ABCC3 p.Arg99Gln
| Predicted by SNAP2: | A: N (82%), C: D (53%), D: D (66%), E: N (53%), F: D (53%), G: D (53%), H: N (61%), I: N (82%), K: N (78%), L: N (61%), M: N (61%), N: N (61%), P: D (59%), Q: N (93%), S: N (78%), T: N (66%), V: N (61%), W: D (71%), Y: D (53%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Xenobiotic, bile acid, and cholesterol transporter... Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26. Klaassen CD, Aleksunes LM
Xenobiotic, bile acid, and cholesterol transporters: function and regulation.
Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26., [PMID:20103563]
Abstract [show]
Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.
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7118 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization ABCC1 MRP1 G128C C43S 1↔ Intracellular C218T T73I 1↔ Normal C257T S92F 2↔ Normal C350T T117M 2↔ Normal G689A R230Q ↔ Normal G1057A V353M N.D. N.D. G1299T R433S 2↔ Normal G1898A R633Q 2↔ Normal G2012T G671V ↔ Normal G2168A R723Q 2 Normal G2965A A989T 2↔ Normal G3140C C1047S 1↔ Normal G3173A R1058Q ↔ Normal C4535T S1512L ↔ Normal ABCC2 MRP2 C-24T N.D. N.D. G1058A R353H N.D. N.D. G1249A V417I ↔ Normal C2366T S789F 12 Intracellular T2780G L927R N.D. N.D. C3298T R1100C N.D. N.D. G3299A R1100H N.D. N.D. T3563A V1188E N.D. N.D. G4348A A1450T ↔ Normal/Intracellular G4544A C1515Y N.D. N.D. ABCC3 MRP3 G32A G11D ↔ Normal C202T H68Y N.D. N.D. G296A R99Q N.D. Normal C1037T S346F 2 Normal C1537A Q513K N.D. N.D. T1643A L548Q N.D. N.D. G1820A S607N 2 Normal C2221T Gln741STOP N.D. N.D. G2293C V765L ↔ Normal G2395A V799M N.D. N.D. C2758T P920S 1 Normal G2768A R923Q 1 Normal C3657A S1219R N.D. N.D. C3856G R1286G ↔ Normal G3890A R1297H N.D. N.D. C4042T R1348C 1 Normal A4094G Q1365R ↔ Normal C4141A R1381S ↔ Intracellular C4217T T1406M N.D. N.D. G4267A G1423R N.D. N.D. ABCC4 MRP4 C52A L18I N.D. N.D. C232G P78A 2↔ Normal T551C M184T N.D. N.D. G559T G187W 2 Reduced A877G K293E ↔ Normal G912T K304N ↔ Normal C1067T T356M N.D. N.D. C1208T P403L 2↔ Normal G1460A G487E 2 Normal A1492G K498E ↔ Normal A1875G I625M N.D. N.D. C2000T P667L N.D. N.D. A2230G M744V ↔ Normal G2269A E757K N.D. Intracellular G2459T R820I N.D. N.D. G2560T V854F N.D. N.D. G2698T V900L N.D. N.D. G2867C C956S 1↔ Normal G3211A V1071I ↔ Normal C3425T T1142M N.D. N.D. G3659A R1220Q N.D. N.D. A3941G Q1314R N.D. N.D. 2, reduced function; 1, increased function; ↔, no change in function; N.D. not determined.
