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High affinity choline transporter 1 (Hemicholinium-3-sensitive choline transporter) (CHT) (Solute carrier family 5 member 7)

 SC5A7_HUMAN             Reviewed;         580 AA.
Q9GZV3; Q53TF2;
07-DEC-2004, integrated into UniProtKB/Swiss-Prot.
01-MAR-2001, sequence version 1.
27-SEP-2017, entry version 131.
RecName: Full=High affinity choline transporter 1;
AltName: Full=Hemicholinium-3-sensitive choline transporter;
Short=CHT;
AltName: Full=Solute carrier family 5 member 7;
Name=SLC5A7; Synonyms=CHT1;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND SUBCELLULAR LOCATION.
TISSUE=Spinal cord;
PubMed=11027560; DOI=10.1006/bbrc.2000.3561;
Apparsundaram S., Ferguson S.M., George A.L. Jr., Blakely R.D.;
"Molecular cloning of a human, hemicholinium-3-sensitive choline
transporter.";
Biochem. Biophys. Res. Commun. 276:862-867(2000).
[2]
NUCLEOTIDE SEQUENCE [MRNA].
TISSUE=Spinal cord;
PubMed=11068039; DOI=10.1016/S0014-5793(00)02134-7;
Okuda T., Haga T.;
"Functional characterization of the human high-affinity choline
transporter.";
FEBS Lett. 484:92-97(2000).
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
TISSUE=Hypothalamus;
Wieland A., Bonisch H., Bruess M.;
"Molecular cloning of the human and murine high affinity choline
transporters and characterization of the human gene structure.";
Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15815621; DOI=10.1038/nature03466;
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
Waterston R.H., Wilson R.K.;
"Generation and annotation of the DNA sequences of human chromosomes 2
and 4.";
Nature 434:724-731(2005).
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[6]
INTERACTION WITH SEC14L1.
PubMed=17092608; DOI=10.1016/j.neuint.2006.09.010;
Ribeiro F.M., Ferreira L.T., Marion S., Fontes S., Gomez M.,
Ferguson S.S., Prado M.A., Prado V.F.;
"SEC14-like protein 1 interacts with cholinergic transporters.";
Neurochem. Int. 50:356-364(2007).
[7]
INVOLVEMENT IN HMN7A.
PubMed=23141292; DOI=10.1016/j.ajhg.2012.09.019;
Barwick K.E., Wright J., Al-Turki S., McEntagart M.M., Nair A.,
Chioza B., Al-Memar A., Modarres H., Reilly M.M., Dick K.J.,
Ruggiero A.M., Blakely R.D., Hurles M.E., Crosby A.H.;
"Defective presynaptic choline transport underlies hereditary motor
neuropathy.";
Am. J. Hum. Genet. 91:1103-1107(2012).
[8]
TOPOLOGY, SUBUNIT, AND MUTAGENESIS OF ILE-89 AND GLU-451.
PubMed=23132865; DOI=10.1074/jbc.M112.405027;
Okuda T., Osawa C., Yamada H., Hayashi K., Nishikawa S., Ushio T.,
Kubo Y., Satou M., Ogawa H., Haga T.;
"Transmembrane topology and oligomeric structure of the high-affinity
choline transporter.";
J. Biol. Chem. 287:42826-42834(2012).
[9]
FUNCTION, SUBCELLULAR LOCATION, INVOLVEMENT IN CMS20, VARIANTS CMS20
GLY-48; GLU-65; SER-105; HIS-111; CYS-175; THR-291; LEU-344; GLN-361;
VAL-418 AND GLY-446, AND CHARACTERIZATION OF VARIANTS CMS20 GLY-48;
GLU-65; SER-105; GLN-361 AND GLY-446.
