Human and mouse orthologs of a new ATP-binding cassette gene, ABCG4 (original) (raw)
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ABCG subfamily of human ATP-binding cassette proteins
Pure and Applied Chemistry, 2002
ATP-binding cassette (ABC) proteins form one of the largest known protein families and have been found in all known organisms. Most members of the human ABC protein family are membrane-spanning transporters that use energy derived from the hydrolysis of ATP to transport specific substrates across cell membranes. Mutations in certain human ABC transporters of the subfamilies A, B, C, and D have been shown to cause a wide variety of inherited diseases such as the lung condition cystic fibrosis, the nervous degenerative condition adrenoleukodystrophy (of Lorenzo's Oil fame), hereditary macular degeneration of the eye (Stargardt's disease), and inherited deficiency of circulating high-density lipoproteins (Tangier disease or familial hypoalphalipoproteinemia). Very recent studies showed that mutations in two members of the subfamily G of human ABC transporters (ABCG5 and ABCG8) cause a condition called sitosterolemia in which plant sterols accumulate in the body and may be responsible for influencing total body sterol homeostasis. In addition, other members of the subfamily G, namely ABCG1 and ABCG4, have also been shown to be involved in cellular lipid trafficking and are thought to play important roles during foam cell formation of human macrophages. By contrast, ABCG2 is a multidrug resistance transporter. In this review, we focus on the current knowledge and physiological background of the members of the subfamily G. We also present new insights on the evolutionary relationship of human and nonhuman ABCG proteins.
ATP-binding cassette (ABC) transporters in human metabolism and diseases
Physiol Res, 2004
The ATP-binding cassette (ABC) superfamily of active transporters involves a large number of functionally diverse transmembrane proteins. They transport a variety of substrates including amino acids, lipids, inorganic ions, peptides, saccharides, metals, drugs, and proteins. The ABC transporters not only move a variety of substrates into and out of the cell, but also are also involved in intracellular compartmental transport. Energy derived from the hydrolysis of ATP is used to transport the substrate across the membrane against a concentration gradient. The typical ABC transporter consists of two transmembrane domains and two nucleotide-binding domains. Defects in 14 of these transporters cause 13 genetic diseases (cystic fibrosis, Stargardt disease, adrenoleukodystrophy, Tangier disease, etc.). Mutations in three genes affect lipid levels expressively. Mutations in ABCA1 cause severe HDL deficiency syndromes called Tangier disease and familial high-density lipoprotein deficiency, which are characterized by a severe deficiency or absence of high-density lipoprotein in the plasma. Two other ABCG transporters, ABCG5 and ABCG8, mutations of which cause sitosterolemia, have been identified. The affected individuals absorb and retain plant sterols, as well as shellfish sterols.
Gene, 2001
Several years ago, we initiated a long-term project of cloning new human ATP-binding cassette (ABC) transporters and linking them to various disease phenotypes. As one of the results of this project, we present two new members of the human ABCC subfamily, ABCC11 and ABCC12. These two new human ABC transporters were fully characterized and mapped to the human chromosome 16q12. With the addition of these two genes, the complete human ABCC subfamily has 12 identi®ed members (ABCC1±12), nine from the multidrug resistance-like subgroup, two from the sulfonylurea receptor subgroup, and the CFTR gene. Phylogenetic analysis determined that ABCC11 and ABCC12 are derived by duplication, and are most closely related to the ABCC5 gene. Genetic variation in some ABCC subfamily members is associated with human inherited diseases, including cystic ®brosis (CFTR/ABCC7), Dubin±Johnson syndrome (ABCC2), pseudoxanthoma elasticum (ABCC6) and familial persistent hyperinsulinemic hypoglycemia of infancy (ABCC8). Since ABCC11 and ABCC12 were mapped to a region harboring gene(s) for paroxysmal kinesigenic choreoathetosis, the two genes represent positional candidates for this disorder.
Evolution of the Atp-Binding Cassette (Abc) Transporter Superfamily in Vertebrates
Annual Review of Genomics and Human Genetics, 2005
▪ The ATP-binding cassette (ABC) superfamily of genes encode membrane proteins that transport a diverse set of substrates across membranes. Mutations in ABC transporters cause or contribute to many different Mendelian and complex disorders including adrenoleukodystrophy, cystic fibrosis, retinal degeneration, hypercholesterolemia, and cholestasis. The genes play important roles in protecting organisms from xenobiotics and transport compounds across the intestine, blood-brain barrier, and the placenta. There are 48 ABC genes in the human genome divided into seven subfamilies based on amino acid sequence similarities and phylogeny. These seven subfamilies are represented in all eukaryotic genomes and are therefore of ancient origin. Sequencing the genomes of numerous vertebrate organisms has allowed the complement of ABC transporters to be characterized and the evolution of the genes to be assessed. Most ABC transporters are conserved in all vertebrates, but there are also several e...
