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Database: UniProt
Entry: S39AE_PONAB
LinkDB: S39AE_PONAB
Original site: 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   03-MAY-2023, entry version 60.
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   GlyCosmos; Q5RAB7; 3 sites, No reported glycans.
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: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: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:0015296; F:monoatomic anion:monoatomic cation symporter 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: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:0006882; P:intracellular zinc ion homeostasis; 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   PANTHER; PTHR12191:SF5; METAL CATION SYMPORTER ZIP14; 1.
DR   PANTHER; PTHR12191; SOLUTE CARRIER FAMILY 39; 1.
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
//
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