PubMed=27569547; DOI=10.1016/j.ajhg.2016.06.033;
Bauche S., O'Regan S., Azuma Y., Laffargue F., McMacken G.,
Sternberg D., Brochier G., Buon C., Bouzidi N., Topf A., Lacene E.,
Remerand G., Beaufrere A.M., Pebrel-Richard C., Thevenon J.,
El Chehadeh-Djebbar S., Faivre L., Duffourd Y., Ricci F., Mongini T.,
Fiorillo C., Astrea G., Burloiu C.M., Butoianu N., Sandu C.,
Servais L., Bonne G., Nelson I., Desguerre I., Nougues M.C., Boeuf B.,
Romero N., Laporte J., Boland A., Lechner D., Deleuze J.F.,
Fontaine B., Strochlic L., Lochmuller H., Eymard B., Mayer M.,
Nicole S.;
"Impaired presynaptic high-affinity choline transporter causes a
congenital myasthenic syndrome with episodic apnea.";
Am. J. Hum. Genet. 99:753-761(2016).
[10]
VARIANT VAL-89.
PubMed=12237312; DOI=10.1074/jbc.M207742200;
Okuda T., Okamura M., Kaitsuka C., Haga T., Gurwitz D.;
"Single nucleotide polymorphism of the human high affinity choline
transporter alters transport rate.";
J. Biol. Chem. 277:45315-45322(2002).
-!- FUNCTION: Transmembrane transporter that imports choline from the
extracellular space into the neuron with high affinity. Choline
uptake is the rate-limiting step in acetylcholine synthesis.
Sodium ion- and chloride ion-dependent.
{ECO:0000269|PubMed:11027560, ECO:0000269|PubMed:27569547}.
-!- SUBUNIT: Homooligomerizes at cell surface (PubMed:23132865).
Interacts with SEC14L1; may regulate SLC5A7 (PubMed:17092608).
{ECO:0000269|PubMed:17092608, ECO:0000269|PubMed:23132865}.
-!- SUBCELLULAR LOCATION: Membrane {ECO:0000269|PubMed:11027560};
Multi-pass membrane protein {ECO:0000269|PubMed:11027560}. Cell
membrane {ECO:0000269|PubMed:27569547}. Cell junction, synapse
{ECO:0000269|PubMed:27569547}. Note=Localized at the neuromuscular
junction. {ECO:0000269|PubMed:27569547}.
-!- TISSUE SPECIFICITY: Expressed in putamen, spinal cord and medulla.
Specific for cholinergic neurons.
-!- PTM: Phosphorylated. {ECO:0000250}.
-!- DISEASE: Neuronopathy, distal hereditary motor, 7A (HMN7A)
[MIM:158580]: A neuromuscular disorder. Distal hereditary motor
neuronopathies constitute a heterogeneous group of neuromuscular
disorders caused by selective degeneration of motor neurons in the
anterior horn of the spinal cord, without sensory deficit in the
posterior horn. The overall clinical picture consists of a
classical distal muscular atrophy syndrome in the legs without
clinical sensory loss. The disease starts with weakness and
wasting of distal muscles of the anterior tibial and peroneal
compartments of the legs. Later on, weakness and atrophy may
expand to the proximal muscles of the lower limbs and/or to the
distal upper limbs. HMN7A is characterized by onset in the second
decade of progressive distal muscle wasting and weakness affecting
the upper and lower limbs and resulting in walking difficulties
and hand grip. There is significant muscle atrophy of the hands
and lower limbs. The disorder is associated with vocal cord
paresis due to involvement of the tenth cranial nerve.
{ECO:0000269|PubMed:23141292}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- DISEASE: Myasthenic syndrome, congenital, 20, presynaptic (CMS20)
[MIM:617143]: A form of congenital myasthenic syndrome, a group of
disorders characterized by failure of neuromuscular transmission,
including pre-synaptic, synaptic, and post-synaptic disorders that
are not of autoimmune origin. Clinical features are easy
fatigability and muscle weakness. CMS20 is an autosomal recessive,
pre-synaptic form characterized by severe hypotonia and episodic
apnea soon after birth, generalized limb fatigability and
weakness, delayed walking, ptosis, poor sucking and swallowing.
{ECO:0000269|PubMed:27569547}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- MISCELLANEOUS: Specifically inhibited by nanomolar concentrations
of hemicholinium 3.
