MRP4_HUMAN
ID MRP4_HUMAN Reviewed; 1325 AA.
AC O15439; A9Z1Z7; B7Z3Q7; Q8IVZ4; Q8IZN6; Q8NEW8; Q9Y6J2;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 23-SEP-2008, sequence version 3.
DT 03-AUG-2022, entry version 207.
DE RecName: Full=ATP-binding cassette sub-family C member 4;
DE EC=7.6.2.- {ECO:0000269|PubMed:11856762, ECO:0000269|PubMed:12523936, ECO:0000269|PubMed:12835412, ECO:0000269|PubMed:12883481, ECO:0000269|PubMed:15364914, ECO:0000269|PubMed:15454390, ECO:0000269|PubMed:16282361};
DE EC=7.6.2.2 {ECO:0000269|PubMed:11856762, ECO:0000269|PubMed:12105214, ECO:0000269|PubMed:15454390, ECO:0000269|PubMed:17344354, ECO:0000269|PubMed:18300232};
DE EC=7.6.2.3 {ECO:0000269|PubMed:11856762, ECO:0000269|PubMed:17959747, ECO:0000269|PubMed:26721430};
DE AltName: Full=MRP/cMOAT-related ABC transporter;
DE AltName: Full=Multi-specific organic anion transporter B {ECO:0000303|PubMed:9661885};
DE Short=MOAT-B {ECO:0000303|PubMed:9661885};
DE AltName: Full=Multidrug resistance-associated protein 4;
GN Name=ABCC4; Synonyms=MOATB, MRP4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ILE-18.
RX PubMed=9661885;
RA Lee K., Belinsky M.G., Bell D.W., Testa J.R., Kruh G.D.;
RT "Isolation of MOAT-B, a widely expressed multidrug resistance-associated
RT protein/canalicular multispecific organic anion transporter-related
RT transporter.";
RL Cancer Res. 58:2741-2747(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT ILE-18, CATALYTIC ACTIVITY,
RP AND FUNCTION.
RX PubMed=12105214; DOI=10.1074/jbc.m203262200;
RA Adachi M., Sampath J., Lan L.B., Sun D., Hargrove P., Flatley R., Tatum A.,
RA Edwards M.Z., Wezeman M., Matherly L., Drake R., Schuetz J.;
RT "Expression of MRP4 confers resistance to ganciclovir and compromises
RT bystander cell killing.";
RL J. Biol. Chem. 277:38998-39004(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Kidney;
RA Kato R., Ishikawa T.;
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S.,
RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L.,
RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C.,
RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P.,
RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L.,
RA Frankish A.G., Frankland J., French L., Garner P., Garnett J.,
RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M.,
RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D.,
RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D.,
RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S.,
RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R.,
RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W.,
RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L.,
RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R.,
RA Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Brain;
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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1155-1316 (ISOFORMS 1/2).
RC TISSUE=Brain;
RX PubMed=9270026;
RA Kool M., de Haas M., Scheffer G.L., Scheper R.J., van Eijk M.J.,
RA Juijn J.A., Baas F., Borst P.;
RT "Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues
RT of the multidrug resistance-associated protein gene (MRP1), in human cancer
RT cell lines.";
RL Cancer Res. 57:3537-3547(1997).
RN [9]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=11106685; DOI=10.1093/jnci/92.23.1934;
RA Lee K., Klein-Szanto A.J., Kruh G.D.;
RT "Analysis of the MRP4 drug resistance profile in transfected NIH3T3
RT cells.";
RL J. Natl. Cancer Inst. 92:1934-1940(2000).
RN [10]
RP SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, FUNCTION, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=11856762; DOI=10.1681/asn.v133595;
RA van Aubel R.A., Smeets P.H., Peters J.G., Bindels R.J., Russel F.G.;
RT "The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in
RT human kidney proximal tubules: putative efflux pump for urinary cAMP and
RT cGMP.";
RL J. Am. Soc. Nephrol. 13:595-603(2002).
RN [11]
RP CATALYTIC ACTIVITY, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=12883481; DOI=10.1053/jhep.2003.50331;
RA Rius M., Nies A.T., Hummel-Eisenbeiss J., Jedlitschky G., Keppler D.;
RT "Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4)
RT localized to the basolateral hepatocyte membrane.";
RL Hepatology 38:374-384(2003).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=12523936; DOI=10.1042/bj20021886;
RA Zelcer N., Reid G., Wielinga P., Kuil A., van der Heijden I., Schuetz J.D.,
RA Borst P.;
RT "Steroid and bile acid conjugates are substrates of human multidrug-
RT resistance protein (MRP) 4 (ATP-binding cassette C4).";
RL Biochem. J. 371:361-367(2003).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY
RP REGULATION.
RX PubMed=12835412; DOI=10.1073/pnas.1033060100;
RA Reid G., Wielinga P., Zelcer N., van der Heijden I., Kuil A., de Haas M.,
RA Wijnholds J., Borst P.;
RT "The human multidrug resistance protein MRP4 functions as a prostaglandin
RT efflux transporter and is inhibited by nonsteroidal antiinflammatory
RT drugs.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:9244-9249(2003).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND COFACTOR.
RX PubMed=15364914; DOI=10.1074/jbc.m408849200;
RA Sauna Z.E., Nandigama K., Ambudkar S.V.;
RT "Multidrug resistance protein 4 (ABCC4)-mediated ATP hydrolysis: effect of
RT transport substrates and characterization of the post-hydrolysis transition
RT state.";
RL J. Biol. Chem. 279:48855-48864(2004).
RN [15]
RP CATALYTIC ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY
RP REGULATION.
