Transporter that appears to play an indispensable role in the selective transport of the dietary cholesterol in and out of the enterocytes and in the selective sterol excretion by the liver into bile.
CuratedUniProtKB
According to TCDB this is a transporter from family:
Mutations in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 lead to sitosterolemia, a disorder characterized by sterol accumulation and premature atherosclerosis. ABCG5 and ABCG8 are both half-size transporters that have been proposed to function as heterodimers in vivo. We have expressed the recombinant human ABCG5 and ABCG8 genes in the yeast Pichia pastoris and purified the proteins to near homogeneity. Purified ABCG5 and ABCG8 had very low ATPase activities (<5 nmol min(-)(1) mg(-)(1)), suggesting that expression of ABCG5 or ABCG8 alone yielded nonfunctional transporters. Coexpression of the two genes in P. pastoris greatly increased the yield of pure proteins, indicating that the two transporters stabilize each other during expression and purification. Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). The ATPase activity was not stimulated by sterols. The catalytic activity of copurified ABCG5/G8 was characterized in detail, demonstrating low affinity for MgATP, a preference for Mg as a metal cofactor and ATP as a hydrolyzed substrate, and a pH optimum near 8.0. AlFx and BeFx inhibited MgATP hydrolysis by specific trapping of nucleotides in the ABCG5/G8 proteins. Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. The data suggest that the hetero-dimer is the catalytically active species, and likely the active species in vivo.
Mutations in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 lead to sitosterolemia, a disorder characterized by sterol accumulation and premature atherosclerosis. ABCG5 and ABCG8 are both half-size transporters that have been proposed to function as heterodimers in vivo. We have expressed the recombinant human ABCG5 and ABCG8 genes in the yeast Pichia pastoris and purified the proteins to near homogeneity. Purified ABCG5 and ABCG8 had very low ATPase activities (<5 nmol min(-)(1) mg(-)(1)), suggesting that expression of ABCG5 or ABCG8 alone yielded nonfunctional transporters. Coexpression of the two genes in P. pastoris greatly increased the yield of pure proteins, indicating that the two transporters stabilize each other during expression and purification. Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). The ATPase activity was not stimulated by sterols. The catalytic activity of copurified ABCG5/G8 was characterized in detail, demonstrating low affinity for MgATP, a preference for Mg as a metal cofactor and ATP as a hydrolyzed substrate, and a pH optimum near 8.0. AlFx and BeFx inhibited MgATP hydrolysis by specific trapping of nucleotides in the ABCG5/G8 proteins. Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. The data suggest that the hetero-dimer is the catalytically active species, and likely the active species in vivo.
Enables the directed movement of cholesterol into, out of or within a cell, or between cells. Cholesterol is the principal sterol of vertebrates and the precursor of many steroids, including bile acids and steroid hormones.
Evidence
1:
Inferred from Genetic InteractionBHF-UCL
ABCG5 (G5) and ABCG8 (G8) are ATP-binding cassette (ABC) transporters that limit intestinal absorption and promote biliary excretion of neutral sterols. Mutations in either ABCG5 or ABCG8 result in an identical clinical phenotype, suggesting that these two half-transporters function as heterodimers. Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. In this paper we used immunofluorescence microscopy to confirm, in vivo, that G5 is localized to the apical membranes of mouse enterocytes and hepatocytes. Other ABC half-transporters function as homodimers or as heterodimers with other subfamily members. To determine whether G5 or G8 complex with other ABCG half-transporters, we co-expressed G1, G2, and G4 with either G5 or G8 in cultured cells. G1, G2, and G4 co-immunoprecipitated with G5, and G4 co-immunoprecipitated with G8, but the putative dimers were retained in the endoplasmic reticulum (ER). Adenovirus-mediated expression of either G5 or G8 in the liver of G5G8 null mice resulted in ER retention of the expressed proteins and no increase in biliary cholesterol. In contrast, co-expression of G5 and G8 resulted in transit of the proteins out of the ER and a 10-fold increase in biliary cholesterol concentration. Finally, adenoviral expression of G2 in the presence or absence of G5 or G8 failed to promote sterol excretion into bile. These experiments indicate that G5 and G8 function as obligate heterodimers to promote sterol excretion into bile.