-!- SIMILARITY: Belongs to the sodium:solute symporter (SSF) (TC
2.A.21) family. {ECO:0000305}.
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EMBL; AF276871; AAG25940.1; -; mRNA.
EMBL; AB043997; BAB18161.1; -; mRNA.
EMBL; AJ401466; CAC03717.1; -; mRNA.
EMBL; AJ308378; CAC88115.1; -; Genomic_DNA.
EMBL; AJ308379; CAC88115.1; JOINED; Genomic_DNA.
EMBL; AJ308380; CAC88115.1; JOINED; Genomic_DNA.
EMBL; AJ308381; CAC88115.1; JOINED; Genomic_DNA.
EMBL; AJ308382; CAC88115.1; JOINED; Genomic_DNA.
EMBL; AJ308383; CAC88115.1; JOINED; Genomic_DNA.
EMBL; AJ308384; CAC88115.1; JOINED; Genomic_DNA.
EMBL; AC009963; AAY14927.1; -; Genomic_DNA.
EMBL; BC111525; AAI11526.1; -; mRNA.
CCDS; CCDS2074.1; -.
PIR; JC7502; JC7502.
RefSeq; NP_001291934.1; NM_001305005.2.
RefSeq; NP_068587.1; NM_021815.4.
UniGene; Hs.287758; -.
ProteinModelPortal; Q9GZV3; -.
BioGrid; 121915; 3.
STRING; 9606.ENSP00000264047; -.
BindingDB; Q9GZV3; -.
ChEMBL; CHEMBL4507; -.
DrugBank; DB00122; Choline.
GuidetoPHARMACOLOGY; 914; -.
TCDB; 2.A.21.8.2; the solute:sodium symporter (sss) family.
iPTMnet; Q9GZV3; -.
PhosphoSitePlus; Q9GZV3; -.
BioMuta; SLC5A7; -.
DMDM; 56404957; -.
EPD; Q9GZV3; -.
PaxDb; Q9GZV3; -.
PeptideAtlas; Q9GZV3; -.
PRIDE; Q9GZV3; -.
Ensembl; ENST00000264047; ENSP00000264047; ENSG00000115665.
Ensembl; ENST00000409059; ENSP00000387346; ENSG00000115665.
GeneID; 60482; -.
KEGG; hsa:60482; -.
UCSC; uc002tdv.4; human.
CTD; 60482; -.
DisGeNET; 60482; -.
EuPathDB; HostDB:ENSG00000115665.8; -.
GeneCards; SLC5A7; -.
HGNC; HGNC:14025; SLC5A7.
HPA; HPA046105; -.
MalaCards; SLC5A7; -.
MIM; 158580; phenotype.
MIM; 608761; gene.
MIM; 617143; phenotype.
neXtProt; NX_Q9GZV3; -.
OpenTargets; ENSG00000115665; -.
Orphanet; 139589; Distal hereditary motor neuropathy type 7.
PharmGKB; PA37838; -.
eggNOG; KOG3761; Eukaryota.
eggNOG; COG0591; LUCA.
GeneTree; ENSGT00690000101915; -.
HOGENOM; HOG000016386; -.
HOVERGEN; HBG054160; -.
InParanoid; Q9GZV3; -.
KO; K14387; -.
OMA; YTWLDSF; -.
OrthoDB; EOG091G050W; -.
PhylomeDB; Q9GZV3; -.
TreeFam; TF314588; -.
Reactome; R-HSA-264642; Acetylcholine Neurotransmitter Release Cycle.
Reactome; R-HSA-425366; Transport of bile salts and organic acids, metal ions and amine compounds.
GeneWiki; Choline_transporter; -.
GenomeRNAi; 60482; -.
PRO; PR:Q9GZV3; -.
Proteomes; UP000005640; Chromosome 2.
Bgee; ENSG00000115665; -.
CleanEx; HS_SLC5A7; -.
Genevisible; Q9GZV3; HS.