RX PubMed=15454390; DOI=10.1152/ajprenal.00133.2004;
RA Van Aubel R.A., Smeets P.H., van den Heuvel J.J., Russel F.G.;
RT "Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the
RT purine end metabolite urate with multiple allosteric substrate binding
RT sites.";
RL Am. J. Physiol. 288:F327-F333(2005).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=16282361; DOI=10.1152/ajpgi.00354.2005;
RA Rius M., Hummel-Eisenbeiss J., Hofmann A.F., Keppler D.;
RT "Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile
RT acids and reduced glutathione.";
RL Am. J. Physiol. 290:G640-G649(2006).
RN [17]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=17344354; DOI=10.1124/mol.106.031823;
RA Ci L., Kusuhara H., Adachi M., Schuetz J.D., Takeuchi K., Sugiyama Y.;
RT "Involvement of MRP4 (ABCC4) in the luminal efflux of ceftizoxime and
RT cefazolin in the kidney.";
RL Mol. Pharmacol. 71:1591-1597(2007).
RN [18]
RP CATALYTIC ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY
RP REGULATION.
RX PubMed=17959747; DOI=10.1124/jpet.107.131342;
RA Rius M., Hummel-Eisenbeiss J., Keppler D.;
RT "ATP-dependent transport of leukotrienes B4 and C4 by the multidrug
RT resistance protein ABCC4 (MRP4).";
RL J. Pharmacol. Exp. Ther. 324:86-94(2008).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-646, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-646, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-646, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [24]
RP INTERACTION WITH SNX27.
RX PubMed=22411990; DOI=10.1074/jbc.m111.337931;
RA Hayashi H., Naoi S., Nakagawa T., Nishikawa T., Fukuda H., Imajoh-Ohmi S.,
RA Kondo A., Kubo K., Yabuki T., Hattori A., Hirouchi M., Sugiyama Y.;
RT "Sorting nexin 27 interacts with multidrug resistance-associated protein 4
RT (MRP4) and mediates internalization of MRP4.";
RL J. Biol. Chem. 287:15054-15065(2012).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-646; THR-648; SER-664 AND
RP SER-668, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [26]
RP VARIANTS CYS-556; ILE-776; ILE-820; PHE-854 AND VAL-866, CHARACTERIZATION
RP OF VARIANTS TRP-187; ASN-304; GLU-487; CYS-556; LYS-757; ILE-776; ILE-820;
RP PHE-854; VAL-866 AND MET-1142, CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=18300232; DOI=10.1002/humu.20694;
RA Janke D., Mehralivand S., Strand D., Goedtel-Armbrust U., Habermeier A.,
RA Gradhand U., Fischer C., Toliat M.R., Fritz P., Zanger U.M., Schwab M.,
RA Fromm M.F., Nuernberg P., Wojnowski L., Closs E.I., Lang T.;
RT "6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA)
RT transport altered by two missense mutations in the drug transporter gene
RT ABCC4.";
RL Hum. Mutat. 29:659-669(2008).
RN [27]
RP FUNCTION, CATALYTIC ACTIVITY, GLYCOSYLATION AT ASN-746 AND ASN-754,
RP MUTAGENESIS OF ASN-746 AND ASN-754, AND SUBCELLULAR LOCATION.
RX PubMed=26721430; DOI=10.1016/j.bbrc.2015.12.095;
RA Miah M.F., Conseil G., Cole S.P.;
RT "N-linked glycans do not affect plasma membrane localization of multidrug
RT resistance protein 4 (MRP4) but selectively alter its prostaglandin E2
RT transport activity.";
RL Biochem. Biophys. Res. Commun. 469:954-959(2016).
RN [28]
RP VARIANT LYS-757.
RX PubMed=20547088; DOI=10.1016/j.legalmed.2010.04.001;
RA Yuasa I., Umetsu K., Matsusue A., Nishimukai H., Harihara S., Fukumori Y.,
RA Saitou N., Jin F., Chattopadhyay P.K., Henke L., Henke J.;
RT "A Japanese-specific allele in the GALNT11 gene.";
RL Leg. Med. 12:208-211(2010).
CC -!- FUNCTION: ATP-dependent transporter of the ATP-binding cassette (ABC)
CC family that actively extrudes physiological compounds and xenobiotics
CC from cells. Transports a range of endogenous molecules that have a key
CC role in cellular communication and signaling, including cyclic
CC nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile
CC acids, steroid conjugates, urate, and prostaglandins (PubMed:11856762,
CC PubMed:12883481, PubMed:12523936, PubMed:12835412, PubMed:15364914,
CC PubMed:15454390, PubMed:16282361, PubMed:17959747, PubMed:18300232,
CC PubMed:26721430). Mediates the ATP-dependent efflux of glutathione
CC conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too.
CC The presence of GSH is necessary for the ATP-dependent transport of
CC LTB4, whereas GSH is not required for the transport of LTC4
CC (PubMed:17959747). Mediates the cotransport of bile acids with reduced
CC glutathione (GSH) (PubMed:12883481, PubMed:12523936, PubMed:16282361).
CC Transports a wide range of drugs and their metabolites, including
CC anticancer, antiviral and antibiotics molecules (PubMed:11856762,
CC PubMed:12105214, PubMed:15454390, PubMed:18300232, PubMed:17344354).
