MRP6_RAT
ID MRP6_RAT Reviewed; 1502 AA.
AC O88269;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 1.
DT 03-AUG-2022, entry version 170.
DE RecName: Full=ATP-binding cassette sub-family C member 6;
DE EC=7.6.2.- {ECO:0000269|PubMed:10692506};
DE EC=7.6.2.3 {ECO:0000250|UniProtKB:O95255};
DE AltName: Full=MRP-like protein 1;
DE Short=MLP-1;
DE AltName: Full=Multidrug resistance-associated protein 6;
GN Name=Abcc6; Synonyms=Mlp1, Mrp6;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Liver;
RX PubMed=9614210;
RA Hirohashi T., Suzuki H., Ito K., Ogawa K., Kume K., Shimizu T.,
RA Sugiyama Y.;
RT "Hepatic expression of multidrug resistance-associated protein-like
RT proteins maintained in eisai hyperbilirubinemic rats.";
RL Mol. Pharmacol. 53:1068-1075(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, FUNCTION, CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
RC STRAIN=Sprague-Dawley; TISSUE=Liver;
RX PubMed=10692506; DOI=10.1124/mol.57.3.634;
RA Madon J., Hagenbuch B., Landmann L., Meier P.J., Stieger B.;
RT "Transport function and hepatocellular localization of mrp6 in rat liver.";
RL Mol. Pharmacol. 57:634-641(2000).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-891, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [4]
RP DISRUPTION PHENOTYPE, FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR
RP LOCATION.
RX PubMed=28111129; DOI=10.1016/j.jid.2016.11.042;
RA Li Q., Kingman J., van de Wetering K., Tannouri S., Sundberg J.P.,
RA Uitto J.;
RT "Abcc6 Knockout Rat Model Highlights the Role of Liver in PPi Homeostasis
RT in Pseudoxanthoma Elasticum.";
RL J. Invest. Dermatol. 137:1025-1032(2017).
RN [5]
RP SUBCELLULAR LOCATION, FUNCTION, AND MUTAGENESIS OF GLU-1426.
RX PubMed=33058196; DOI=10.1002/1873-3468.13957;
RA Szeri F., Niaziorimi F., Donnelly S., Orndorff J., van de Wetering K.;
RT "Generation of fully functional fluorescent fusion proteins to gain
RT insights into ABCC6 biology.";
RL FEBS Lett. 595:799-810(2021).
CC -!- FUNCTION: ATP-dependent transporter of the ATP-binding cassette (ABC)
CC family that actively extrudes physiological compounds, and xenobiotics
CC from cells. Mediates ATP-dependent transport of glutathione conjugates
CC such as leukotriene-c4 (LTC4) and N-ethylmaleimide S-glutathione (NEM-
CC GS) (in vitro) (By similarity). Transports also an anionic
CC cyclopentapeptide endothelin antagonist, BQ-123 (PubMed:10692506).
CC {ECO:0000250|UniProtKB:O95255, ECO:0000269|PubMed:10692506}.
CC -!- FUNCTION: Mediates the release of nucleoside triphosphates,
CC predominantly ATP, into the circulation, where it is rapidly converted
CC into AMP and the mineralization inhibitor inorganic pyrophosphate (PPi)
CC by the ecto-enzyme ectonucleotide pyrophosphatase phosphodiesterase 1
CC (ENPP1), therefore playing a role in PPi homeostasis.
CC {ECO:0000269|PubMed:28111129, ECO:0000269|PubMed:33058196}.
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:0000250|UniProtKB:O95255};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19122;
CC Evidence={ECO:0000250|UniProtKB:O95255};
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:0000250|UniProtKB:O95255};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38964;
CC Evidence={ECO:0000250|UniProtKB:O95255};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=17 uM for BQ-123 {ECO:0000269|PubMed:10692506};
CC -!- SUBCELLULAR LOCATION: Basolateral cell membrane
CC {ECO:0000269|PubMed:10692506, ECO:0000269|PubMed:28111129}; Multi-pass
CC membrane protein {ECO:0000255}. Cell membrane
CC {ECO:0000269|PubMed:33058196}; Multi-pass membrane protein
CC {ECO:0000255}. Lateral cell membrane {ECO:0000269|PubMed:10692506};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Predominantly expressed in the liver and to a
CC lesser extent in kidney, small intestine, and colon.
CC {ECO:0000269|PubMed:10692506, ECO:0000269|PubMed:28111129}.
CC -!- PTM: Glycosylated. {ECO:0000250|UniProtKB:O95255}.
CC -!- DISRUPTION PHENOTYPE: Deficient rats develop ectopic mineralization in
CC the skin, eyes, and the arterial blood vessels. Plasma inorganic
CC pyrophosphate (PPi) level is reduced by 70 % in deficient rats leading
CC to a lowered PPi/Pi ratio. {ECO:0000269|PubMed:28111129}.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCC family.