GO; GO:0030424; C:axon; IBA:GO_Central.
GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
GO; GO:0030425; C:dendrite; IBA:GO_Central.
GO; GO:0016021; C:integral component of membrane; IDA:UniProtKB.
GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
GO; GO:0031594; C:neuromuscular junction; IDA:UniProtKB.
GO; GO:0043204; C:perikaryon; IBA:GO_Central.
GO; GO:0005886; C:plasma membrane; IDA:MGI.
GO; GO:0098793; C:presynapse; IEA:GOC.
GO; GO:0033265; F:choline binding; IBA:GO_Central.
GO; GO:0015220; F:choline transmembrane transporter activity; IMP:UniProtKB.
GO; GO:0005307; F:choline:sodium symporter activity; IMP:MGI.
GO; GO:0008292; P:acetylcholine biosynthetic process; IMP:UniProtKB.
GO; GO:0007274; P:neuromuscular synaptic transmission; IBA:GO_Central.
GO; GO:0007269; P:neurotransmitter secretion; TAS:Reactome.
GO; GO:0007271; P:synaptic transmission, cholinergic; IBA:GO_Central.
GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
InterPro; IPR001734; Na/solute_symporter.
Pfam; PF00474; SSF; 1.
PROSITE; PS50283; NA_SOLUT_SYMP_3; 1.
1: Evidence at protein level;
Cell junction; Cell membrane; Complete proteome;
Congenital myasthenic syndrome; Disease mutation; Glycoprotein;
Ion transport; Membrane; Neurodegeneration;
Neurotransmitter biosynthesis; Phosphoprotein; Polymorphism;
Reference proteome; Sodium; Sodium transport; Symport; Synapse;
Transmembrane; Transmembrane helix; Transport.
CHAIN 1 580 High affinity choline transporter 1.
/FTId=PRO_0000105391.
TOPO_DOM 1 6 Extracellular. {ECO:0000255}.
TRANSMEM 7 27 Helical. {ECO:0000255}.
TOPO_DOM 28 48 Cytoplasmic. {ECO:0000255}.
TRANSMEM 49 69 Helical. {ECO:0000255}.
TOPO_DOM 70 81 Extracellular. {ECO:0000255}.
TRANSMEM 82 102 Helical. {ECO:0000255}.
TOPO_DOM 103 125 Cytoplasmic. {ECO:0000255}.
TRANSMEM 126 146 Helical. {ECO:0000255}.
TOPO_DOM 147 164 Extracellular. {ECO:0000255}.
TRANSMEM 165 185 Helical. {ECO:0000255}.
TOPO_DOM 186 191 Cytoplasmic. {ECO:0000255}.
TRANSMEM 192 212 Helical. {ECO:0000255}.
TOPO_DOM 213 237 Extracellular. {ECO:0000255}.
TRANSMEM 238 258 Helical. {ECO:0000255}.
TOPO_DOM 259 274 Cytoplasmic. {ECO:0000255}.
TRANSMEM 275 295 Helical. {ECO:0000255}.
TOPO_DOM 296 317 Extracellular. {ECO:0000255}.
TRANSMEM 318 338 Helical. {ECO:0000255}.
TOPO_DOM 339 376 Cytoplasmic. {ECO:0000255}.
TRANSMEM 377 397 Helical. {ECO:0000255}.
TOPO_DOM 398 406 Extracellular. {ECO:0000255}.
TRANSMEM 407 427 Helical. {ECO:0000255}.
TOPO_DOM 428 435 Cytoplasmic. {ECO:0000255}.
TRANSMEM 436 456 Helical. {ECO:0000255}.
TOPO_DOM 457 481 Extracellular. {ECO:0000255}.
TRANSMEM 482 502 Helical. {ECO:0000255}.
TOPO_DOM 503 580 Cytoplasmic. {ECO:0000255}.
REGION 502 580 Mediates interaction with SEC14L1.
{ECO:0000250|UniProtKB:Q9JMD7}.