CC Confers resistance to anticancer agents such as methotrexate
CC (PubMed:11106685). {ECO:0000269|PubMed:11106685,
CC ECO:0000269|PubMed:11856762, ECO:0000269|PubMed:12105214,
CC ECO:0000269|PubMed:12523936, ECO:0000269|PubMed:12835412,
CC ECO:0000269|PubMed:12883481, ECO:0000269|PubMed:15364914,
CC ECO:0000269|PubMed:15454390, ECO:0000269|PubMed:16282361,
CC ECO:0000269|PubMed:17344354, ECO:0000269|PubMed:17959747,
CC ECO:0000269|PubMed:18300232, ECO:0000269|PubMed:26721430}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + xenobioticSide 1 = ADP + phosphate +
CC xenobioticSide 2.; EC=7.6.2.2; Evidence={ECO:0000269|PubMed:11856762,
CC ECO:0000269|PubMed:12105214, ECO:0000269|PubMed:15454390,
CC ECO:0000269|PubMed:17344354, ECO:0000269|PubMed:18300232};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an S-substituted glutathione(in) + ATP + H2O = ADP + an S-
CC substituted glutathione(out) + H(+) + phosphate;
CC Xref=Rhea:RHEA:19121, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:90779,
CC ChEBI:CHEBI:456216; EC=7.6.2.3;
CC Evidence={ECO:0000269|PubMed:11856762, ECO:0000269|PubMed:17959747,
CC ECO:0000269|PubMed:26721430};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19122;
CC Evidence={ECO:0000305|PubMed:17959747};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=17beta-estradiol 17-O-(beta-D-glucuronate)(in) + ATP + H2O =
CC 17beta-estradiol 17-O-(beta-D-glucuronate)(out) + ADP + H(+) +
CC phosphate; Xref=Rhea:RHEA:60128, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:82961, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:11856762, ECO:0000269|PubMed:26721430};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60129;
CC Evidence={ECO:0000305|PubMed:11856762, ECO:0000305|PubMed:26721430};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + dehydroepiandrosterone 3-sulfate(in) + H2O = ADP +
CC dehydroepiandrosterone 3-sulfate(out) + H(+) + phosphate;
CC Xref=Rhea:RHEA:61364, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57905,
CC ChEBI:CHEBI:456216; Evidence={ECO:0000269|PubMed:12523936};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61365;
CC Evidence={ECO:0000305|PubMed:12523936};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + leukotriene C4(in) = ADP + H(+) + leukotriene
CC C4(out) + phosphate; Xref=Rhea:RHEA:38963, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57973, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:17959747};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38964;
CC Evidence={ECO:0000305|PubMed:17959747};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + leukotriene B4(in) = ADP + H(+) + leukotriene
CC B4(out) + phosphate; Xref=Rhea:RHEA:66424, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57461, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:17959747};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + urate(in) = ADP + H(+) + phosphate + urate(out);
CC Xref=Rhea:RHEA:16461, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17775, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:456216; Evidence={ECO:0000269|PubMed:15454390};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16462;
CC Evidence={ECO:0000305|PubMed:15454390};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3',5'-cyclic GMP(in) + ATP + H2O = 3',5'-cyclic GMP(out) + ADP
CC + H(+) + phosphate; Xref=Rhea:RHEA:66188, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57746, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:11856762, ECO:0000269|PubMed:15454390};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66189;
CC Evidence={ECO:0000305|PubMed:15454390};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3',5'-cyclic AMP(in) + ATP + H2O = 3',5'-cyclic AMP(out) + ADP
CC + H(+) + phosphate; Xref=Rhea:RHEA:66184, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:58165, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:11856762};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66185;
CC Evidence={ECO:0000305|PubMed:11856762};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + prostaglandin E2(in) = ADP + H(+) + phosphate +
CC prostaglandin E2(out); Xref=Rhea:RHEA:66388, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:456216, ChEBI:CHEBI:606564;
CC Evidence={ECO:0000269|PubMed:12835412, ECO:0000269|PubMed:15364914,
CC ECO:0000269|PubMed:26721430};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66389;
CC Evidence={ECO:0000305|PubMed:15364914, ECO:0000305|PubMed:26721430};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + prostaglandin E1(in) = ADP + H(+) + phosphate +
CC prostaglandin E1(out); Xref=Rhea:RHEA:66392, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57397, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:12835412, ECO:0000269|PubMed:15364914};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66393;
CC Evidence={ECO:0000305|PubMed:15364914};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + glutathione(in) + glycodeoxycholate(in) + H2O = ADP +
CC glutathione(out) + glycodeoxycholate(out) + H(+) + phosphate;
CC Xref=Rhea:RHEA:66380, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57925,
CC ChEBI:CHEBI:82982, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:16282361};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66381;
CC Evidence={ECO:0000305|PubMed:16282361};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + cholate(in) + glutathione(in) + H2O = ADP + cholate(out)
CC + glutathione(out) + H(+) + phosphate; Xref=Rhea:RHEA:66396,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:29747,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57925,
CC ChEBI:CHEBI:456216; Evidence={ECO:0000269|PubMed:16282361};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66397;
CC Evidence={ECO:0000305|PubMed:16282361};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + glutathione(in) + glycocholate(in) + H2O = ADP +
