S39AE_PONAB
ID S39AE_PONAB Reviewed; 490 AA.
AC Q5RAB7;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 04-DEC-2007, sequence version 2.
DT 25-MAY-2022, entry version 57.
DE RecName: Full=Metal cation symporter ZIP14 {ECO:0000250|UniProtKB:Q15043};
DE AltName: Full=Solute carrier family 39 member 14 {ECO:0000250|UniProtKB:Q15043};
DE AltName: Full=Zrt- and Irt-like protein 14 {ECO:0000250|UniProtKB:Q15043};
DE Short=ZIP-14 {ECO:0000250|UniProtKB:Q15043};
DE Flags: Precursor;
GN Name=SLC39A14 {ECO:0000250|UniProtKB:Q15043};
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
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 (By similarity). Functions as an energy-dependent
CC symporter, transporting through the membranes an electroneutral complex
CC composed of a divalent metal cation and two bicarbonate anions. Beside
CC these endogenous cellular substrates, can also import cadmium a non-
CC essential metal which is cytotoxic and carcinogenic. 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. 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 (By similarity). Through zinc cellular uptake also plays a role
CC 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. Also involved
CC in manganese extracellular uptake by cells of the blood-brain barrier
CC (By similarity). May also play a role in manganese and zinc homeostasis
CC participating in their elimination from the blood through the
CC hepatobiliary excretion (By similarity). Also functions in the
CC extracellular uptake of free iron. May also function intracellularly
CC and mediate the transport from endosomes to cytosol of iron endocytosed
CC by transferrin. Plays a role in innate immunity by regulating the
CC expression of cytokines by activated macrophages (By similarity).
CC {ECO:0000250|UniProtKB:Q15043, ECO:0000250|UniProtKB:Q75N73}.
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:0000250|UniProtKB:Q75N73};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62253;
CC Evidence={ECO:0000250|UniProtKB:Q75N73};
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:0000250|UniProtKB:Q75N73};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62261;
CC Evidence={ECO:0000250|UniProtKB:Q75N73};
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:0000250|UniProtKB:Q15043}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q15043};
CC Multi-pass membrane protein {ECO:0000255}. Apical cell membrane
CC {ECO:0000250|UniProtKB:Q15043}; Multi-pass membrane protein
CC {ECO:0000255}. Basolateral cell membrane
CC {ECO:0000250|UniProtKB:Q15043}; Multi-pass membrane protein
CC {ECO:0000255}. Early endosome membrane {ECO:0000250|UniProtKB:Q15043};
CC Multi-pass membrane protein {ECO:0000255}. Late endosome membrane
CC {ECO:0000250|UniProtKB:Q15043}; Multi-pass membrane protein
CC {ECO:0000255}. Lysosome membrane {ECO:0000250|UniProtKB:Q15043}; 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. Localized at
CC the basolateral membrane of enterocytes. Enriched at the plasma
CC membrane upon glucose uptake. {ECO:0000250|UniProtKB:Q15043}.
CC -!- PTM: Ubiquitinated. Ubiquitination occurs upon iron depletion. The
CC ubiquitinated form undergoes proteasomal degradation.
CC {ECO:0000250|UniProtKB:Q15043}.
CC -!- PTM: N-glycosylated. N-glycosylation at Asn-100 is required for iron-
CC regulated extraction of the transporter from membranes and subsequent
CC proteasomal degradation. {ECO:0000250|UniProtKB:Q15043}.
CC -!- SIMILARITY: Belongs to the ZIP transporter (TC 2.A.5) family.
CC {ECO:0000305}.
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DR EMBL; CR859101; CAH91293.1; -; mRNA.
DR AlphaFoldDB; Q5RAB7; -.
DR SMR; Q5RAB7; -.
DR STRING; 9601.ENSPPYP00000020643; -.
DR eggNOG; KOG2693; Eukaryota.
DR InParanoid; Q5RAB7; -.
DR Proteomes; UP000001595; Unplaced.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB.
DR GO; GO:0031901; C:early endosome membrane; ISS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0031902; C:late endosome membrane; ISS:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0015296; F:anion:cation symporter activity; ISS:UniProtKB.
DR GO; GO:0015086; F:cadmium ion transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0005381; F:iron ion transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; ISS:UniProtKB.
DR GO; GO:0032869; P:cellular response to insulin stimulus; ISS:UniProtKB.
DR GO; GO:0006882; P:cellular zinc ion homeostasis; ISS:UniProtKB.
DR GO; GO:0002062; P:chondrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0006094; P:gluconeogenesis; ISS: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:0055071; P:manganese ion homeostasis; ISS:UniProtKB.
DR GO; GO:0051344; P:negative regulation of cyclic-nucleotide phosphodiesterase activity; ISS:UniProtKB.
DR GO; GO:0045745; P:positive regulation of G protein-coupled receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0010817; P:regulation of hormone levels; ISS:UniProtKB.
DR GO; GO:0071578; P:zinc ion import across plasma membrane; ISS:UniProtKB.
DR GO; GO:0071577; P:zinc ion transmembrane transport; ISS:UniProtKB.
DR InterPro; IPR003689; ZIP.
DR Pfam; PF02535; Zip; 1.
PE 2: Evidence at transcript level;
KW Cell membrane; Endosome; Glycoprotein; Ion transport; Lysosome; Membrane;
KW Reference proteome; Signal; Transmembrane; Transmembrane helix; Transport;
KW Ubl conjugation; Zinc; Zinc transport.
FT SIGNAL 1..28
FT /evidence="ECO:0000255"
FT CHAIN 29..490
FT /note="Metal cation symporter ZIP14"
FT /id="PRO_0000312196"
FT TOPO_DOM 29..155
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 156..176
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 177..184
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 185..205
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 206..222
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 223..243
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 244..395
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 396..416
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 417..422
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 423..443
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 444..458
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 459..479
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 480..490
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT MOTIF 249..256
FT /note="HHHGHXHX-motif"
FT /evidence="ECO:0000250|UniProtKB:Q15043"
FT MOTIF 374..379
FT /note="XEXPHE-motif"
FT /evidence="ECO:0000250|UniProtKB:Q15043"
FT CARBOHYD 75
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 85
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 100
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
SQ SEQUENCE 490 AA; 53965 MW; E4C499F7E5DAA42F CRC64;
MKLLHPAFQS CLLLTLLGLW RTTPEAHASS PGAPAISAAS FLQDLIHRYG EGDSLTLQQL
KALLNHLDVG VGRGNVTQHV QGHRNLSTCF SSGDLFAAHN FSEQSRIGSS ELQEFCPTIL
QQLDSRACTS ENQENEENEQ TEEGWPSAVE VWGYGLLCVT VISLCSLLGA SVVPFMKKTF
YKRLLLYFIA LAIGTLYSNA LFQLIPEAFG FNPLEDYYVS KSAVVFGGFY LFFFTEKILK
ILLKQKNEHH HGHSHYASET LPSKKDQEEG VMEKLQNGDL DHMIPQHCNS ELDGKAPVVD
EKVIVGSLSV QDLQASQSAC YWLKGVRYSD IGTLAWMITL SDGLHNFIDG LAIGASFTVS
VFQGISTSVA ILCEEFPHEL GDFVILLNAG MSIQQALFFN FLSACCCYLG LAFGILAGSH
FSANWIFALA GGMFLYISLA DMFPEMNEVC QEDERKGSIL IPFVIQNLGL LTGFTIMVVL
TMYSGQIQIG
