Reviewed, UniProtKB/Swiss-Prot Q7RTT9 (S29A4_HUMAN)

Names and origin

Protein names

Recommended name:
    Equilibrative nucleoside transporter 4
      Short name=hENT4
Alternative name(s):
    Solute carrier family 29 member 4
    Plasma membrane monoamine transporter

Gene names

Name:	SLC29A4
Synonyms:	ENT4, PMAT
ORF Names:	PSEC0113

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	530 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Functions as a polyspecific organic cation transporter, efficiently transporting many organic cations such as monoamine neurotransmitters 1-methyl-4-phenylpyridinium and biogenic amines including serotonin, dopamine, norepinephrine and epinephrine. May play a role in regulating central nervous system homeostasis of monoamine neurotransmitters. May be involved in luminal transport of organic cations in the kidney and seems to use luminal proton gradient to drive organic cation reabsorption. Does not seem to transport nucleoside and nucleoside analogs such as uridine, cytidine, thymidine, adenosine, inosine, guanosine, and azidothymidine. In (Ref.7) adenosine is efficiently transported but in a fashion highly sensitive to extracellular pH, with maximal activity in the pH range 5.5 to 6.5. Glu-206 is essential for the cation selectivity and may function as the charge sensor for cationic substrates. Transport is chloride and sodium-independent but appears to be sensitive to changes in membrane potential. Weakly inhibited by the classical inhibitors of equilibrative nucleoside transport, dipyridamole, dilazep, and nitrobenzylthioinosine. May play a role in the regulation of extracellular adenosine concentrations in cardiac tissues, in particular during ischemia. Ref.1 Ref.7 Ref.8 Ref.9
Subcellular location	Cell membrane; Multi-pass membrane protein Potential. Apical cell membrane; Multi-pass membrane protein Potential. Note: Located to the plasma membranes of ventricular myocytes and vascular endothelial cells. Targeted to the apical membranes of differentiated kidney epithelial cells.
Tissue specificity	Expressed abundantly in the heart, in both cardiomyocytes and vascular endothelial cells (at protein level). Highly espressed in brain, kidney and skeletal muscle. In the brain expressed in cerebellum, cerebral cortex, medulla, occipital pole, frontal and temporal lobes putamen and in the spinal cord. Lower expression in liver, pancreas, and liver. Expressed in endometrial tissue, exclusively in the stroma. Expression is high in the proliferative phase, decreases during the secretory phase, and is no longer detectable in the menstrual phase. Ref.1 Ref.7 Ref.8 Ref.10
Post-translational modification	N-glycosylated. Ref.7
Sequence similarities	Belongs to the SLC29A transporter family.

Ontologies

Keywords
Biological process	Transport
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Transmembrane
PTM	Glycoprotein Phosphoprotein
Gene Ontology (GO)
Biological process	transport Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	apical plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	nucleoside transmembrane transporter activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q7RTT9-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q7RTT9-2)

The sequence of this isoform differs from the canonical sequence as follows:
     139-182: GYLLALGPLLFISICDVWLQLFSRDQAYAINLAAVGTVAFGCTV → ASATCGCSSSLGTRPTPSTWPLWAPWPSAA

