S39A8_RAT
ID S39A8_RAT Reviewed; 462 AA.
AC Q5FVQ0;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2005, sequence version 1.
DT 03-AUG-2022, entry version 97.
DE RecName: Full=Metal cation symporter ZIP8 {ECO:0000305|PubMed:22898811};
DE AltName: Full=Solute carrier family 39 member 8 {ECO:0000312|RGD:1308236};
DE AltName: Full=Zrt- and Irt-like protein 8 {ECO:0000250|UniProtKB:Q91W10};
DE Short=ZIP-8 {ECO:0000250|UniProtKB:Q91W10};
DE Flags: Precursor;
GN Name=Slc39a8 {ECO:0000312|RGD:1308236};
GN Synonyms=Zip8 {ECO:0000303|PubMed:22898811};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 [2]
RP FUNCTION, TRANSPORTER ACTIVITY, SUBSTRATE SPECIFICITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, SUBUNIT, SUBCELLULAR LOCATION, MUTAGENESIS OF ASN-40; ASN-88
RP AND ASN-96, TOPOLOGY, AND GLYCOSYLATION AT ASN-40; ASN-88 AND ASN-96.
RX PubMed=22898811; DOI=10.1074/jbc.m112.367284;
RA Wang C.Y., Jenkitkasemwong S., Duarte S., Sparkman B.K., Shawki A.,
RA Mackenzie B., Knutson M.D.;
RT "ZIP8 is an iron and zinc transporter whose cell-surface expression is up-
RT regulated by cellular iron loading.";
RL J. Biol. Chem. 287:34032-34043(2012).
CC -!- FUNCTION: Electroneutral transporter of the plasma membrane mediating
CC the cellular uptake of zinc and manganese, two divalent metal cations
CC important for development, tissue homeostasis or immunity
CC (PubMed:22898811). Functions as an energy-dependent symporter,
CC transporting through the membranes an electroneutral complex composed
CC of a divalent metal cation, a bicarbonate and a selenite anion or yet a
CC metal cation and two bicarbonate anions (PubMed:22898811). May also
CC transport iron, mercury and cobalt through membranes (PubMed:22898811).
CC Beside these endogenous cellular substrates, also imports cadmium a
CC non-essential metal which is cytotoxic and carcinogenic. Through zinc
CC import, indirectly regulates the metal-dependent transcription factor
CC MTF1 and the expression of some metalloproteases involved in cartilage
CC catabolism and also probably heart development. Also indirectly
CC regulates the expression of proteins involved in cell morphology and
CC cytoskeleton organization. Indirectly controls innate immune function
CC and inflammatory response by regulating zinc cellular uptake which in
CC turn modulates the expression of genes specific of these processes.
CC Protects, for instance, cells from injury and death at the onset of
CC inflammation (By similarity). By regulating zinc influx into monocytes
CC also directly modulates their adhesion to endothelial cells and
CC arteries (By similarity). At the apical membrane of hepatocytes,
CC reclaims manganese from the bile and regulates, through the systemic
CC levels of the nutrient, the activity of manganese-dependent enzymes.
CC Also participates in manganese reabsorption in the proximal tubule of
CC the kidney. By mediating the extracellular uptake of manganese by cells
CC of the blood-brain barrier, may also play a role in the transport of
CC the micronutrient to the brain. Through manganese cellular uptake also
CC participates in mitochondrial proper function. Finally, also probably
CC functions intracellularly, translocating zinc from lysosome to cytosol
CC to indirectly enhance the expression of specific genes during TCR-
CC mediated T cell activation (By similarity).
