MDR3_CRIGR
ID MDR3_CRIGR Reviewed; 1281 AA.
AC P23174;
DT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1991, sequence version 1.
DT 03-AUG-2022, entry version 126.
DE RecName: Full=Phosphatidylcholine translocator ABCB4 {ECO:0000250|UniProtKB:P21439};
DE EC=7.6.2.1 {ECO:0000250|UniProtKB:P21440};
DE AltName: Full=ATP-binding cassette sub-family B member 4;
DE AltName: Full=Multidrug resistance protein 3 {ECO:0000250|UniProtKB:P21439};
DE AltName: Full=P-glycoprotein 3 {ECO:0000250|UniProtKB:Q08201};
GN Name=ABCB4 {ECO:0000250|UniProtKB:P21439};
GN Synonyms=PGP3 {ECO:0000250|UniProtKB:Q08201}, PGY3;
OS Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Cricetulus.
OX NCBI_TaxID=10029;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1685679; DOI=10.3109/10425179109039677;
RA Endicott J.A., Sarangi F., Ling V.;
RT "Complete cDNA sequences encoding the Chinese hamster P-glycoprotein gene
RT family.";
RL DNA Seq. 2:89-101(1991).
CC -!- FUNCTION: Energy-dependent phospholipid efflux translocator that acts
CC as a positive regulator of biliary lipid secretion. Functions as a
CC floppase that translocates specifically phosphatidylcholine (PC) from
CC the inner to the outer leaflet of the canalicular membrane bilayer into
CC the canaliculi of hepatocytes. Translocation of PC makes the biliary
CC phospholipids available for extraction into the canaliculi lumen by
CC bile salt mixed micelles and therefore protects the biliary tree from
CC the detergent activity of bile salts. Plays a role in the recruitment
CC of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and
CC sphingomyelin (SM) molecules to nonraft membranes and to further
CC enrichment of SM and cholesterol in raft membranes in hepatocytes.
CC Required for proper phospholipid bile formation. Indirectly involved in
CC cholesterol efflux activity from hepatocytes into the canalicular lumen
CC in the presence of bile salts in an ATP-dependent manner. May promote
CC biliary phospholipid secretion as canaliculi-containing vesicles from
CC the canalicular plasma membrane. In cooperation with ATP8B1, functions
CC to protect hepatocytes from the deleterious detergent activity of bile
CC salts. Does not confer multidrug resistance.
CC {ECO:0000250|UniProtKB:P21439, ECO:0000250|UniProtKB:P21440}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + phospholipidSide 1 = ADP + phosphate +
CC phospholipidSide 2.; EC=7.6.2.1;
CC Evidence={ECO:0000250|UniProtKB:P21440};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phosphocholine(in) + ATP + H2O = a
CC 1,2-diacyl-sn-glycero-3-phosphocholine(out) + ADP + H(+) + phosphate;
CC Xref=Rhea:RHEA:66272, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57643,
CC ChEBI:CHEBI:456216; Evidence={ECO:0000250|UniProtKB:P21440};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66273;
CC Evidence={ECO:0000250|UniProtKB:P21440};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phosphoethanolamine(in) + ATP + H2O
CC = a 1,2-diacyl-sn-glycero-3-phosphoethanolamine(out) + ADP + H(+) +
CC phosphate; Xref=Rhea:RHEA:36439, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:64612, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000250|UniProtKB:P21439};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:36440;
CC Evidence={ECO:0000250|UniProtKB:P21439};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a sphingomyelin(in) + ATP + H2O = a sphingomyelin(out) + ADP +
CC H(+) + phosphate; Xref=Rhea:RHEA:38903, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17636, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000250|UniProtKB:P21439};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38904;
CC Evidence={ECO:0000250|UniProtKB:P21439};
CC -!- ACTIVITY REGULATION: Translocation activity is inhibited by the ATPase
CC inhibitor vanadate and the calcium channel blocker verapamil.
CC Translocation activity is enhanced by the addition of the bile salt
CC taurocholate. {ECO:0000250|UniProtKB:P21439}.
CC -!- SUBUNIT: Interacts with HAX1. May interact with RACK1.
CC {ECO:0000250|UniProtKB:P21439, ECO:0000250|UniProtKB:Q08201}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P21439};
CC Multi-pass membrane protein {ECO:0000255|PROSITE-ProRule:PRU00441}.