CC glutathione(out) + glycocholate(out) + H(+) + phosphate;
CC Xref=Rhea:RHEA:66400, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29746, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57925, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:16282361};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66401;
CC Evidence={ECO:0000305|PubMed:16282361};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + glutathione(in) + H2O + taurocholate(in) = ADP +
CC glutathione(out) + H(+) + phosphate + taurocholate(out);
CC Xref=Rhea:RHEA:66404, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:36257, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57925, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:16282361};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66405;
CC Evidence={ECO:0000305|PubMed:16282361};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + glutathione(in) + glycochenodeoxycholate(in) + H2O = ADP
CC + glutathione(out) + glycochenodeoxycholate(out) + H(+) + phosphate;
CC Xref=Rhea:RHEA:66408, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:36252, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57925, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:16282361};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66409;
CC Evidence={ECO:0000305|PubMed:16282361};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + glutathione(in) + H2O + taurochenodeoxycholate(in) = ADP
CC + glutathione(out) + H(+) + phosphate + taurochenodeoxycholate(out);
CC Xref=Rhea:RHEA:66412, ChEBI:CHEBI:9407, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57925, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:16282361};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66413;
CC Evidence={ECO:0000305|PubMed:16282361};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + glutathione(in) + glycoursodeoxycholate(in) + H2O = ADP
CC + glutathione(out) + glycoursodeoxycholate(out) + H(+) + phosphate;
CC Xref=Rhea:RHEA:66416, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57925,
CC ChEBI:CHEBI:132030, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:16282361};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66417;
CC Evidence={ECO:0000305|PubMed:16282361};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + glutathione(in) + H2O + tauroursodeoxycholate(in) = ADP
CC + glutathione(out) + H(+) + phosphate + tauroursodeoxycholate(out);
CC Xref=Rhea:RHEA:66420, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57925,
CC ChEBI:CHEBI:132028, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:16282361};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66421;
CC Evidence={ECO:0000305|PubMed:16282361};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:15364914};
CC -!- ACTIVITY REGULATION: GSH stimulates the transport of MRP4
CC (PubMed:17959747). Urate inhibits methotrexate transport but stimulates
CC cGMP transport (PubMed:15454390). Nonsteroidal anti-inflammatory drugs
CC (NSAIDs) strongly suppress the transport of MRP4 substrates
CC (PubMed:12835412). {ECO:0000269|PubMed:12835412,
CC ECO:0000269|PubMed:15454390, ECO:0000269|PubMed:17959747}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.1 uM for prostaglandin E1 {ECO:0000269|PubMed:12835412};
CC KM=3.4 uM for prostaglandin E2 {ECO:0000269|PubMed:12835412};
CC KM=25.8 uM for cholylglycine (in the presence of 5 mM GSH)
CC {ECO:0000269|PubMed:16282361};
CC KM=7.7 uM for cholyltaurine (in the presence of 5 mM GSH)
CC {ECO:0000269|PubMed:16282361};
CC KM=6.7 uM for deoxycholylglycine (in the presence of 5 mM GSH)
CC {ECO:0000269|PubMed:16282361};
CC KM=5.9 uM for chenodeoxycholylglycine (in the presence of 5 mM GSH)
CC {ECO:0000269|PubMed:16282361};
CC KM=3.6 uM for chenodeoxycholyltaurine (in the presence of 5 mM GSH)
CC {ECO:0000269|PubMed:16282361};
CC KM=12.5 uM for ursodeoxycholylglycine (in the presence of 5 mM GSH)
CC {ECO:0000269|PubMed:16282361};
CC KM=7.8 uM for ursodeoxycholyltaurine (in the presence of 5 mM GSH)
CC {ECO:0000269|PubMed:16282361};
CC KM=14.8 uM for cholate (in the presence of 5 mM GSH)
CC {ECO:0000269|PubMed:16282361};
CC KM=1500 uM for urate {ECO:0000269|PubMed:15454390};
CC KM=180 uM for cGMP {ECO:0000269|PubMed:15454390};
CC KM=0.62 uM for ATP {ECO:0000269|PubMed:15364914};
CC KM=0.13 uM for LTC4 {ECO:0000269|PubMed:17959747};
CC KM=1.3 uM for methotrexate {ECO:0000269|PubMed:11856762};
CC KM=5.2 uM for LTB4 (in the presence of 5 mM GSH)
CC {ECO:0000269|PubMed:17959747};
CC KM=2 uM for 3beta-sulfooxy-androst-5-en-17-one
CC {ECO:0000269|PubMed:12523936};
CC Vmax=430 pmol/min/mg enzyme for methotrexate transport
CC {ECO:0000269|PubMed:11856762};
CC Vmax=47 pmol/min/mg enzyme for urate transport
CC {ECO:0000269|PubMed:15454390};
CC Vmax=75 pmol/min/mg enzyme for cholate transport (in the presence of
CC 5 mM GSH) {ECO:0000269|PubMed:16282361};
CC Vmax=175 pmol/min/mg enzyme for cholylglycine transport (in the
CC presence of 5 mM GSH) {ECO:0000269|PubMed:16282361};
CC Vmax=154 pmol/min/mg enzyme for cholyltaurine transport (in the
CC presence of 5 mM GSH) {ECO:0000269|PubMed:16282361};
CC Vmax=93 pmol/min/mg enzyme for chenodeoxycholylglycine transport (in
CC the presence of 5 mM GSH) {ECO:0000269|PubMed:16282361};
CC Vmax=83 pmol/min/mg enzyme for chenodeoxycholyltaurine transport (in
CC the presence of 5 mM GSH) {ECO:0000269|PubMed:16282361};
CC Vmax=130 pmol/min/mg enzyme for ursodeoxycholylglycine (in the
CC presence of 5 mM GSH) {ECO:0000269|PubMed:16282361};
CC Vmax=133 pmol/min/mg enzyme for ursodeoxycholyltaurine (in the
CC presence of 5 mM GSH) {ECO:0000269|PubMed:16282361};
CC Vmax=45 pmol/min/mg enzyme for 3beta-sulfooxy-androst-5-en-17-one
CC transport {ECO:0000269|PubMed:12523936};
CC -!- SUBUNIT: Interacts (via PDZ-binding motif) with SNX27 (via PDZ domain);
CC this interaction accelerates MRP4 internalization.
CC {ECO:0000269|PubMed:22411990}.