The ATP-binding cassette transporter ABCG1 mediates the transport of excess cholesterol from macrophages and other cell types to high density lipoprotein (HDL) but not to lipid-depleted apolipoprotein AI. Several splice variants which may have different functions have been identified in mammals. In the current study, we characterized the human splice variant ABCG1(666), which differs from full-length ABCG1(678) by absence of an internal segment of 12 amino acids (VKQTKRLKGLRK). Accordingly spliced ABCG1 transcripts were detected in macrophages and liver in approximately twofold higher amounts than the alternatively spliced ABCG1 form encoding full-length ABCG1. We used transient and stable expression of ABCG1(666) fusion proteins to characterize glycosylation, subcellular localization, molecular interaction and functions of this ABCG1 variant. It could be demonstrated that ABCG1(666) is located at the cell surface and has the ability to form cholesterol transport competent homodimers which affect cellular cholesterol export in a similar manner as previously characterized forms of ABCG1. Our results support that ABCG1(666) may in fact be the most prominent form of functional ABCG1 expressed in the human.
The chemical reactions and pathways resulting in the breakdown of ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
Mutations in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 lead to sitosterolemia, a disorder characterized by sterol accumulation and premature atherosclerosis. ABCG5 and ABCG8 are both half-size transporters that have been proposed to function as heterodimers in vivo. We have expressed the recombinant human ABCG5 and ABCG8 genes in the yeast Pichia pastoris and purified the proteins to near homogeneity. Purified ABCG5 and ABCG8 had very low ATPase activities (<5 nmol min(-)(1) mg(-)(1)), suggesting that expression of ABCG5 or ABCG8 alone yielded nonfunctional transporters. Coexpression of the two genes in P. pastoris greatly increased the yield of pure proteins, indicating that the two transporters stabilize each other during expression and purification. Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). The ATPase activity was not stimulated by sterols. The catalytic activity of copurified ABCG5/G8 was characterized in detail, demonstrating low affinity for MgATP, a preference for Mg as a metal cofactor and ATP as a hydrolyzed substrate, and a pH optimum near 8.0. AlFx and BeFx inhibited MgATP hydrolysis by specific trapping of nucleotides in the ABCG5/G8 proteins. Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. The data suggest that the hetero-dimer is the catalytically active species, and likely the active species in vivo.
ABCG5 (G5) and ABCG8 (G8) are ATP-binding cassette (ABC) transporters that limit intestinal absorption and promote biliary excretion of neutral sterols. Mutations in either ABCG5 or ABCG8 result in an identical clinical phenotype, suggesting that these two half-transporters function as heterodimers. Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. In this paper we used immunofluorescence microscopy to confirm, in vivo, that G5 is localized to the apical membranes of mouse enterocytes and hepatocytes. Other ABC half-transporters function as homodimers or as heterodimers with other subfamily members. To determine whether G5 or G8 complex with other ABCG half-transporters, we co-expressed G1, G2, and G4 with either G5 or G8 in cultured cells. G1, G2, and G4 co-immunoprecipitated with G5, and G4 co-immunoprecipitated with G8, but the putative dimers were retained in the endoplasmic reticulum (ER). Adenovirus-mediated expression of either G5 or G8 in the liver of G5G8 null mice resulted in ER retention of the expressed proteins and no increase in biliary cholesterol. In contrast, co-expression of G5 and G8 resulted in transit of the proteins out of the ER and a 10-fold increase in biliary cholesterol concentration. Finally, adenoviral expression of G2 in the presence or absence of G5 or G8 failed to promote sterol excretion into bile. These experiments indicate that G5 and G8 function as obligate heterodimers to promote sterol excretion into bile.