CC {ECO:0000250|UniProtKB:Q91W10, ECO:0000250|UniProtKB:Q9C0K1,
CC ECO:0000269|PubMed:22898811}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=hydrogencarbonate(out) + selenite(out) + Zn(2+)(out) =
CC hydrogencarbonate(in) + selenite(in) + Zn(2+)(in);
CC Xref=Rhea:RHEA:62264, ChEBI:CHEBI:17544, ChEBI:CHEBI:18212,
CC ChEBI:CHEBI:29105; Evidence={ECO:0000305|PubMed:22898811};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62265;
CC Evidence={ECO:0000269|PubMed:22898811};
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:22898811};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62253;
CC Evidence={ECO:0000269|PubMed:22898811};
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:22898811};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62261;
CC Evidence={ECO:0000269|PubMed:22898811};
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:0000305|PubMed:22898811};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62257;
CC Evidence={ECO:0000269|PubMed:22898811};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Fe(2+)(in) = Fe(2+)(out); Xref=Rhea:RHEA:28486,
CC ChEBI:CHEBI:29033; Evidence={ECO:0000269|PubMed:22898811};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:28488;
CC Evidence={ECO:0000269|PubMed:22898811};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Co(2+)(in) = Co(2+)(out); Xref=Rhea:RHEA:28578,
CC ChEBI:CHEBI:48828; Evidence={ECO:0000269|PubMed:22898811};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:28580;
CC Evidence={ECO:0000269|PubMed:22898811};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Hg(2+)(in) = Hg(2+)(out); Xref=Rhea:RHEA:32815,
CC ChEBI:CHEBI:16793; Evidence={ECO:0000250|UniProtKB:Q91W10};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:32817;
CC Evidence={ECO:0000250|UniProtKB:Q91W10};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 7.5 for iron transport. {ECO:0000269|PubMed:22898811};
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:22898811}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:22898811};
CC Multi-pass membrane protein {ECO:0000255}. Lysosome membrane
CC {ECO:0000250|UniProtKB:Q9C0K1}; Multi-pass membrane protein
CC {ECO:0000255}. Apical cell membrane {ECO:0000250|UniProtKB:Q9C0K1};
CC Multi-pass membrane protein {ECO:0000255}. Basolateral cell membrane
CC {ECO:0000250|UniProtKB:Q9C0K1}; Multi-pass membrane protein
CC {ECO:0000255}. Note=Localizes to the lysosome of activated T-cells. A
CC large fraction of the protein is found intracellularly in microvascular
CC capillary endothelial cells that constitute the blood-brain barrier.
CC Localized and functional at both apical and basolateral membranes of
CC microvascular capillary endothelial cells that constitute the blood-
CC brain barrier. {ECO:0000250|UniProtKB:Q9C0K1}.
CC -!- INDUCTION: Up-regulation upon iron or zinc loading increases expression
CC at the plasma membrane (at protein level).
CC {ECO:0000269|PubMed:22898811}.
CC -!- PTM: N-glycosylated. N-glycosylation is not required for proper iron
CC and zinc transport. {ECO:0000269|PubMed:22898811}.
CC -!- SIMILARITY: Belongs to the ZIP transporter (TC 2.A.5) family.
CC {ECO:0000305}.
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DR EMBL; BC089844; AAH89844.1; -; mRNA.
DR RefSeq; NP_001011952.1; NM_001011952.1.
DR RefSeq; XP_006233418.1; XM_006233356.2.
DR RefSeq; XP_006233419.1; XM_006233357.2.
DR RefSeq; XP_017446276.1; XM_017590787.1.
DR AlphaFoldDB; Q5FVQ0; -.
DR STRING; 10116.ENSRNOP00000030977; -.
DR GlyGen; Q5FVQ0; 3 sites.
DR PaxDb; Q5FVQ0; -.
DR Ensembl; ENSRNOT00000033413; ENSRNOP00000030977; ENSRNOG00000012508.
DR GeneID; 295455; -.
DR KEGG; rno:295455; -.
DR CTD; 64116; -.
DR RGD; 1308236; Slc39a8.
DR eggNOG; KOG2693; Eukaryota.
DR GeneTree; ENSGT00940000158926; -.
DR HOGENOM; CLU_015114_13_0_1; -.
DR InParanoid; Q5FVQ0; -.
DR OMA; WLRGQRI; -.
DR OrthoDB; 657777at2759; -.
DR PhylomeDB; Q5FVQ0; -.
DR TreeFam; TF318470; -.
DR Reactome; R-RNO-442380; Zinc influx into cells by the SLC39 gene family.
DR PRO; PR:Q5FVQ0; -.
DR Proteomes; UP000002494; Chromosome 2.
DR Bgee; ENSRNOG00000012508; Expressed in liver and 18 other tissues.
DR Genevisible; Q5FVQ0; RN.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB.
DR GO; GO:0031090; C:organelle membrane; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0015296; F:anion:cation symporter activity; ISS:UniProtKB.
DR GO; GO:0015106; F:bicarbonate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0015086; F:cadmium ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015087; F:cobalt ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0005381; F:iron ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0097079; F:selenite:proton symporter activity; ISS:UniProtKB.
DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0140412; F:zinc:bicarbonate symporter activity; ISO:RGD.
DR GO; GO:0006525; P:arginine metabolic process; ISS:UniProtKB.