Genomics, 1997
The sequencing of the longest clone (2684 bp-Gen-We report here on the identification and genomic Bank Accession No. U43892) by systematic subcloning mapping of a novel member of the family of the ATPin plasmid vectors and oligonucleotide walk was carbinding cassette (ABC) transporters, ABC7, conserved ried out on both strands by the Sanger dideoxy chain in mouse and in humans. The ABC7 gene encodes a termination method on double-stranded templates protein with the typical features of half-transporters, (U.S. Biochemicals; Sequenase kits). A single open such as those involved in translocation of antigenic reading frame starting from ATG 196 was detected by peptides or in peroxisomal disorders. ABC7 shows a standard analytical tools. However, since no in-frame ubiquitous expression pattern and maps to the X chrostop codon could be found upstream to ATG 196, we mosome both in mouse and in humans. The high secannot unambiguously conclude that the whole coding quence similarity to those of two yeast half-transportregion has been identified. Provided that this ATG eners supports once again the extreme evolutionary concodes the amino-terminal methionine, a protein of 629 servation of this family of proteins. ᭧ 1997 Academic Press amino acids (bp 196-2085) in length will be produced upon translation. The hydrophobicity analysis of the conceptual protein sequence was carried out accord-The family of ATP-binding cassette (ABC) transingly to Kyte-Doolittle and Eisenberg hydrophobicity porters is extremely conserved across evolution from algorithms, and it revealed the presence of six putative bacteria to humans, and is the largest protein family transmembrane spanners in close succession in the Nknown so far, since it comprises more than 150 memterminal segment. This membrane-anchoring domain bers (4). Relatively few mammalian members have is followed by a canonical ATP-binding cassette, therebeen identified in the recent years, but most of them fore allowing us to classify ABC7 as a typical halfare at the molecular basis of clinically relevant phetransporter (4). notypes. We reported recently on the identification A search of sequence databases using the BLAST of several novel transporters conserved in mouse and program (2) revealed two yeast ABC transporters in humans, via a strategy based on cDNA amplificacloser to ABC7 than to the other members of the family, tion with degenerate primers targeted to diagnostic since the homology extends beyond the most conserved consensus sequences (7, 8,. region of the ABC domain. HTM1_SCHPO, expressed The isolation and partial characterization of an addion the vacuolar membrane of Schizosaccharomyces tional novel member of this family, named ABC7, are pombe and involved in resistance to heavy metals reported here. The ABC7-encoding sequence was first (10,11), displays an identity to ABC7 of 37.2% on a 490isolated from mouse macrophage cDNA by the already nt segment. ATM1_YEAST, a mitochondrial transdescribed procedure as an amplification product of 340 porter required for yeast growth , shows an identity bp spanning the ATP-binding cassette (12). The sets of of 49.3% over 600 residues . The homology bedegenerate primers were as described in Ref. 12. The tween ABC7 and both these transporters is more eviassessment of its bona fide belonging to a transcript dent in the 200-aa-long region of the ABC domain (52% for a novel ABC transporter led to the screening of a identity in both cases), whereas the C-and N-terminal cDNA library derived from the same P388D1 cell line parts are more divergent. Several clusters of conserved and the isolation of 17 overlapping l clones.
Arteriosclerosis, thrombosis, and vascular biology, 2016
ATP-binding cassette transporter G1 (ABCG1) mediates cholesterol efflux to lipidated lipoproteins. Conflicting data about cellular localization of ABCG1 and its effect on cholesterol efflux have been reported. Here, we investigated the underlying mechanisms for these different observations. Confocal microscopy and biotinylation were used to assess cell surface localization of ABCG1. We found that mouse ABCG1 (mABCG1) used in one previous study has a substitution of Leu to Pro at position 550 (mG1-L550P). When the corresponding Leu at position 562 in human ABCG1 (hABCG1) was mutated to Pro (hG1-L562P), the mutant hABCG1, like mG1-L550P, mainly resided intracellularly, whereas wild-type mABCG1 and hABCG1 were localized on the plasma membrane. However, replacement of this Leu with Pro had no significant effect on mABCG1- and hABCG1-mediated cholesterol efflux. Leu at position 550/562 in mABCG1/hABCG1 is critical for their plasma membrane localization but not for ABCG1-mediated choleste...
Molecular basis of cholesterol efflux via ABCG subfamily transporters
Proceedings of the National Academy of Sciences, 2021
Significance Cholesterol is an essential component of animal cell membranes whose level in cells is maintained within a narrow range. Cholesterol is actively excreted from cells by two ATP-binding cassette (ABC) transporters, ABCG5–ABCG8 (G5G8) in the liver and gut and ABCG1 (G1) in macrophages. The mechanism(s) by which these proteins translocate rigid, planar sterol molecules across the membrane bilayer remain unknown. Here, we report the structure of human G1 and G5G8 in their unbound and cholesterol-bound states. We also determined the structure of G1 bound to ATP. These structures, together with functional studies in model organisms and biochemical studies, identify the binding site for cholesterol and provide the basis for a model of cholesterol transport by ABC transporters.
Identification of a Novel Human Sterol-Sensitive ATP-Binding Cassette Transporter (ABCA7
Biochemical and Biophysical Research Communications, 2000
We report the identification of the full-length cDNA for a novel ATP-binding cassette (ABC) transporter from human macrophages. The mRNA is of 6.8 kb size and contains an open reading frame encoding a polypeptide of 2146 amino acids with a calculated molecular weight of 220 kDa. The predicted protein product is composed of two transmembrane domains and two nucleotide binding folds indicating that it pertains to the group of full-size ABC transporters. The novel transporter shows highest protein sequence homology with the recently cloned human cholesterol and phospholipid exporter ABCA1 (54%) and the human retinal transporter ABCR (49%), both members of the ABC transporter subfamily A. In accordance with the currently proposed classification, the novel transporter was designated ABCA7. ABCA7 mRNA was detected predominantly in myelo-lymphatic tissues with highest expression in peripheral leukocytes, thymus, spleen, and bone marrow. Expression of ABCA7 is induced during in vitro differentiation of human monocytes into macrophages. In macrophages, both the ABCA7 mRNA and protein expression are upregulated in the presence of modified low density lipoprotein and downregulated by HDL 3 . Our results suggest a role for ABCA7 in macrophage transmembrane lipid transport.