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 530	530	Equilibrative nucleoside transporter 4		PRO_0000326251
Regions
	Topological domain	1 – 68	68	Extracellular Potential
	Transmembrane	69 – 89	21	Potential
	Topological domain	90 – 101	12	Cytoplasmic Potential
	Transmembrane	102 – 122	21	Potential
	Topological domain	123 – 139	17	Extracellular Potential
	Transmembrane	140 – 160	21	Potential
	Topological domain	161 – 166	6	Cytoplasmic Potential
	Transmembrane	167 – 187	21	Potential
	Topological domain	188 – 231	44	Extracellular Potential
	Transmembrane	232 – 252	21	Potential
	Topological domain	253 – 351	99	Cytoplasmic Potential
	Transmembrane	352 – 372	21	Potential
	Topological domain	373 – 381	9	Extracellular Potential
	Transmembrane	382 – 402	21	Potential
	Topological domain	403 – 416	14	Cytoplasmic Potential
	Transmembrane	417 – 437	21	Potential
	Topological domain	438 – 450	13	Extracellular Potential
	Transmembrane	451 – 471	21	Potential
	Topological domain	472 – 486	15	Cytoplasmic Potential
	Transmembrane	487 – 509	23	Potential
	Topological domain	510 – 530	21	Extracellular Potential
Amino acid modifications
	Modified residue	220	1	Phosphothreonine By similarity
	Glycosylation	523	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	139 – 182	44	GYLLA…FGCTV → ASATCGCSSSLGTRPTPSTW PLWAPWPSAA in isoform 2.		VSP_032647
	Natural variant	79	1	V → E: dbSNP rs17854505. Ref.4		VAR_040044
	Natural variant	124	1	N → K: dbSNP rs17855675. Ref.4		VAR_040045
	Natural variant	429	1	P → T: dbSNP rs17857336. Ref.4		VAR_040046
Experimental info
	Mutagenesis	91	1	D → A: No significant change in cationic transport activity. Ref.9
	Mutagenesis	107	1	D → A: Loss of cationic transport activity. Ref.9
	Mutagenesis	128	1	E → A: No significant change in cationic transport activity. Ref.9
	Mutagenesis	154	1	D → A: Loss of cationic transport activity; increase in uridine uptake. Ref.9
	Mutagenesis	163	1	D → A: Loss of cationic transport activity. Ref.9
	Mutagenesis	206	1	E → A: Loss of cationic transport activity. Ref.7 Ref.9
	Mutagenesis	206	1	E → D: No loss of cationic transporter activity; no activity towards uridine. Ref.7 Ref.9
	Mutagenesis	206	1	E → Q: Loss of cationic transporter activity; increase in uridine uptake. Ref.7 Ref.9
	Mutagenesis	206	1	E → R: Loss of cationic transporter activity. Ref.7 Ref.9
	Mutagenesis	220	1	T → A: Reduced cationic transport activity. Ref.9
	Mutagenesis	220	1	T → I: Loss of cationic transporter activity. Ref.9
	Mutagenesis	220	1	T → S: Reduced cationic transport activity. Ref.9
	Mutagenesis	227	1	E → A: Functional with slight increased cationic transport activity. Ref.9
	Mutagenesis	242	1	E → A: Reduced cationic transport activity. Ref.9
	Mutagenesis	336	1	W → A: Loss of cationic transport activity. Ref.9
	Mutagenesis	375	1	E → A: Functional with slight increased cationic transport activity. Ref.7 Ref.9
	Mutagenesis	375	1	E → Q: No change in cationic activity and pH sensitivity. Ref.7 Ref.9
	Sequence conflict	25	1	S → C in BAC03836. Ref.2
	Sequence conflict	41	1	Q → R in BAC03836. Ref.2
	Sequence conflict	196	1	K → R in BAC03836. Ref.2