In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitosterolemia, an autosomal recessive disorder characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, and premature coronary atherosclerosis. We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia. The two genes are expressed at highest levels in liver and intestine and, in mice, cholesterol feeding up-regulates expressions of both genes. These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.
The elimination by an organism of the waste products that arise as a result of metabolic activity. These products include water, carbon dioxide (CO2), and nitrogenous compounds.
Evidence
1:
Inferred from Genetic InteractionBHF-UCL
ABCG5 (G5) and ABCG8 (G8) are ATP-binding cassette (ABC) transporters that limit intestinal absorption and promote biliary excretion of neutral sterols. Mutations in either ABCG5 or ABCG8 result in an identical clinical phenotype, suggesting that these two half-transporters function as heterodimers. Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. In this paper we used immunofluorescence microscopy to confirm, in vivo, that G5 is localized to the apical membranes of mouse enterocytes and hepatocytes. Other ABC half-transporters function as homodimers or as heterodimers with other subfamily members. To determine whether G5 or G8 complex with other ABCG half-transporters, we co-expressed G1, G2, and G4 with either G5 or G8 in cultured cells. G1, G2, and G4 co-immunoprecipitated with G5, and G4 co-immunoprecipitated with G8, but the putative dimers were retained in the endoplasmic reticulum (ER). Adenovirus-mediated expression of either G5 or G8 in the liver of G5G8 null mice resulted in ER retention of the expressed proteins and no increase in biliary cholesterol. In contrast, co-expression of G5 and G8 resulted in transit of the proteins out of the ER and a 10-fold increase in biliary cholesterol concentration. Finally, adenoviral expression of G2 in the presence or absence of G5 or G8 failed to promote sterol excretion into bile. These experiments indicate that G5 and G8 function as obligate heterodimers to promote sterol excretion into bile.
Two ATP-binding cassette (ABC) transporters, ABCG5 and ABCG8, have been proposed to limit sterol absorption and to promote biliary sterol excretion in humans. To test this hypothesis, a P1 clone containing the human ABCG5 and ABCG8 genes was used to generate transgenic mice. The transgenes were expressed primarily in the liver and small intestine, mirroring the expression pattern of the endogenous genes. Transgene expression only modestly affected plasma and liver cholesterol levels but profoundly altered cholesterol transport. The fractional absorption of dietary cholesterol was reduced by about 50%, and biliary cholesterol levels were increased more than fivefold. Fecal neutral sterol excretion was increased three- to sixfold and hepatic cholesterol synthesis increased two- to fourfold in the transgenic mice. No significant changes in the pool size, composition, and fecal excretion of bile acids were observed in the transgenic mice. Transgene expression attenuated the increase in hepatic cholesterol content induced by consumption of a high cholesterol diet. These results demonstrate that increased expression of ABCG5 and ABCG8 selectively drives biliary neutral sterol secretion and reduces intestinal cholesterol absorption, leading to a selective increase in neutral sterol excretion and a compensatory increase in cholesterol synthesis.
In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitosterolemia, an autosomal recessive disorder characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, and premature coronary atherosclerosis. We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia. The two genes are expressed at highest levels in liver and intestine and, in mice, cholesterol feeding up-regulates expressions of both genes. These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.
Any process that stops, prevents, or reduces the frequency, rate or extent of the directed movement of phytosterols into the blood by absorption from the small intestine.
In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitosterolemia, an autosomal recessive disorder characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, and premature coronary atherosclerosis. We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia. The two genes are expressed at highest levels in liver and intestine and, in mice, cholesterol feeding up-regulates expressions of both genes. These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.
The directed movement of phospholipids into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore. Phospholipids are any lipids containing phosphoric acid as a mono- or diester.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a drug stimulus. A drug is a substance used in the diagnosis, treatment or prevention of a disease.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a nutrient stimulus.
IEAOrtholog Compara
Pathways
According to KEGG, this protein belongs to the following pathways:
Protein involved in the transport of a molecule (metabolite, protein, etc), a ion or an electron across cell membranes, inside the cell or in a tissue fluid.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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