CARBOHYD 301 301 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
VARIANT 48 48 D -> G (in CMS20; decreased choline
transmembrane transporter activity; no
effect on localization at plasma
membrane). {ECO:0000269|PubMed:27569547}.
/FTId=VAR_077854.
VARIANT 65 65 G -> E (in CMS20; loss of choline
transmembrane transporter activity; no
effect on localization at plasma
membrane). {ECO:0000269|PubMed:27569547}.
/FTId=VAR_077855.
VARIANT 89 89 I -> V (40% reduction in choline uptake
rate; found in 0.06 of Ashkenazi Jews;
dbSNP:rs1013940).
{ECO:0000269|PubMed:12237312}.
/FTId=VAR_020524.
VARIANT 105 105 P -> S (in CMS20; decreased choline
transmembrane transporter activity; no
effect on localization at plasma
membrane). {ECO:0000269|PubMed:27569547}.
/FTId=VAR_077856.
VARIANT 111 111 Y -> H (in CMS20; no effect on
localization at plasma membrane).
{ECO:0000269|PubMed:27569547}.
/FTId=VAR_077857.
VARIANT 175 175 Y -> C (in CMS20; unknown pathological
significance).
{ECO:0000269|PubMed:27569547}.
/FTId=VAR_077858.
VARIANT 291 291 I -> T (in CMS20; unknown pathological
significance; dbSNP:rs375397889).
{ECO:0000269|PubMed:27569547}.
/FTId=VAR_077859.
VARIANT 344 344 V -> L (in CMS20; unknown pathological
significance).
{ECO:0000269|PubMed:27569547}.
/FTId=VAR_077860.
VARIANT 361 361 R -> Q (in CMS20; decreased choline
transmembrane transporter activity; no
effect on localization at plasma
membrane; dbSNP:rs147656110).
{ECO:0000269|PubMed:27569547}.
/FTId=VAR_077861.
VARIANT 418 418 F -> V (in CMS20; unknown pathological
significance).
{ECO:0000269|PubMed:27569547}.
/FTId=VAR_077862.
VARIANT 446 446 R -> G (in CMS20; decreased choline
transmembrane transporter activity; no
effect on localization at plasma
membrane). {ECO:0000269|PubMed:27569547}.
/FTId=VAR_077863.
MUTAGEN 89 89 I->A: Only 20% of wild-type choline
uptake activity.
{ECO:0000269|PubMed:23132865}.
MUTAGEN 451 451 E->Q: Only 5% of wild-type choline uptake
activity. {ECO:0000269|PubMed:23132865}.
SEQUENCE 580 AA; 63204 MW; 66CB35496CB6E2D6 CRC64;
MAFHVEGLIA IIVFYLLILL VGIWAAWRTK NSGSAEERSE AIIVGGRDIG LLVGGFTMTA
TWVGGGYING TAEAVYVPGY GLAWAQAPIG YSLSLILGGL FFAKPMRSKG YVTMLDPFQQ
IYGKRMGGLL FIPALMGEMF WAAAIFSALG ATISVIIDVD MHISVIISAL IATLYTLVGG
LYSVAYTDVV QLFCIFVGLW ISVPFALSHP AVADIGFTAV HAKYQKPWLG TVDSSEVYSW
LDSFLLLMLG GIPWQAYFQR VLSSSSATYA QVLSFLAAFG CLVMAIPAIL IGAIGASTDW
NQTAYGLPDP KTTEEADMIL PIVLQYLCPV YISFFGLGAV SAAVMSSADS SILSASSMFA
RNIYQLSFRQ NASDKEIVWV MRITVFVFGA SATAMALLTK TVYGLWYLSS DLVYIVIFPQ
LLCVLFVKGT NTYGAVAGYV SGLFLRITGG EPYLYLQPLI FYPGYYPDDN GIYNQKFPFK
TLAMVTSFLT NICISYLAKY LFESGTLPPK LDVFDAVVAR HSEENMDKTI LVKNENIKLD
ELALVKPRQS MTLSSTFTNK EAFLDVDSSP EGSGTEDNLQ


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