CC -!- INTERACTION:
CC O15439; Q00013: MPP1; NbExp=10; IntAct=EBI-4319622, EBI-711788;
CC -!- SUBCELLULAR LOCATION: Basolateral cell membrane
CC {ECO:0000269|PubMed:11106685, ECO:0000269|PubMed:12883481,
CC ECO:0000269|PubMed:26721430}; Multi-pass membrane protein
CC {ECO:0000255}. Apical cell membrane {ECO:0000269|PubMed:11856762,
CC ECO:0000269|PubMed:26721430}; Multi-pass membrane protein
CC {ECO:0000255}. Note=Its localization to the basolateral or apical
CC membranes is tissue-dependent. {ECO:0000305|PubMed:26721430}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=O15439-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O15439-2; Sequence=VSP_035426;
CC Name=3;
CC IsoId=O15439-3; Sequence=VSP_043283, VSP_043284;
CC Name=4;
CC IsoId=O15439-4; Sequence=VSP_057413, VSP_043283, VSP_043284;
CC -!- TISSUE SPECIFICITY: Widely expressed, with particularly high levels in
CC prostate, but is barely detectable in liver. sinusoidal membrane of
CC hepatocytes.
CC -!- PTM: N-glycosylated; leading to substrate-selective effects on its
CC transport activity. {ECO:0000269|PubMed:26721430}.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCC family.
CC Conjugate transporter (TC 3.A.1.208) subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=ABCMdb; Note=Database for mutations in ABC proteins;
CC URL="http://abcm2.hegelab.org/search";
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DR EMBL; AF071202; AAC27076.1; -; mRNA.
DR EMBL; AY081219; AAL88745.1; -; mRNA.
DR EMBL; AY207008; AAO37649.1; -; mRNA.
DR EMBL; AF541977; AAN17334.1; -; mRNA.
DR EMBL; AK296247; BAH12293.1; -; mRNA.
DR EMBL; AL139381; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL157818; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL356257; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL359750; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471085; EAX08951.1; -; Genomic_DNA.
DR EMBL; CH471085; EAX08950.1; -; Genomic_DNA.
DR EMBL; BC041560; AAH41560.1; -; mRNA.
DR EMBL; U83660; AAB71757.1; -; mRNA.
DR CCDS; CCDS45061.1; -. [O15439-3]
DR CCDS; CCDS76643.1; -. [O15439-4]
DR CCDS; CCDS86356.1; -. [O15439-2]
DR CCDS; CCDS9474.1; -. [O15439-1]
DR RefSeq; NP_001098985.1; NM_001105515.2. [O15439-3]
DR RefSeq; NP_001288758.1; NM_001301829.1. [O15439-2]
DR RefSeq; NP_001288759.1; NM_001301830.1. [O15439-4]
DR RefSeq; NP_005836.2; NM_005845.4. [O15439-1]
DR AlphaFoldDB; O15439; -.
DR SMR; O15439; -.
DR BioGRID; 115551; 68.
DR IntAct; O15439; 20.
DR MINT; O15439; -.
DR STRING; 9606.ENSP00000366084; -.
DR BindingDB; O15439; -.
DR ChEMBL; CHEMBL1743128; -.
DR DrugBank; DB00718; Adefovir dipivoxil.
DR DrugBank; DB00770; Alprostadil.
DR DrugBank; DB01076; Atorvastatin.
DR DrugBank; DB00171; ATP.
DR DrugBank; DB01327; Cefazolin.
DR DrugBank; DB00482; Celecoxib.
DR DrugBank; DB02659; Cholic Acid.
DR DrugBank; DB00286; Conjugated estrogens.
DR DrugBank; DB02527; Cyclic adenosine monophosphate.
DR DrugBank; DB09213; Dexibuprofen.
DR DrugBank; DB00586; Diclofenac.
DR DrugBank; DB00917; Dinoprostone.
DR DrugBank; DB00975; Dipyridamole.
DR DrugBank; DB13146; Fluciclovine (18F).
DR DrugBank; DB00544; Fluorouracil.
DR DrugBank; DB00712; Flurbiprofen.
DR DrugBank; DB00158; Folic acid.
DR DrugBank; DB08884; Gadoxetic acid.
DR DrugBank; DB00143; Glutathione.
DR DrugBank; DB00999; Hydrochlorothiazide.
DR DrugBank; DB01050; Ibuprofen.
DR DrugBank; DB00328; Indomethacin.
DR DrugBank; DB01009; Ketoprofen.
DR DrugBank; DB00709; Lamivudine.
DR DrugBank; DB00814; Meloxicam.
DR DrugBank; DB01033; Mercaptopurine.
DR DrugBank; DB00563; Methotrexate.
DR DrugBank; DB00731; Nateglinide.
DR DrugBank; DB00198; Oseltamivir.
DR DrugBank; DB01708; Prasterone.
DR DrugBank; DB01032; Probenecid.
DR DrugBank; DB01069; Promethazine.
DR DrugBank; DB00481; Raloxifene.
DR DrugBank; DB14761; Remdesivir.
DR DrugBank; DB00533; Rofecoxib.
DR DrugBank; DB01098; Rosuvastatin.
DR DrugBank; DB12332; Rucaparib.
DR DrugBank; DB00203; Sildenafil.
DR DrugBank; DB00398; Sorafenib.
DR DrugBank; DB01138; Sulfinpyrazone.
DR DrugBank; DB01268; Sunitinib.
DR DrugBank; DB04348; Taurocholic acid.
DR DrugBank; DB14126; Tenofovir.
DR DrugBank; DB09299; Tenofovir alafenamide.
DR DrugBank; DB00300; Tenofovir disoproxil.
DR DrugBank; DB00352; Tioguanine.
DR DrugBank; DB01586; Ursodeoxycholic acid.
DR DrugBank; DB00661; Verapamil.
DR DrugBank; DB00495; Zidovudine.
DR DrugCentral; O15439; -.
DR GuidetoPHARMACOLOGY; 782; -.
