAL PLAHVNGCAE HNGGPSLDTY GSDGLSRRDA REVAIEVSLD SCLSDHGQSL NKTQEDQCYV NRTHF //