CC Conjugate transporter (TC 3.A.1.208) subfamily. {ECO:0000305}.
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DR EMBL; AB010466; BAA28954.1; -; mRNA.
DR EMBL; U73038; AAD12747.1; -; mRNA.
DR PIR; T42216; T42216.
DR RefSeq; NP_112275.1; NM_031013.1.
DR AlphaFoldDB; O88269; -.
DR SMR; O88269; -.
DR STRING; 10116.ENSRNOP00000051412; -.
DR ChEMBL; CHEMBL2073712; -.
DR TCDB; 3.A.1.208.1; the atp-binding cassette (abc) superfamily.
DR GlyGen; O88269; 1 site.
DR iPTMnet; O88269; -.
DR PhosphoSitePlus; O88269; -.
DR jPOST; O88269; -.
DR PaxDb; O88269; -.
DR PRIDE; O88269; -.
DR Ensembl; ENSRNOT00000042115; ENSRNOP00000051412; ENSRNOG00000028781.
DR GeneID; 81642; -.
DR KEGG; rno:81642; -.
DR UCSC; RGD:620268; rat.
DR CTD; 368; -.
DR RGD; 620268; Abcc6.
DR eggNOG; KOG0054; Eukaryota.
DR GeneTree; ENSGT00940000157145; -.
DR HOGENOM; CLU_000604_27_3_1; -.
DR InParanoid; O88269; -.
DR OMA; AAMYLTY; -.
DR OrthoDB; 138195at2759; -.
DR PhylomeDB; O88269; -.
DR TreeFam; TF105199; -.
DR Reactome; R-RNO-382556; ABC-family proteins mediated transport.
DR PRO; PR:O88269; -.
DR Proteomes; UP000002494; Chromosome 1.
DR Bgee; ENSRNOG00000028781; Expressed in liver and 10 other tissues.
DR Genevisible; O88269; RN.
DR GO; GO:0016324; C:apical plasma membrane; IDA:RGD.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:RGD.
DR GO; GO:0005576; C:extracellular region; ISO:RGD.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016328; C:lateral plasma membrane; IDA:RGD.
DR GO; GO:0016020; C:membrane; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0015431; F:ABC-type glutathione S-conjugate transporter activity; ISS:UniProtKB.
DR GO; GO:0008559; F:ABC-type xenobiotic transporter activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:RGD.
DR GO; GO:0016887; F:ATP hydrolysis activity; IDA:RGD.
DR GO; GO:0042626; F:ATPase-coupled transmembrane transporter activity; ISO:RGD.
DR GO; GO:0030504; F:inorganic diphosphate transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0046034; P:ATP metabolic process; ISO:RGD.
DR GO; GO:0015867; P:ATP transport; IDA:UniProtKB.
DR GO; GO:0110148; P:biomineralization; ISO:RGD.
DR GO; GO:0055074; P:calcium ion homeostasis; ISO:RGD.
DR GO; GO:0030643; P:cellular phosphate ion homeostasis; IMP:UniProtKB.
DR GO; GO:0010467; P:gene expression; ISO:RGD.
DR GO; GO:0030505; P:inorganic diphosphate transport; IDA:UniProtKB.
DR GO; GO:0071716; P:leukotriene transport; ISS:UniProtKB.
DR GO; GO:0055062; P:phosphate ion homeostasis; ISO:RGD.
DR GO; GO:0032026; P:response to magnesium ion; ISO:RGD.
DR GO; GO:1904383; P:response to sodium phosphate; ISO:RGD.
DR GO; GO:0055085; P:transmembrane transport; IBA:GO_Central.
DR GO; GO:0006855; P:xenobiotic transmembrane transport; IDA:UniProtKB.
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; IPR030239; ABCC6.
DR InterPro; IPR005292; Multidrug-R_assoc.
DR InterPro; IPR027417; P-loop_NTPase.
DR PANTHER; PTHR24223:SF339; PTHR24223:SF339; 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 TIGRFAMs; TIGR00957; MRP_assoc_pro; 1.