DR TCDB; 3.A.1.208.7; the atp-binding cassette (abc) superfamily.
DR GlyGen; O15439; 2 sites.
DR iPTMnet; O15439; -.
DR PhosphoSitePlus; O15439; -.
DR SwissPalm; O15439; -.
DR BioMuta; ABCC4; -.
DR EPD; O15439; -.
DR jPOST; O15439; -.
DR MassIVE; O15439; -.
DR MaxQB; O15439; -.
DR PaxDb; O15439; -.
DR PeptideAtlas; O15439; -.
DR PRIDE; O15439; -.
DR ProteomicsDB; 48664; -. [O15439-1]
DR ProteomicsDB; 48665; -. [O15439-2]
DR ProteomicsDB; 48666; -. [O15439-3]
DR ProteomicsDB; 6540; -.
DR Antibodypedia; 3448; 459 antibodies from 37 providers.
DR DNASU; 10257; -.
DR Ensembl; ENST00000536256.3; ENSP00000442024.1; ENSG00000125257.16. [O15439-4]
DR Ensembl; ENST00000629385.1; ENSP00000487081.1; ENSG00000125257.16. [O15439-3]
DR Ensembl; ENST00000645237.2; ENSP00000494609.1; ENSG00000125257.16. [O15439-1]
DR Ensembl; ENST00000646439.1; ENSP00000494751.1; ENSG00000125257.16. [O15439-2]
DR GeneID; 10257; -.
DR KEGG; hsa:10257; -.
DR MANE-Select; ENST00000645237.2; ENSP00000494609.1; NM_005845.5; NP_005836.2.
DR UCSC; uc001vmd.5; human. [O15439-1]
DR UCSC; uc010tih.2; human.
DR CTD; 10257; -.
DR DisGeNET; 10257; -.
DR GeneCards; ABCC4; -.
DR HGNC; HGNC:55; ABCC4.
DR HPA; ENSG00000125257; Tissue enhanced (prostate).
DR MIM; 605250; gene.
DR neXtProt; NX_O15439; -.
DR OpenTargets; ENSG00000125257; -.
DR PharmGKB; PA397; -.
DR VEuPathDB; HostDB:ENSG00000125257; -.
DR eggNOG; KOG0054; Eukaryota.
DR GeneTree; ENSGT00940000153931; -.
DR HOGENOM; CLU_000604_27_1_1; -.
DR InParanoid; O15439; -.
DR OMA; PWYLLNT; -.
DR OrthoDB; 926074at2759; -.
DR PhylomeDB; O15439; -.
DR TreeFam; TF105202; -.
DR BRENDA; 7.6.2.2; 2681.
DR BRENDA; 7.6.2.3; 2681.
DR PathwayCommons; O15439; -.
DR Reactome; R-HSA-114608; Platelet degranulation.
DR Reactome; R-HSA-382556; ABC-family proteins mediated transport.
DR Reactome; R-HSA-9748787; Azathioprine ADME.
DR Reactome; R-HSA-9753281; Paracetamol ADME.
DR SignaLink; O15439; -.
DR SIGNOR; O15439; -.
DR BioGRID-ORCS; 10257; 12 hits in 1076 CRISPR screens.
DR ChiTaRS; ABCC4; human.
DR GeneWiki; ABCC4; -.
DR GenomeRNAi; 10257; -.
DR Pharos; O15439; Tchem.
DR PRO; PR:O15439; -.
DR Proteomes; UP000005640; Chromosome 13.
DR RNAct; O15439; protein.
DR Bgee; ENSG00000125257; Expressed in palpebral conjunctiva and 155 other tissues.
DR ExpressionAtlas; O15439; baseline and differential.
DR Genevisible; O15439; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:ARUK-UCL.
DR GO; GO:0098591; C:external side of apical plasma membrane; ISS:ARUK-UCL.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:ARUK-UCL.
DR GO; GO:0031088; C:platelet dense granule membrane; IDA:MGI.
DR GO; GO:0016404; F:15-hydroxyprostaglandin dehydrogenase (NAD+) activity; NAS:UniProtKB.
DR GO; GO:0015432; F:ABC-type bile acid transporter activity; IMP:UniProtKB.
DR GO; GO:0015431; F:ABC-type glutathione S-conjugate transporter activity; IDA:UniProtKB.
DR GO; GO:0140359; F:ABC-type transporter activity; TAS:Reactome.
DR GO; GO:0008559; F:ABC-type xenobiotic transporter activity; IEA:UniProtKB-EC.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0043225; F:ATPase-coupled inorganic anion transmembrane transporter activity; TAS:Reactome.
DR GO; GO:0042626; F:ATPase-coupled transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015562; F:efflux transmembrane transporter activity; IMP:ARUK-UCL.
DR GO; GO:0034634; F:glutathione transmembrane transporter activity; IMP:UniProtKB.
DR GO; GO:0001409; F:guanine nucleotide transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015132; F:prostaglandin transmembrane transporter activity; IMP:UniProtKB.
DR GO; GO:0015216; F:purine nucleotide transmembrane transporter activity; IMP:ARUK-UCL.
DR GO; GO:0015143; F:urate transmembrane transporter activity; IMP:UniProtKB.
DR GO; GO:0042910; F:xenobiotic transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015721; P:bile acid and bile salt transport; IMP:UniProtKB.
DR GO; GO:0070730; P:cAMP transport; IDA:UniProtKB.
DR GO; GO:0060271; P:cilium assembly; IMP:MGI.
DR GO; GO:0140115; P:export across plasma membrane; IMP:ARUK-UCL.
DR GO; GO:0071716; P:leukotriene transport; IDA:UniProtKB.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0032310; P:prostaglandin secretion; IDA:MGI.
