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3.A.1.208.7
MRP4 (ABCC4); exporter of cyclic nucleotides (cAMP, cGMP and other nucleotide analogues, particularly purine analogues, methotrexate, bile acids, prostaglandins E1 and E2, reduced folates, 9-(2-phosphonylmethyoxyethyl)adenine, leukotrienes, estradiol 17-β-D-glucuronide) and drug sulfate conjugates (inhibited by nonsteroidal antiinflammatory drugs Reid et al., 2003; Rius et al., 2008)). When overexpressed, it can lower the intracellular concentration of nucleoside/nucleotide analogs, such as the antiviral compounds PMEA (9-(2-phosphonylmethoxyethyl)adenine), adefovir, or ganciclovir (Nigam 2015), and of anticancer nucleobase analogs, such as 6-mercaptopurine, after their conversion into the respective nucleotides. MRP4 interacts directly with CFTR (3.A.1.202.1) to control Cl- secretion (Li et al., 2007). It also functions in urate elimination across the renal tubule apical membrane (Prestin et al. 2014). Thus, MRP4 is a broad specificity organic anion exporter (Ritter et al., 2005). MRP4 and CFTR together function in the regulation of cAMP and beta-adrenergic contraction in cardiac myocytes (Sellers et al., 2012). Amino acid changes can alter the uptake of drugs such as 6-mercaptopurine (6-MP) and 9-(2-phosphonyl methoxyethyl) adenine (PMEA) (Janke et al. 2008).  Positions of L1 (the linker between the two halves of the exporter), L0 (the N-terminal domain), and the zipper helices (between the two NBDs) have been suggested (Chantemargue et al. 2018). ABCC4 exports proinflammatory molecules including leukotriene, prostaglandin and sphingosine-1-phosphate across the plasma membrane. These metabolites play roles in asthma (Palikhe et al. 2017). Symmetrical 1,4-dihydropyridines are inhibitors of the MRP4 Efflux Pump and can be used for anticancer therapy (Döring et al. 2020). MRP4 contributes to platelet activation by extruding endogenous molecules responsible for their activation and accumulation and may also export various drugs (Angelis et al. 2021).

Accession Number:O15439
Protein Name:MRP4 aka ABCC4
Length:1325
Molecular Weight:149527.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:10
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate Cyclic nucleotides, Nucleotide analogues, methotrexate, bile acids, Prostagland E1, Prostaglandin E2, Reduced folates, 9-(2-phosphonylmethyoxyethyl)adenine, Leukotrienes, Estradiol 17-beta-D-glucuronides, Drug sulfate conjugates

Cross database links:

RefSeq: NP_001098985.1    NP_005836.2   
Entrez Gene ID: 10257   
Pfam: PF00664    PF00005   
OMIM: 605250  gene
KEGG: hsa:10257   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005624 C:membrane fraction
GO:0005886 C:plasma membrane
GO:0031088 C:platelet dense granule membrane
GO:0016404 F:15-hydroxyprostaglandin dehydrogenase (NAD+...
GO:0005524 F:ATP binding
GO:0042626 F:ATPase activity, coupled to transmembrane m...
GO:0005254 F:chloride channel activity
GO:0006811 P:ion transport
GO:0055085 P:transmembrane transport

References (8)

[1] “Isolation of MOAT-B, a widely expressed multidrug resistance-associated protein/canalicular multispecific organic anion transporter-related transporter.”  Lee K.et.al.   9661885
[2] “Expression of MRP4 confers resistance to ganciclovir and compromises bystander cell killing.”  Adachi M.et.al.   12105214
[3] “The DNA sequence and analysis of human chromosome 13.”  Dunham A.et.al.   15057823
[4] “Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines.”  Kool M.et.al.   9270026
[5] “Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.”  Olsen J.V.et.al.   17081983
[6] “A quantitative atlas of mitotic phosphorylation.”  Dephoure N.et.al.   18669648
[7] “Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.”  Mayya V.et.al.   19690332
[8] “6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA) transport altered by two missense mutations in the drug transporter gene ABCC4.”  Janke D.et.al.   18300232

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MLPVYQEVKP NPLQDANLCS RVFFWWLNPL FKIGHKRRLE EDDMYSVLPE DRSQHLGEEL 
61:	QGFWDKEVLR AENDAQKPSL TRAIIKCYWK SYLVLGIFTL IEESAKVIQP IFLGKIINYF 
121:	ENYDPMDSVA LNTAYAYATV LTFCTLILAI LHHLYFYHVQ CAGMRLRVAM CHMIYRKALR 
181:	LSNMAMGKTT TGQIVNLLSN DVNKFDQVTV FLHFLWAGPL QAIAVTALLW MEIGISCLAG 
241:	MAVLIILLPL QSCFGKLFSS LRSKTATFTD ARIRTMNEVI TGIRIIKMYA WEKSFSNLIT 
301:	NLRKKEISKI LRSSCLRGMN LASFFSASKI IVFVTFTTYV LLGSVITASR VFVAVTLYGA 
361:	VRLTVTLFFP SAIERVSEAI VSIRRIQTFL LLDEISQRNR QLPSDGKKMV HVQDFTAFWD 
421:	KASETPTLQG LSFTVRPGEL LAVVGPVGAG KSSLLSAVLG ELAPSHGLVS VHGRIAYVSQ 
481:	QPWVFSGTLR SNILFGKKYE KERYEKVIKA CALKKDLQLL EDGDLTVIGD RGTTLSGGQK 
541:	ARVNLARAVY QDADIYLLDD PLSAVDAEVS RHLFELCICQ ILHEKITILV THQLQYLKAA 
601:	SQILILKDGK MVQKGTYTEF LKSGIDFGSL LKKDNEESEQ PPVPGTPTLR NRTFSESSVW 
661:	SQQSSRPSLK DGALESQDTE NVPVTLSEEN RSEGKVGFQA YKNYFRAGAH WIVFIFLILL 
721:	NTAAQVAYVL QDWWLSYWAN KQSMLNVTVN GGGNVTEKLD LNWYLGIYSG LTVATVLFGI 
781:	ARSLLVFYVL VNSSQTLHNK MFESILKAPV LFFDRNPIGR ILNRFSKDIG HLDDLLPLTF 
841:	LDFIQTLLQV VGVVSVAVAV IPWIAIPLVP LGIIFIFLRR YFLETSRDVK RLESTTRSPV 
901:	FSHLSSSLQG LWTIRAYKAE ERCQELFDAH QDLHSEAWFL FLTTSRWFAV RLDAICAMFV 
961:	IIVAFGSLIL AKTLDAGQVG LALSYALTLM GMFQWCVRQS AEVENMMISV ERVIEYTDLE 
1021:	KEAPWEYQKR PPPAWPHEGV IIFDNVNFMY SPGGPLVLKH LTALIKSQEK VGIVGRTGAG 
1081:	KSSLISALFR LSEPEGKIWI DKILTTEIGL HDLRKKMSII PQEPVLFTGT MRKNLDPFNE 
1141:	HTDEELWNAL QEVQLKETIE DLPGKMDTEL AESGSNFSVG QRQLVCLARA ILRKNQILII 
1201:	DEATANVDPR TDELIQKKIR EKFAHCTVLT IAHRLNTIID SDKIMVLDSG RLKEYDEPYV 
1261:	LLQNKESLFY KMVQQLGKAE AAALTETAKQ VYFKRNYPHI GHTDHMVTNT SNGQPSTLTI 
1321:	FETAL