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ABCC3 p.Arg99Gln 20103563:7118:836
status: NEW7115 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization ABCC1 MRP1 G128C C43S 1 Intracellular C218T T73I 1 Normal C257T S92F 2 Normal C350T T117M 2 Normal G689A R230Q Normal G1057A V353M N.D. N.D. G1299T R433S 2 Normal G1898A R633Q 2 Normal G2012T G671V Normal G2168A R723Q 2 Normal G2965A A989T 2 Normal G3140C C1047S 1 Normal G3173A R1058Q Normal C4535T S1512L Normal ABCC2 MRP2 C-24T N.D. N.D. G1058A R353H N.D. N.D. G1249A V417I Normal C2366T S789F 12 Intracellular T2780G L927R N.D. N.D. C3298T R1100C N.D. N.D. G3299A R1100H N.D. N.D. T3563A V1188E N.D. N.D. G4348A A1450T Normal/Intracellular G4544A C1515Y N.D. N.D. ABCC3 MRP3 G32A G11D Normal C202T H68Y N.D. N.D. G296A R99Q N.D. Normal C1037T S346F 2 Normal C1537A Q513K N.D. N.D. T1643A L548Q N.D. N.D. G1820A S607N 2 Normal C2221T Gln741STOP N.D. N.D. G2293C V765L Normal G2395A V799M N.D. N.D. C2758T P920S 1 Normal G2768A R923Q 1 Normal C3657A S1219R N.D. N.D. C3856G R1286G Normal G3890A R1297H N.D. N.D. C4042T R1348C 1 Normal A4094G Q1365R Normal C4141A R1381S Intracellular C4217T T1406M N.D. N.D. G4267A G1423R N.D. N.D. ABCC4 MRP4 C52A L18I N.D. N.D. C232G P78A 2 Normal T551C M184T N.D. N.D. G559T G187W 2 Reduced A877G K293E Normal G912T K304N Normal C1067T T356M N.D. N.D. C1208T P403L 2 Normal G1460A G487E 2 Normal A1492G K498E Normal A1875G I625M N.D. N.D. C2000T P667L N.D. N.D. A2230G M744V Normal G2269A E757K N.D. Intracellular G2459T R820I N.D. N.D. G2560T V854F N.D. N.D. G2698T V900L N.D. N.D. G2867C C956S 1 Normal G3211A V1071I Normal C3425T T1142M N.D. N.D. G3659A R1220Q N.D. N.D. A3941G Q1314R N.D. N.D. 2, reduced function; 1, increased function; , no change in function; N.D. not determined.
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ABCC3 p.Arg99Gln 20103563:7115:821
status: NEW[hide] Functional analysis of nonsynonymous single nucleo... Pharmacogenet Genomics. 2008 Sep;18(9):823-33. Kobayashi K, Ito K, Takada T, Sugiyama Y, Suzuki H
Functional analysis of nonsynonymous single nucleotide polymorphism type ATP-binding cassette transmembrane transporter subfamily C member 3.
Pharmacogenet Genomics. 2008 Sep;18(9):823-33., [PMID:18698235]
Abstract [show]
OBJECTIVES: The multidrug resistance-associated protein 3/ATP-binding cassette transmembrane transporter subfamily C member 3 (MRP3/ABCC3) plays an important role in exporting endogenous and xenobiotic anionic substrates, including glucuronide conjugates of xenobiotics, from hepatocytes into the blood circulation. This excretory function of ABCC3 becomes very apparent particularly under cholestatic conditions, since ABCC3 is induced when the biliary excretion pathway is impaired. In this study, we analyzed the functional properties of 11 nonsynonymous single nucleotide polymorphisms (SNPs) in the ABCC3 gene found in the public SNP database. METHODS: HeLa and Sf9 insect cells were used to analyze the protein expression and transport function, respectively. RESULTS: After transient transfection of cDNA into HeLa cells, it was found that R1381S ABCC3 exhibits intracellular accumulation of immature protein, the localization of which was mostly merged with a marker for the endoplasmic reticulum. Two kinds of SNPs type ABCC3 (S346F and S607N) lost their transport activity for [H]estradiol-17beta-D-glucuronide in membrane vesicles from Sf9 cells infected with the recombinant baculoviruses, although the band length and the amount of protein expression remained normal. In contrast, the cellular localization, protein expression and function of other eight kinds of SNPs type ABCC3 (G11D, R99Q, V765L, P920S, R923Q, R1286G, R1348C, and Q1365R ABCC3) remained normal. CONCLUSION: The results of this study suggest that the possession of R1381S, S346F, and S607N types of ABCC3 sequences may be a possible risk factor for the acquisition of hepatotoxicity, due to their poor ability to transport toxic compounds across the sinusoidal membrane.
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No. Sentence Comment
6 In contrast, the cellular localization, protein expression and function of other eight kinds of SNPs type ABCC3 (G11D, R99Q, V765L, P920S, R923Q, R1286G, R1348C, and Q1365R ABCC3) remained normal.
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ABCC3 p.Arg99Gln 18698235:6:119
status: NEW40 Using site-directed mutagenesis, SNP-type ABCC3 (G11D, R99Q, S346F, S607N, V765L, P920S, R923Q, R1286G, R1348C, Q1365R, and R1381S ABCC3) was constructed on a pBluescript SK ( - ) vector.
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ABCC3 p.Arg99Gln 18698235:40:55
status: NEW93 Protein expression of ATP-binding cassette transmembrane transporter subfamily C member 3 in HeLa cells The protein expression and modification of ABCC3 in HeLa cells were determined by Western blot analysis Fig. 1 G11D 0.18% R99Q 0.54% S346F 0.91% S607N 0.99% V765L 1.09% P920S 3.88% R923Q 0.55% R1286G 0.18% R1348C 1.65% R1381S 0.22% Q1365R 0.33% Outside Inside NBD2 NBD1 Predicted secondary structure of ATP-binding cassette transmembrane transporter subfamily C member 3 showing the position of the eleven nonsynonymous variants.
