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3.A.1.208.10
Multidrug (anthracycline) resistance organic anion efflux pump (ABC-C6; MRP6; MOAT-E - the ectopic mineralization disorder, pseudoxanthoma elasticum disease (PXE), protein (Vanakker et al. 2013; Rasmussen et al. 2013) exports glutathione conjugates including leukotriene C4, DNP, and N-ethylmaleimide S-glutathione; also exports anthracyclines, epipodophyllotoxins, cisplatin, and probably exports probenecid, benzbromarone and indomethacin (Chen and Tiwari, 2011).  The system participates in networds of complex diseases (De Vilder et al. 2015). This transporter has an extra N-terminal domain (TMD0) and a loop, L0.  TMD0 is not required for transport function, but L0 maintains ABCC6 in a targeting-competent state for the basolateral membrane and might be involved in regulating the NBDs (Miglionico et al. 2016). PXE is a disease of altered elastic properties in multiple tissues. Many of these mutations influence various steps in the biosynthetic pathway, minimally altering local domain structure but adversely impacting ABCC6 assembly and trafficking (Ran and Thibodeau 2016). PXE is an ectopic, metabolic mineralization disorder that affects the skin, eye, and vessels. ABCC6 is assumed to mediate efflux of one or several small molecule compounds from the liver cytosol to the circulation. In mice, abrogating ABCC6 function causes alterations in the liver metabolic profile, suggesting that PXE is a metabolic disease originating from a liver disturbance (Rasmussen et al. 2016). Thus, MRP6 is involved in the regulation of tissue calcification in mammals, and mutations are associated with human ectopic calcification disorders. Comparative analyses of the ABCC6 and ABCC1 from invertebrates to vertebrates where a bony endoskeleton first evolved. The ABCC6 gene was only found in bony vertebrate genomes (Parreira et al. 2018).

Accession Number:O95255
Protein Name:ABCC6 aka MRPb aka MRP6 aka ARA
Length:1503
Molecular Weight:164906.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:14
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate Anthracycline, Organoanions, Glutathione conjugates, Leukotriene C4, DNP, N-ethylmaleimide S-glutathione, epipodophyllotoxins, Cisplatin, Probenecid, benzbromarone, Indomethacin

Cross database links:

Genevestigator: O95255
HEGENOM: HBG758042
RefSeq: NP_001162.4   
Entrez Gene ID: 368   
Pfam: PF00664    PF00005   
OMIM: 177850  phenotype
264800  phenotype
603234  gene

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005524 F:ATP binding
GO:0042626 F:ATPase activity, coupled to transmembrane m...
GO:0042493 P:response to drug
GO:0055085 P:transmembrane transport
GO:0007601 P:visual perception

References (18)

[1] “Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells.”  Kool M.et.al.   9892204
[2] “The sequence and analysis of duplication-rich human chromosome 16.”  Martin J.et.al.   15616553
[3] “Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q.”  Loftus B.J.et.al.   10493829
[4] “MOAT-E (ARA) is a full-length MRP/cMOAT subfamily transporter expressed in kidney and liver.”  Belinsky M.G.et.al.   10424734
[5] “Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6).”  Ilias A.et.al.   11880368
[6] “Molecular genetics of pseudoxanthoma elasticum: a metabolic disorder at the environment-genome interface?”  Uitto J.et.al.   11427982
[7] “Subcellular localization and N-glycosylation of human ABCC6, expressed in MDCKII cells.”  Sinko E.et.al.   12901863
[8] “Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra.”  Yu L.-R.et.al.   17924679
[9] “Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach.”  Gauci S.et.al.   19413330
[10] “Homozygosity for the R1268Q mutation in MRP6, the pseudoxanthoma elasticum gene, is not disease-causing.”  Germain D.P.et.al.   10913334
[11] “Identification of two polymorphisms (c189G>C; c190T>C) in exon 2 of the human MRP6 gene (ABCC6) by screening of Pseudoxanthoma elasticum patients: possible sequence correction?”  Germain D.P.et.al.   11058917
[12] “Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum.”  Struk B.et.al.   10954200
[13] “Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum.”  Le Saux O.et.al.   10835642
[14] “Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter.”  Ringpfeil F.et.al.   10811882
[15] “A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum.”  Le Saux O.et.al.   11536079
[16] “Identification of ABCC6 pseudogenes on human chromosome 16p: implications for mutation detection in pseudoxanthoma elasticum.”  Pulkkinen L.et.al.   11702217
[17] “ABCC6 gene polymorphism associated with variation in plasma lipoproteins.”  Wang J.et.al.   11776382
[18] “DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.”  Ley T.J.et.al.   18987736