	Sequence conflict	261	1	Y → H in BAC11612. Ref.5
	Sequence conflict	301	1	L → P in BAC03836. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 15, 2003. Version 1. Checksum: 3FE5D5ED1D248A13	FASTA	530	58,059
	10 20 30 40 50 60 MGSVGSQRLE EPSVAGTPDP GVVMSFTFDS HQLEEAAEAA QGQGLRARGV PAFTDTTLDE 70 80 90 100 110 120 PVPDDRYHAI YFAMLLAGVG FLLPYNSFIT DVDYLHHKYP GTSIVFDMSL TYILVALAAV 130 140 150 160 170 180 LLNNVLVERL TLHTRITAGY LLALGPLLFI SICDVWLQLF SRDQAYAINL AAVGTVAFGC 190 200 210 220 230 240 TVQQSSFYGY TGMLPKRYTQ GVMTGESTAG VMISLSRILT KLLLPDERAS TLIFFLVSVA 250 260 270 280 290 300 LELLCFLLHL LVRRSRFVLF YTTRPRDSHR GRPGLGRGYG YRVHHDVVAG DVHFEHPAPA 310 320 330 340 350 360 LAPNESPKDS PAHEVTGSGG AYMRFDVPRP RVQRSWPTFR ALLLHRYVVA RVIWADMLSI 370 380 390 400 410 420 AVTYFITLCL FPGLESEIRH CILGEWLPIL IMAVFNLSDF VGKILAALPV DWRGTHLLAC 430 440 450 460 470 480 SCLRVVFIPL FILCVYPSGM PALRHPAWPC IFSLLMGISN GYFGSVPMIL AAGKVSPKQR 490 500 510 520 530 ELAGNTMTVS YMSGLTLGSA VAYCTYSLTR DAHGSCLHAS TANGSILAGL
	Isoform 2. Checksum: 601976FF77817BFD	FASTA	516	56,401
	10 20 30 40 50 60 MGSVGSQRLE EPSVAGTPDP GVVMSFTFDS HQLEEAAEAA QGQGLRARGV PAFTDTTLDE 70 80 90 100 110 120 PVPDDRYHAI YFAMLLAGVG FLLPYNSFIT DVDYLHHKYP GTSIVFDMSL TYILVALAAV 130 140 150 160 170 180 LLNNVLVERL TLHTRITAAS ATCGCSSSLG TRPTPSTWPL WAPWPSAAQQ SSFYGYTGML 190 200 210 220 230 240 PKRYTQGVMT GESTAGVMIS LSRILTKLLL PDERASTLIF FLVSVALELL CFLLHLLVRR 250 260 270 280 290 300 SRFVLFYTTR PRDSHRGRPG LGRGYGYRVH HDVVAGDVHF EHPAPALAPN ESPKDSPAHE 310 320 330 340 350 360 VTGSGGAYMR FDVPRPRVQR SWPTFRALLL HRYVVARVIW ADMLSIAVTY FITLCLFPGL 370 380 390 400 410 420 ESEIRHCILG EWLPILIMAV FNLSDFVGKI LAALPVDWRG THLLACSCLR VVFIPLFILC 430 440 450 460 470 480 VYPSGMPALR HPAWPCIFSL LMGISNGYFG SVPMILAAGK VSPKQRELAG NTMTVSYMSG 490 500 510 LTLGSAVAYC TYSLTRDAHG SCLHASTANG SILAGL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification and characterization of a novel monoamine transporter in the human brain." Engel K., Zhou M., Wang J. J. Biol. Chem. 279:50042-50049(2004) [PubMed: 15448143] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION, TOPOLOGY, TISSUE SPECIFICITY. Tissue: Kidney.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), VARIANTS GLU-79; LYS-124 AND THR-429. Tissue: Brain and Eye.
[5]	"HRI human cDNA sequencing project." Ota T., Nishikawa T., Suzuki Y., Kawai-Hio Y., Hayashi K., Ishii S., Saito K., Yamamoto J., Wakamatsu A., Nagai T., Nakamura Y., Nagahari K., Sugano S., Isogai T. Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 89-530 (ISOFORM 1). Tissue: Teratocarcinoma.
[6]	"Molecular evolution of the equilibrative nucleoside transporter family: identification of novel family members in prokaryotes and eukaryotes." Acimovic Y., Coe I.R. Mol. Biol. Evol. 19:2199-2210(2002) [PubMed: 12446811] [Abstract] Cited for: IDENTIFICATION.
[7]	"Distribution and functional characterization of equilibrative nucleoside transporter-4, a novel cardiac adenosine transporter activated at acidic pH." Barnes K., Dobrzynski H., Foppolo S., Beal P.R., Ismat F., Scullion E.R., Sun L., Tellez J., Ritzel M.W., Claycomb W.C., Cass C.E., Young J.D., Billeter-Clark R., Boyett M.R., Baldwin S.A. Circ. Res. 99:510-519(2006) [PubMed: 16873718] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, GLYCOSYLATION AT ASN-523, MUTAGENESIS OF GLU-206 AND GLU-375.