CC Apical cell membrane {ECO:0000250|UniProtKB:P21439}; Multi-pass
CC membrane protein {ECO:0000255|PROSITE-ProRule:PRU00441}. Membrane raft
CC {ECO:0000250|UniProtKB:P21439}. Cytoplasm
CC {ECO:0000250|UniProtKB:P21439}. Cytoplasmic vesicle, clathrin-coated
CC vesicle {ECO:0000250|UniProtKB:Q08201}. Note=Localized at the apical
CC canalicular membrane of the epithelial cells lining the lumen of the
CC bile canaliculi and biliary ductules. Localized preferentially in lipid
CC nonraft domains of canalicular plasma membranes. Transported from the
CC Golgi to the apical bile canalicular membrane in a RACK1-dependent
CC manner. Redistributed into pseudocanaliculi formed between cells in a
CC bezafibrate- or PPARA-dependent manner. {ECO:0000250|UniProtKB:P21439,
CC ECO:0000250|UniProtKB:P21440}.
CC -!- PTM: Phosphorylated. Phosphorylation is required for PC efflux
CC activity. Phosphorylation occurs on serine and threonine residues in a
CC protein kinase A- or C-dependent manner. May be phosphorylated on Thr-
CC 44 and Ser-49. {ECO:0000250|UniProtKB:P21439}.
CC -!- PTM: Glycosylated. {ECO:0000250|UniProtKB:P21439}.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCB family.
CC Multidrug resistance exporter (TC 3.A.1.201) subfamily. {ECO:0000305}.
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DR EMBL; M60042; AAA68885.1; -; mRNA.
DR PIR; I48120; I48120.
DR PIR; I48123; I48123.
DR RefSeq; NP_001230916.1; NM_001243987.1.
DR AlphaFoldDB; P23174; -.
DR SMR; P23174; -.
DR STRING; 10029.NP_001230916.1; -.
DR PRIDE; P23174; -.
DR GeneID; 100682535; -.
DR KEGG; cge:100682535; -.
DR CTD; 5244; -.
DR eggNOG; KOG0055; Eukaryota.
DR OrthoDB; 186078at2759; -.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0030136; C:clathrin-coated vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0140359; F:ABC-type transporter activity; IEA:InterPro.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042626; F:ATPase-coupled transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0090554; F:phosphatidylcholine floppase activity; ISS:UniProtKB.
DR GO; GO:0032782; P:bile acid secretion; ISS:UniProtKB.
DR GO; GO:1903413; P:cellular response to bile acid; ISS:UniProtKB.
DR GO; GO:0055088; P:lipid homeostasis; ISS:UniProtKB.
DR GO; GO:0032376; P:positive regulation of cholesterol transport; ISS:UniProtKB.
DR GO; GO:0061092; P:positive regulation of phospholipid translocation; ISS:UniProtKB.
DR GO; GO:2001140; P:positive regulation of phospholipid transport; ISS:UniProtKB.
DR GO; GO:1901557; P:response to fenofibrate; ISS:UniProtKB.
DR Gene3D; 1.20.1560.10; -; 1.
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; IPR030275; MDR3.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR039421; Type_1_exporter.
DR PANTHER; PTHR24221; PTHR24221; 1.
DR PANTHER; PTHR24221:SF241; PTHR24221:SF241; 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; 1.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2.