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FASTA formatted sequence
1:	MAAPAEPCAG QGVWNQTEPE PAATSLLSLC FLRTAGVWVP PMYLWVLGPI YLLFIHHHGR 
61:	GYLRMSPLFK AKMVLGFALI VLCTSSVAVA LWKIQQGTPE APEFLIHPTV WLTTMSFAVF 
121:	LIHTERKKGV QSSGVLFGYW LLCFVLPATN AAQQASGAGF QSDPVRHLST YLCLSLVVAQ 
181:	FVLSCLADQP PFFPEDPQQS NPCPETGAAF PSKATFWWVS GLVWRGYRRP LRPKDLWSLG 
241:	RENSSEELVS RLEKEWMRNR SAARRHNKAI AFKRKGGSGM KAPETEPFLR QEGSQWRPLL 
301:	KAIWQVFHST FLLGTLSLII SDVFRFTVPK LLSLFLEFIG DPKPPAWKGY LLAVLMFLSA 
361:	CLQTLFEQQN MYRLKVLQMR LRSAITGLVY RKVLALSSGS RKASAVGDVV NLVSVDVQRL 
421:	TESVLYLNGL WLPLVWIVVC FVYLWQLLGP SALTAIAVFL SLLPLNFFIS KKRNHHQEEQ 
481:	MRQKDSRARL TSSILRNSKT IKFHGWEGAF LDRVLGIRGQ ELGALRTSGL LFSVSLVSFQ 
541:	VSTFLVALVV FAVHTLVAEN AMNAEKAFVT LTVLNILNKA QAFLPFSIHS LVQARVSFDR 
601:	LVTFLCLEEV DPGVVDSSSS GSAAGKDCIT IHSATFAWSQ ESPPCLHRIN LTVPQGCLLA 
661:	VVGPVGAGKS SLLSALLGEL SKVEGFVSIE GAVAYVPQEA WVQNTSVVEN VCFGQELDPP 
721:	WLERVLEACA LQPDVDSFPE GIHTSIGEQG MNLSGGQKQR LSLARAVYRK AAVYLLDDPL 
781:	AALDAHVGQH VFNQVIGPGG LLQGTTRILV THALHILPQA DWIIVLANGA IAEMGSYQEL 
841:	LQRKGALMCL LDQARQPGDR GEGETEPGTS TKDPRGTSAG RRPELRRERS IKSVPEKDRT 
901:	TSEAQTEVPL DDPDRAGWPA GKDSIQYGRV KATVHLAYLR AVGTPLCLYA LFLFLCQQVA 
961:	SFCRGYWLSL WADDPAVGGQ QTQAALRGGI FGLLGCLQAI GLFASMAAVL LGGARASRLL 
1021:	FQRLLWDVVR SPISFFERTP IGHLLNRFSK ETDTVDVDIP DKLRSLLMYA FGLLEVSLVV 
1081:	AVATPLATVA ILPLFLLYAG FQSLYVVSSC QLRRLESASY SSVCSHMAET FQGSTVVRAF 
1141:	RTQAPFVAQN NARVDESQRI SFPRLVADRW LAANVELLGN GLVFAAATCA VLSKAHLSAG 
1201:	LVGFSVSAAL QVTQTLQWVV RNWTDLENSI VSVERMQDYA WTPKEAPWRL PTCAAQPPWP 
1261:	QGGQIEFRDF GLRYRPELPL AVQGVSFKIH AGEKVGIVGR TGAGKSSLAS GLLRLQEAAE 
1321:	GGIWIDGVPI AHVGLHTLRS RISIIPQDPI LFPGSLRMNL DLLQEHSDEA IWAALETVQL 
1381:	KALVASLPGQ LQYKCADRGE DLSVGQKQLL CLARALLRKT QILILDEATA AVDPGTELQM 
1441:	QAMLGSWFAQ CTVLLIAHRL RSVMDCARVL VMDKGQVAES GSPAQLLAQK GLFYRLAQES 
1501:	GLV