[8]	"Membrane localization and pH-dependent transport of a newly cloned organic cation transporter (PMAT) in kidney cells." Xia L., Engel K., Zhou M., Wang J. Am. J. Physiol. 292:F682-F690(2007) [PubMed: 17018840] [Abstract] Cited for: FUNCTION, TOPOLOGY, TISSUE SPECIFICITY.
[9]	"Molecular determinants of substrate selectivity of a novel organic cation transporter (PMAT) in the SLC29 family." Zhou M., Xia L., Engel K., Wang J. J. Biol. Chem. 282:3188-3195(2007) [PubMed: 17121826] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ASP-91; ASP-107; GLU-128; ASP-154; ASP-163; GLU-206; THR-220; GLU-227; GLU-242; TRP-336 AND GLU-375.
[10]	"The organic cation transporters (OCT1, OCT2, EMT) and the plasma membrane monoamine transporter (PMAT) show differential distribution and cyclic expression pattern in human endometrium and early pregnancy decidua." Bottalico B., Noskova V., Pilka R., Larsson I., Domanski H., Casslen B., Hansson S.R. Mol. Reprod. Dev. 74:1303-1311(2007) [PubMed: 17393420] [Abstract] Cited for: TISSUE SPECIFICITY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AY485959 mRNA. Translation: AAS65965.1. AK092242 mRNA. Translation: BAC03836.1. CH471144 Genomic DNA. Translation: EAW87329.1. CH471144 Genomic DNA. Translation: EAW87330.1. BC025325 mRNA. Translation: AAH25325.1. BC047592 mRNA. Translation: AAH47592.1. AK075422 mRNA. Translation: BAC11612.1. Different initiation. BK000627 Genomic DNA. Translation: DAA00308.1.
IPI	IPI00641511. IPI00888339.
RefSeq	NP_001035751.1. NP_694979.2.
UniGene	Hs.4302
3D structure databases
ModBase	Search...
Protein family/group databases
TCDB	2.A.57.1.5. equilibrative nucleoside transporter (ENT) family.
PTM databases
PhosphoSite	Q7RTT9.
Proteomic databases
PRIDE	Q7RTT9.
Genome annotation databases
Ensembl	ENSG00000164638. Homo sapiens. [Contig view]
GeneID	222962.
KEGG	hsa:222962.
Organism-specific databases
GeneCards	GC07P005289.
HGNC	HGNC:23097. SLC29A4.
MIM	609149. gene.
PharmGKB	PA134976472.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q7RTT9.
HOVERGEN	Q7RTT9.
OMA	Q7RTT9. HTRITVG.
Gene expression databases
Bgee	Q7RTT9.
CleanEx	HS_SLC29A4.
Family and domain databases
InterPro	IPR002259. DER/eqnu_transpt. [Graphical view]
PANTHER	PTHR10332. DER/eqnu_transpt. 1 hit.
Pfam	PF01733. Nucleoside_tran. 1 hit. [Graphical view]
PRINTS	PR01130. DERENTRNSPRT.
ProDom	PD005103. DER/eqnu_transpt. 1 hit. [Graphical view] [Entries sharing at least one domain]
ProtoNet	Search...
Other Resources
NextBio	91692.
SOURCE	Search...

Entry information

Entry name

S29A4_HUMAN

Accession

Primary (citable) accession number: Q7RTT9
Secondary accession number(s): Q6PJ08 , Q86WY8, Q8NAR3, Q8NBM2

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 18, 2008
Last sequence update:	December 15, 2003
Last modified:	June 16, 2009
This is version 45 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)