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 ATP-binding; Cell membrane; Glycoprotein; Membrane; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Repeat; Translocase; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..1502
FT /note="ATP-binding cassette sub-family C member 6"
FT /id="PRO_0000093368"
FT TOPO_DOM 5..37
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 38..58
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 59..78
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 79..99
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 100..104
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 105..125
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 126..137
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 138..155
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 156..173
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 174..194
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 195..300
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 301..321
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 322..347
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 348..368
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 369..424
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 425..445
FT /note="Helical; Name=8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 446..448
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 449..469
FT /note="Helical; Name=9"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 470..531
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 532..552
FT /note="Helical; Name=10"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 553..574
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 575..595
FT /note="Helical; Name=11"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 596..938
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 939..959
FT /note="Helical; Name=12"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 960..996
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 997..1017
FT /note="Helical; Name=13"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 1018..1060
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 1061..1081
FT /note="Helical; Name=14"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 1082
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 1083..1103
FT /note="Helical; Name=15"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 1104..1174
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 1175..1195
FT /note="Helical; Name=16"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 1196..1197
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 1198..1218
FT /note="Helical; Name=17"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 1219..1502
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT DOMAIN 309..592
FT /note="ABC transmembrane type-1 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 627..851
FT /note="ABC transporter 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT DOMAIN 946..1227
FT /note="ABC transmembrane type-1 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 1264..1498
FT /note="ABC transporter 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT REGION 854..909
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 661..668
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT BINDING 1298..1305
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT MOD_RES 891
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1285
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95255"
FT CARBOHYD 21
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT MUTAGEN 1426
FT /note="E->Q: Does not affect plasma membrane localization.
FT Abolishes cellular ATP release."
FT /evidence="ECO:0000269|PubMed:33058196"
SQ SEQUENCE 1502 AA; 164995 MW; 539901B674A74A28 CRC64;
MNGEHSMATP GESCAGLRVW NQTEQEPVAY HLLNLCFLRA AGSWVPPMYL WVLGPIYLLY
IHRHGCCYLR MSRLFKIKMV LGFALILLYT FNAAVPLWRI HRGMPQAPEL LIHPTVWLTT
MSFATFLIHM ERKKGVRASG LLFGYWLLCC LVPAIDTVQQ ASAGSFRQEP LHHLATYLCL
SLVVAELVLS CLVDQPPFFS EDSKPLNPCP EAEASFPSKA MFWWASGLLW KGYRKLLGPK
DLWSLERENS SEELVSQLER EWRRNFSELP GHKGHSGMGT PETEAFLQPE RSQRGPLLRA
IWRVFRSTFL LGTLSLVISD AFRFAVPKLL SLFLEFMGDL ESSAWTGWLL AVLMFLSACL
QTLFEQQYMY RVKVLQMRLR TAITGLVYRK VLVLSSGSRK SSAAGDVVNL VSVDVQRLVE
SILHLNGLWL LFLWIIVCFV YLWQLLGPSA LTAVAVFLSL LPLNFFITKK RSFHQEEQMR
QKASRARLTS SMLRTVRTIK SHGWECAFLE RLLHIRGQEL GALKTSAFLF SVSLVSFQVS
TFLVALVVFA VHTLVAEDNA MDAEKAFVTL TVLSILNKAQ AFLPFSVHCL VQARVSFDRL
AAFLCLEEVD PNGMVLSPSR CSSKDRISIH NGTFAWSQES PPCLHGINLT VPQGCLLAVV
GPVGAGKSSL LSALLGELLK VEGSVSIEGS VAYVPQEAWV QNTSVVENVC FRQELDLPWL
QEVLEACALG SDVASFPAGV HTPVGEQGMN LSGGQKQRLS LARAVYRRAA VYLMDDPLAA
LDAHVSQEVF KQVIGPSGLL QGTTRILVTH TLHVLPQADQ ILVLANGTIA EMGSYQDLLH
RNGALVGLLD GARQPAGEGE GEAHAAATSD DLGGFSGGGT PTRRPERPRP SDAAPVKGST
SEAQMEPSLD DVEVTGLTAG EDSVQYGRVK SATYLSYLRA VGTPLCTYTL FLFLCQQVAS
FCQGYWLSLW ADDPVVDGKQ MHSALRGSIF GLLGCLQAIG LFASMAAVFL GGARASCLLF
RSLLWDVARS PIGFFERTPV GNLLNRFSKE TDIVDVDIPD KMRTLLTYAF GLLEVGLAVS
MATPLAIVAI LPLMLLYAGF QSLYVATCCQ LRRLESASYS SVCSHLAETF QGSQVVRAFQ
AQGPFTAQHD ALMDENQRIS FPRLVADRWL AANLELLGNG LVFVAATCAV LSKAHLSAGL
AGFSVSAALQ VTQTLQWVVR SWTDLENSMV AVERVQDYVH TPKEAPWRLP SSAAQPLWPC
GGQIEFRDFG LRHRPELPMA VQGVSLKIHA GEKVGIVGRT GAGKSSLTWG LLRLQEATEG
GIWIDGVPIT DMGLHTLRSR ITIIPQDPVL FPGSLRMNLD LLQENTDEGI WAALETVQLK
AFVTSLPGQL QYECSGQGDD LSVGQKQLLC LARALLRKTQ ILILDEATAS VDPGTEIQMQ
AALERWFAQC TVLLIAHRLR SVMNCARVLV MDEGQVAESG SPAQLLAQKG LFYRLAQESG
LA