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ABCC3 p.Arg99Gln 18698235:93:226
status: NEW118 Transport activities of the ATP-binding cassette transmembrane transporter subfamily C member 3 variants The transport function of wild-type and SNP-type ABCC3 was studied by examining the ATP-dependent uptake of [3 H]E217bG into membrane vesicles isolated from Sf9 cells infected with recombinant baculoviruses Table 1 Allele frequency of ABCC3 SNPs examined in this study Ethnic population SNP sequence Asian (%) African-American (%) Pacific islander (%) Mexican (%) Caucasian (%) SubSaharan- African (%) Total (%) Reference G11D 0.83 (120) 0 (160) 0 (12) 0 (100) 0 (160) 0.18 (552) PharmGKB 0.6 (178)a Fukushima-Uesaka et al. 0.5 (206) Lang et al. R99Q 0 (120) 1.88 (160) 0 (12) 0 (100) 0 (160) 0.54 (552) PharmGKB S346F 0 (120) 0.62 (160) 0 (12) 0 (100) 2.5 (160) 0.91 (552) PharmGKB 0.5 (206) Lang et al. S607N 0 (296) 2.76 (290) 0 (10) 1 (100) 0 (210) 0.99 (906) PharmGKB 11.7 (120) dbSNP V765L 0 (120) 3.12 (160) 0 (12) 1 (100) 0 (160) 1.09 (552) PharmGKB P920S 0 (292) 10.3 (290) 0 (12) 0 (100) 2.4 (280) 3.88 (902) PharmGKB R923Q 0 (108) 0.62 (160) 0 (12) 0 (100) 1.25 (160) 0.55 (550) PharmGKB R1286G 0 (120) 0.62 (160) 0 (12) 0 (100) 0 (160) 0.18 (552) PharmGKB R1348C 0 (298) 5.17 (290) 0 (12) 0 (100) 0 (210) 1.65 (910) PharmGKB 7.5 (120) dbSNP Q1365R 0 (298) 1.05 (286) 0 (12) 0 (100) 0 (208) 0.33 (904) PharmGKB R1381S 0 (298) 0 (290) 0 (12) 2 (100) 0 (210) 0.22 (910) PharmGKB Allele frequencies (%) in individual ethnic population are shown.
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ABCC3 p.Arg99Gln 18698235:118:651
status: NEW124 ABCC3 SNP analysis Kobayashi et al. 827 Fig. WT R1381S G11D R99Q S346F S607N V765L P920S R923Q R1286G WT ABCC3 Calnexin Calnexin merge R1381S merge ABCC3 R1348C Q1365R (a) (b) Subcellular localization of ATP-binding cassette transmembrane transporter subfamily C member 3 (ABCC3) in HeLa cells.
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ABCC3 p.Arg99Gln 18698235:124:62
status: NEW140 Discussion On account of its inducible nature under cholestatic conditions, ABCC3/Abcc3 is considered to provide a compensatory efflux pathway for endogenous and exo- Table 2 Corresponding amino acid residues in other ABCC family proteins Protein Species G11D R99Q S346F S607N V765L P920S R923Q R1286G R1348C Q1365R R1381S ABCC3 Human G R S S V P R R R Q R Abcc3 Mouse G S T N V T K R V Q R Abcc3 Rat G S T N V P K S F Q R ABCC1 Human S I D S V R N V I K R ABCC2 Human - A L G T K R K I K R ABCC4 Human - - L L V Q R E W K R ABCC5 Human - - L L L - D E K K R Amino acid residues in other ABCC family proteins at the corresponding positions to 11 amino acid residues in human ABCC3 examined in this study.
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ABCC3 p.Arg99Gln 18698235:140:260
status: NEW142 Fig. 3 (a) (b) Treatment WT R1381S Endo HPNGaseEndo HPNGase 190 kDa 180 kDa 170 kDa 160 kDa 190 kDa 170 kDa 160 kDa WT G11D S346F R99Q S607N V765L P920S R923Q R1286G R1348C Q1365R R1381S pcDNA3.1(+) Western blot analysis of wild-type and single nucleotide polymorphism-type ATP-binding cassette transmembrane transporter subfamily C member 3 (ABCC3) proteins expressed in HeLa cells.
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ABCC3 p.Arg99Gln 18698235:142:130
status: NEW