DR GO; GO:0015732; P:prostaglandin transport; IMP:UniProtKB.
DR GO; GO:0055085; P:transmembrane transport; IBA:GO_Central.
DR GO; GO:0150104; P:transport across blood-brain barrier; NAS:ARUK-UCL.
DR GO; GO:0015747; P:urate transport; IMP:UniProtKB.
DR GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome.
DR GO; GO:0006855; P:xenobiotic transmembrane transport; TAS:Reactome.
DR Gene3D; 1.20.1560.10; -; 2.
DR Gene3D; 3.40.50.300; -; 2.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR011527; ABC1_TM_dom.
DR InterPro; IPR036640; ABC1_TM_sf.
DR InterPro; IPR003439; ABC_transporter-like_ATP-bd.
DR InterPro; IPR017871; ABC_transporter-like_CS.
DR InterPro; IPR030240; ABCC4.
DR InterPro; IPR027417; P-loop_NTPase.
DR PANTHER; PTHR24223:SF357; PTHR24223:SF357; 1.
DR Pfam; PF00664; ABC_membrane; 2.
DR Pfam; PF00005; ABC_tran; 2.
DR SMART; SM00382; AAA; 2.
DR SUPFAM; SSF52540; SSF52540; 2.
DR SUPFAM; SSF90123; SSF90123; 2.
DR PROSITE; PS50929; ABC_TM1F; 2.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; 2.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Cell membrane; Glycoprotein;
KW Lipid transport; Membrane; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Repeat; Translocase; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..1325
FT /note="ATP-binding cassette sub-family C member 4"
FT /id="PRO_0000093362"
FT TRANSMEM 93..113
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 136..156
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 207..227
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 228..248
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 328..348
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 351..371
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 440..460
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 710..730
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 771..791
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 836..856
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 858..878
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 954..974
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 977..997
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 1038..1058
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 92..377
FT /note="ABC transmembrane type-1 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 410..633
FT /note="ABC transporter 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT DOMAIN 714..1005
FT /note="ABC transmembrane type-1 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 1041..1274
FT /note="ABC transporter 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT REGION 657..688
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 1322..1325
FT /note="PDZ-binding"
FT BINDING 445..452
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT BINDING 1075..1082
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT MOD_RES 646
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 648
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 664
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 668
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CARBOHYD 746
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:26721430"
FT CARBOHYD 754
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:26721430"
FT VAR_SEQ 103..177
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_057413"
FT VAR_SEQ 679..725
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_035426"
FT VAR_SEQ 846..859
FT /note="TLLQVVGVVSVAVA -> RWDLAVLSWLVSNS (in isoform 3 and
FT isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_043283"
FT VAR_SEQ 860..1325
FT /note="Missing (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_043284"
FT VARIANT 18
FT /note="L -> I (in dbSNP:rs11568681)"
FT /evidence="ECO:0000269|PubMed:12105214,
FT ECO:0000269|PubMed:9661885"
FT /id="VAR_046445"
FT VARIANT 78
FT /note="P -> A (in dbSNP:rs11568689)"
FT /id="VAR_029121"
FT VARIANT 171
FT /note="C -> G (in dbSNP:rs4148460)"
FT /id="VAR_046446"
FT VARIANT 184
FT /note="M -> T (in dbSNP:rs45454092)"
FT /id="VAR_020241"
FT VARIANT 187
FT /note="G -> W (transport properties comparable to wild-
FT type; dbSNP:rs11568658)"
FT /evidence="ECO:0000269|PubMed:18300232"
FT /id="VAR_020242"
FT VARIANT 293
FT /note="K -> E (in dbSNP:rs11568684)"
FT /id="VAR_046447"
FT VARIANT 304
FT /note="K -> N (transport properties comparable to wild-
FT type; dbSNP:rs2274407)"
FT /evidence="ECO:0000269|PubMed:18300232"
FT /id="VAR_022072"
FT VARIANT 356
FT /note="T -> M (in dbSNP:rs11568701)"
FT /id="VAR_046448"
FT VARIANT 403
FT /note="P -> L (in dbSNP:rs11568705)"
FT /id="VAR_029122"
FT VARIANT 487
FT /note="G -> E (transport properties comparable to wild-
FT type; dbSNP:rs11568668)"
FT /evidence="ECO:0000269|PubMed:18300232"
FT /id="VAR_029123"
FT VARIANT 498
FT /note="K -> E (in dbSNP:rs11568669)"
FT /id="VAR_020243"
FT VARIANT 556
FT /note="Y -> C (40% reduced expression level compared to
FT wild-type; higher transport of 9-(2-phosphonyl-
FT methoxyethyl) adenine than wild-type; dbSNP:rs753414892)"
FT /evidence="ECO:0000269|PubMed:18300232"
FT /id="VAR_045684"
FT VARIANT 625
FT /note="I -> M (in dbSNP:rs11568699)"
FT /id="VAR_029124"
FT VARIANT 667
FT /note="P -> L (in dbSNP:rs11568697)"
FT /id="VAR_029125"
FT VARIANT 744
FT /note="M -> V (in dbSNP:rs9282570)"
FT /id="VAR_020244"
FT VARIANT 757
FT /note="E -> K (10% reduced expression level compared to
FT wild-type; transport properties comparable to wild-type;
FT dbSNP:rs3765534)"
FT /evidence="ECO:0000269|PubMed:18300232,
FT ECO:0000269|PubMed:20547088"
FT /id="VAR_022073"
FT VARIANT 776
FT /note="V -> I (20% reduced expression level compared to
FT wild-type; significant lower activity in 6-mercaptopurine
FT transport than wild-type; dbSNP:rs146708960)"
FT /evidence="ECO:0000269|PubMed:18300232"
FT /id="VAR_045685"
FT VARIANT 820
FT /note="R -> I (transport properties comparable to wild-
FT type; dbSNP:rs11568659)"
FT /evidence="ECO:0000269|PubMed:18300232"
FT /id="VAR_045686"
FT VARIANT 854
FT /note="V -> F (transport properties comparable to wild-
FT type; dbSNP:rs11568694)"
FT /evidence="ECO:0000269|PubMed:18300232"
FT /id="VAR_045687"
FT VARIANT 860
FT /note="V -> M (in dbSNP:rs45477596)"
FT /id="VAR_020245"
FT VARIANT 866
FT /note="I -> V (transport properties comparable to wild-
FT type; dbSNP:rs139970608)"
FT /evidence="ECO:0000269|PubMed:18300232"
FT /id="VAR_045688"
FT VARIANT 900
FT /note="V -> L (in dbSNP:rs45504892)"
FT /id="VAR_020246"
FT VARIANT 1142
FT /note="T -> M (10% reduced expression level compared to
FT wild-type; transport properties comparable to wild-type;
FT dbSNP:rs11568644)"
FT /evidence="ECO:0000269|PubMed:18300232"
FT /id="VAR_029126"
FT MUTAGEN 746
FT /note="N->Q: Does not affect plasma membrane localization;
FT 1.5 fold increase in PEG2 transport; does not affect
FT estradiol 17-beta-D-glucuronide transport."