PE 2: Evidence at transcript level;
KW ATP-binding; Cell membrane; Cytoplasm; Cytoplasmic vesicle; Glycoprotein;
KW Lipid transport; Membrane; Nucleotide-binding; Phosphoprotein; Repeat;
KW Translocase; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1281
FT /note="Phosphatidylcholine translocator ABCB4"
FT /id="PRO_0000093341"
FT TOPO_DOM 1..50
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 51..73
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 74..118
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 119..139
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 140..188
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 189..210
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 211..217
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 218..238
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 239..296
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 297..318
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 319..332
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 333..354
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 355..713
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 714..734
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 735..757
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 758..778
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 779..833
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 834..854
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 855
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 856..875
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 876..937
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 938..958
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 959..974
FT /note="Extracellular"
FT /evidence="ECO:0000250"
FT TRANSMEM 975..996
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TOPO_DOM 997..1281
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT DOMAIN 57..359
FT /note="ABC transmembrane type-1 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 394..630
FT /note="ABC transporter 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT DOMAIN 713..1001
FT /note="ABC transmembrane type-1 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 1036..1274
FT /note="ABC transporter 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT REGION 1..24
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 625..649
FT /note="Interaction with HAX1"
FT /evidence="ECO:0000250"
FT BINDING 406
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P21439"
FT BINDING 432..437
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P21439,
FT ECO:0000255|PROSITE-ProRule:PRU00434"
FT BINDING 477
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P21439"
FT BINDING 536
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P21439"
FT BINDING 1048
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P21439"
FT BINDING 1073..1079
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P21439,
FT ECO:0000255|PROSITE-ProRule:PRU00434"
FT BINDING 1119
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P21439"
FT BINDING 1179..1181
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P21439,
FT ECO:0000255|PROSITE-ProRule:PRU00434"
FT MOD_RES 27
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P21440"
FT CARBOHYD 91
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 97
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
SQ SEQUENCE 1281 AA; 140866 MW; 2203EF61EBB29602 CRC64;
MDLEAARNGT ARRPGTVEGD FELGSISNQG RNKKKKVNLI GPLTLFRYSD WQDKLFMLLG
TIMAIAHGSG LPLMMIVFGE MTDKFVNNAG NFSLPVNFSL SMINPGRILE EEMTRYAYYY
SGLGGGVLVA AYIQVSFWTL AAGRQIKKIR QNFFHAILRQ EMGWFDIKGT TELNTRLTDD
ISKISEGIGD KVGMFFQAVA TFFAGFIVGF IRGWKLTLVI MAISPILGLS AAVWAKILST
FSDKELAAYA KAGAVAEEAL GAIRTVIAFG GQNKELERYQ KHLENAKKIG IKKAISANIS
MGIAFLLIYA SYALAFWYGS TLVISKEYTI GNAMTVFFSI LIGAFSVGQA APCIDAFANA
RGAAYVIFDI IDNNPKIDSF SERGHKPDSI KGNLDFSDVH FSYPSRANIK ILKGLNLKVQ
SGQTVALVGN SGCGKTTTLQ LLQRLYDPTE GTISIDGQDI RNFNVRYLRE IIGVVSQEPV
LFSTTIAENI RYGRGNVTME EIKKAVKEAN AYEFIMKLPQ KFDTLVGERG AQLSGGQKQR
IAIARALVRN PKILLLDEAT SALDTESEAE VQAALDKARE GRTTIVIAHR LSTVRNADVI
AGFEDGVIVE QGSHSELMQK EGVYFKLVNM QTSGSQILSQ EFEVELSEEK AADGMTPNGW
KSHIFRNSTK KSLKSSRAHH HRLDVDADEL DANVPPVSFL KVLKLNKTEW PYFVVGTVCA
IVNGALQPAI SIILSEMIAI FGPGDDAVKQ QKCNLFSLVF LGLGVLSFFT FFLQGFTFGK
AGEILTTRLR SMAFKAMLRQ DMSWFDDYKN STGALSTRLA TDRAQVQGAT GTRLALIAQN
TANLGTGIII SFIYGWQLTL LLLSVVPFIA VSGIVEMKML AGNAKRDKKA LEAAGKIATE
AIENIRTVVS LTQERKFESM YVEKLHEPYR NSVQMAHIYG ITFSISQAFM YFSYAGCFRF
GAYLIVNGHM RFRDVILVFS AIVFGAVALG HASSFAPDYA KAKLSAAHLF SLFERQPLID
SYSGEGLWPD KFEGSVTFNE VVFNYPTRAN MPVLQGLSLE VKKGQTLALV GSSGCGKSTV
VQLLERFYDP MAGTVLLDGQ EAKKLNIQWL RAQLGIVSQE PVLFDCSIAE NIAYGDNSRV
VSQDEIVRAA KAANIHPFIE TLPQKYKTRV GDKGTQLSGG QKQRLAIRRA LIRQPRVLLL
DEATSALDTE SEKVVQEALD KAREGRTCIV IAHRLSTIQN ADLIVVIQNG KVKEHGTHQQ
LLAQKGIYFS MVNIQAGAQN S