DR GO; GO:0015701; P:bicarbonate transport; ISS:UniProtKB.
DR GO; GO:0070574; P:cadmium ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:1990079; P:cartilage homeostasis; ISS:UniProtKB.
DR GO; GO:0006876; P:cellular cadmium ion homeostasis; ISS:UniProtKB.
DR GO; GO:0030026; P:cellular manganese ion homeostasis; ISS:UniProtKB.
DR GO; GO:0006882; P:cellular zinc ion homeostasis; ISS:UniProtKB.
DR GO; GO:0006824; P:cobalt ion transport; IDA:UniProtKB.
DR GO; GO:0030198; P:extracellular matrix organization; ISS:UniProtKB.
DR GO; GO:0098711; P:iron ion import across plasma membrane; IDA:UniProtKB.
DR GO; GO:0061757; P:leukocyte adhesion to arterial endothelial cell; ISS:UniProtKB.
DR GO; GO:0071421; P:manganese ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:1990540; P:mitochondrial manganese ion transmembrane transport; ISS:UniProtKB.
DR GO; GO:0097080; P:plasma membrane selenite transport; ISS:UniProtKB.
DR GO; GO:0006487; P:protein N-linked glycosylation; ISS:UniProtKB.
DR GO; GO:0042391; P:regulation of membrane potential; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0006351; P:transcription, DNA-templated; ISO:RGD.
DR GO; GO:0071578; P:zinc ion import across plasma membrane; IDA:UniProtKB.
DR GO; GO:0071577; P:zinc ion transmembrane transport; ISO:RGD.
DR GO; GO:0006829; P:zinc ion transport; ISS:UniProtKB.
DR InterPro; IPR003689; ZIP.
DR Pfam; PF02535; Zip; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Glycoprotein; Ion transport; Lysosome; Membrane;
KW Reference proteome; Signal; Transmembrane; Transmembrane helix; Transport;
KW Zinc; Zinc transport.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT CHAIN 20..462
FT /note="Metal cation symporter ZIP8"
FT /evidence="ECO:0000255"
FT /id="PRO_0000312709"
FT TOPO_DOM 20..132
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:22898811"
FT TRANSMEM 133..153
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 154..160
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:22898811"
FT TRANSMEM 161..181
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 182..191
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:22898811"
FT TRANSMEM 192..212
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 213..367
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:22898811"
FT TRANSMEM 368..388
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 389..390
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:22898811"
FT TRANSMEM 391..411
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 412..431
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:22898811"
FT TRANSMEM 432..452
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 453..462
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:22898811"
FT MOTIF 345..350
FT /note="XEXPHE-motif"
FT /evidence="ECO:0000250|UniProtKB:Q9C0K1"
FT CARBOHYD 40
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:22898811"
FT CARBOHYD 88
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:22898811"
FT CARBOHYD 96
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:22898811"
FT MUTAGEN 40
FT /note="N->D: Decreased glycosylation."
FT /evidence="ECO:0000269|PubMed:22898811"
FT MUTAGEN 88
FT /note="N->Q: Decreased glycosylation."
FT /evidence="ECO:0000269|PubMed:22898811"
FT MUTAGEN 96
FT /note="N->Q: Decreased glycosylation."
FT /evidence="ECO:0000269|PubMed:22898811"
SQ SEQUENCE 462 AA; 50171 MW; 954467170797180F CRC64;
MAPGRAVAGL LLLAATGLGR PSEGPELAFT EDVLRVFGAN QSLSAAQLGR LLERLGAAPQ
QGALELGQLH FNQCLSAEDI FSLHGFSNVT QITSSNFTAI CPAILQQLNF HPCEDPQKHS
VKPSFSEVWG YGFLSVTIIN LASLLGLILT PLIKKSYFPK ILTYFVGLAI GTLFSNAIFQ
LIPEAFGFNP KIDNYVEKAV AVFGGFYMLF FVERTLKMLL KTYGQNDHTH FRNDDFGSKE
KAHQPKTLPL PPVNGVTCYA NPAVTEPNGH IHFDTVSVVS LQDGKAESSS CTCLKGPKLS
EIGTIAWMIT LCDALHNFID GLAIGASYTL SLLQGLSTSI AILCEEFPHE LGDFVILLNA
GMSTRQALLF NFLSACSCYV GLAFGILVGN NFAPNIIFAL AGGMFLYISL ADMFPEMNDM
LREKVTGRQT DFTFFMIQNA GMLTGFTAIL LITLYAGDIE LQ