FT /evidence="ECO:0000269|PubMed:26721430"
FT MUTAGEN 754
FT /note="N->Q: Does not affect plasma membrane localization;
FT PEG2 transport is decreased by 50%; does not affect
FT estradiol 17-beta-D-glucuronide transport."
FT /evidence="ECO:0000269|PubMed:26721430"
FT CONFLICT 703
FT /note="N -> S (in Ref. 2; AAL88745)"
FT /evidence="ECO:0000305"
FT CONFLICT 757
FT /note="E -> G (in Ref. 2; AAL88745)"
FT /evidence="ECO:0000305"
FT CONFLICT 893
FT /note="E -> G (in Ref. 2; AAL88745)"
FT /evidence="ECO:0000305"
FT CONFLICT 1139
FT /note="N -> K (in Ref. 1; AAC27076)"
FT /evidence="ECO:0000305"
FT CONFLICT 1302
FT /note="H -> D (in Ref. 8; AAB71757)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1325 AA; 149527 MW; BF2D53136B78C0BA CRC64;
MLPVYQEVKP NPLQDANLCS RVFFWWLNPL FKIGHKRRLE EDDMYSVLPE DRSQHLGEEL
QGFWDKEVLR AENDAQKPSL TRAIIKCYWK SYLVLGIFTL IEESAKVIQP IFLGKIINYF
ENYDPMDSVA LNTAYAYATV LTFCTLILAI LHHLYFYHVQ CAGMRLRVAM CHMIYRKALR
LSNMAMGKTT TGQIVNLLSN DVNKFDQVTV FLHFLWAGPL QAIAVTALLW MEIGISCLAG
MAVLIILLPL QSCFGKLFSS LRSKTATFTD ARIRTMNEVI TGIRIIKMYA WEKSFSNLIT
NLRKKEISKI LRSSCLRGMN LASFFSASKI IVFVTFTTYV LLGSVITASR VFVAVTLYGA
VRLTVTLFFP SAIERVSEAI VSIRRIQTFL LLDEISQRNR QLPSDGKKMV HVQDFTAFWD
KASETPTLQG LSFTVRPGEL LAVVGPVGAG KSSLLSAVLG ELAPSHGLVS VHGRIAYVSQ
QPWVFSGTLR SNILFGKKYE KERYEKVIKA CALKKDLQLL EDGDLTVIGD RGTTLSGGQK
ARVNLARAVY QDADIYLLDD PLSAVDAEVS RHLFELCICQ ILHEKITILV THQLQYLKAA
SQILILKDGK MVQKGTYTEF LKSGIDFGSL LKKDNEESEQ PPVPGTPTLR NRTFSESSVW
SQQSSRPSLK DGALESQDTE NVPVTLSEEN RSEGKVGFQA YKNYFRAGAH WIVFIFLILL
NTAAQVAYVL QDWWLSYWAN KQSMLNVTVN GGGNVTEKLD LNWYLGIYSG LTVATVLFGI
ARSLLVFYVL VNSSQTLHNK MFESILKAPV LFFDRNPIGR ILNRFSKDIG HLDDLLPLTF
LDFIQTLLQV VGVVSVAVAV IPWIAIPLVP LGIIFIFLRR YFLETSRDVK RLESTTRSPV
FSHLSSSLQG LWTIRAYKAE ERCQELFDAH QDLHSEAWFL FLTTSRWFAV RLDAICAMFV
IIVAFGSLIL AKTLDAGQVG LALSYALTLM GMFQWCVRQS AEVENMMISV ERVIEYTDLE
KEAPWEYQKR PPPAWPHEGV IIFDNVNFMY SPGGPLVLKH LTALIKSQEK VGIVGRTGAG
KSSLISALFR LSEPEGKIWI DKILTTEIGL HDLRKKMSII PQEPVLFTGT MRKNLDPFNE
HTDEELWNAL QEVQLKETIE DLPGKMDTEL AESGSNFSVG QRQLVCLARA ILRKNQILII
DEATANVDPR TDELIQKKIR EKFAHCTVLT IAHRLNTIID SDKIMVLDSG RLKEYDEPYV
LLQNKESLFY KMVQQLGKAE AAALTETAKQ VYFKRNYPHI GHTDHMVTNT SNGQPSTLTI
FETAL
