Cloning of Two Novel ABC Transporters Mapping on Human Chromosome 9

doi:10.1006/geno.1994.1237

Genomics

Volume 21, Issue 1, 1 May 1994, Pages 150-159

https://doi.org/10.1006/geno.1994.1237 Get rights and content

Abstract

The family of ATP binding cassette (ABC) transporters or traffic ATPases is composed of several membrane-associated proteins that transport a great variety of solutes across cellular membranes. Two novel mammalian members of the family, ABC1 and ABC2, have been identified by a PCR-based approach. They belong to a group of traffic ATPases encoded as a single multifunctional protein, such as CFTR, STE 6, and P-glycoproteins. Their peculiar structural features and close relationship to ABC transporters involved in nodulation suggest that ABC1 and ABC2 define a novel subgroup of mammalian traffic ATPases.

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Cited by (236)

Activity and Structural Dynamics of Human ABCA1 in a Lipid Membrane
2023, Journal of Molecular Biology
The human ATP-binding cassette (ABC) transporter ABCA1 plays a critical role in lipid homeostasis as it extracts sterols and phospholipids from the plasma membrane for excretion to the extracellular apolipoprotein A-I and subsequent formation of high-density lipoprotein (HDL) particles. Deleterious mutations of ABCA1 lead to sterol accumulation and are associated with atherosclerosis, poor cardiovascular outcomes, cancer, and Alzheimer’s disease. The mechanism by which ABCA1 drives lipid movement is poorly understood, and a unified platform to produce active ABCA1 protein for both functional and structural studies has been missing. In this work, we established a stable expression system for both a human cell-based sterol export assay and protein purification for in vitro biochemical and structural studies. ABCA1 produced in this system was active in sterol export and displayed enhanced ATPase activity after reconstitution into a lipid bilayer. Our single-particle cryo-EM study of ABCA1 in nanodiscs showed protein induced membrane curvature, revealed multiple distinct conformations, and generated a structure of nanodisc-embedded ABCA1 at 4.0-Å resolution representing a previously unknown conformation. Comparison of different ABCA1 structures and molecular dynamics simulations demonstrates both concerted domain movements and conformational variations within each domain. Taken together, our platform for producing and characterizing ABCA1 in a lipid membrane enabled us to gain important mechanistic and structural insights and paves the way for investigating modulators that target the functions of ABCA1.
Remembering your A, B, C's: Alzheimer's disease and ABCA1
2022, Acta Pharmaceutica Sinica B
The function of ATP binding cassette protein A1 (ABCA1) is central to cholesterol mobilization. Reduced ABCA1 expression or activity is implicated in Alzheimer's disease (AD) and other disorders. Therapeutic approaches to boost ABCA1 activity have yet to be translated successfully to the clinic. The risk factors for AD development and progression, including comorbid disorders such as type 2 diabetes and cardiovascular disease, highlight the intersection of cholesterol transport and inflammation. Upregulation of ABCA1 can positively impact APOE lipidation, insulin sensitivity, peripheral vascular and blood–brain barrier integrity, and anti-inflammatory signaling. Various strategies towards ABCA1-boosting compounds have been described, with a bias toward nuclear hormone receptor (NHR) agonists. These agonists display beneficial preclinical effects; however, important side effects have limited development. In particular, ligands that bind liver X receptor (LXR), the primary NHR that controls ABCA1 expression, have shown positive effects in AD mouse models; however, lipogenesis and unwanted increases in triglyceride production are often observed. The longstanding approach, focusing on LXRβ vs. LXRα selectivity, is over-simplistic and has failed. Novel approaches such as phenotypic screening may lead to small molecule NHR modulators that elevate ABCA1 function without inducing lipogenesis and are clinically translatable.
Impact of natural products on the cholesterol transporter ABCA1
2020, Journal of Ethnopharmacology
Citation Excerpt :
The ABCA1 gene, originally named ABC1, was identified by a PCR-based approach and first cloned in 1994 (Luciani et al., 1994).
In different countries and areas of the world, traditional medicine has been and is still used for the treatment of various disorders, including chest pain or liver complaints, of which we now know that they can be linked with altered lipid and cholesterol homeostasis. As ATP-binding cassette transporter A1 (ABCA1) plays an essential role in cholesterol metabolism, its modulation may be one of the molecular mechanisms responsible for the experienced benefit of traditional recipes. Intense research activity has been dedicated to the identification of natural products from traditional medicine that regulate ABCA1 expression.
This review surveys natural products, originating from ethnopharmacologically used plants, fungi or marine sources, which influence ABCA1 expression, providing a reference for future study.
Information on regulation of ABCA1 expression by natural compounds from traditional medicine was extracted from ancient and modern books, materia medica, and electronic databases (PubMed, Google Scholar, Science Direct, and ResearchGate).
More than 60 natural compounds from traditional medicine, especially traditional Chinese medicine (TCM), are reported to regulate ABCA1 expression in different in vitro and in vivo models (such as cholesterol efflux and atherosclerotic animal models). These active compounds belong to the classes of polyketides, terpenoids, phenylpropanoids, tannins, alkaloids, steroids, amino acids and others. Several compounds appear very promising in vivo, which need to be further investigated in animal models of diseases related to ABCA1 or in clinical studies.
Natural products from traditional medicine constitute a large promising pool for compounds that regulate ABCA1 expression, and thus may prevent/treat diseases related to cholesterol metabolism, like atherosclerosis or Alzheimer's disease. In many cases, the molecular mechanisms of these natural products remain to be investigated.
ATP-binding cassette transporter-2 (ABCA2) as a therapeutic target
2018, Biochemical Pharmacology
The ATP binding cassette transporter ABCA2 is primarily an endolysosomal membrane protein that demonstrates pleiotropic functionalities, coalescing around the maintenance of homeostasis of sterols, sphingolipids and cholesterol. It is most highly expressed in brain tissue and ABCA2 knockout mice express neurological defects consistent with aberrant myelination. Increased expression of the transporter has been linked with resistance to cancer drugs, particularly those possessing a steroid backbone and gene expression (in concert with other genes involved in cholesterol metabolism) was found to be regulated by sterols. Moreover, in macrophages ABCA2 is influenced by sterols and has a role in regulating cholesterol sequestration, potentially important in cardiovascular disease. Accumulating data indicate the critical importance of ABCA2 in mediating movement of sphingolipids within cellular compartments and these have been implicated in various aspects of cholesterol trafficking. Perhaps because the functions of ABCA2 are linked with membrane building blocks, there are reports linking it with human pathologies, including, cholesterolemias and cardiovascular disease, Alzheimer’s and cancer. The present review addresses whether there is now sufficient information to consider ABCA2 as a plausible therapeutic target.
AGE-albumin enhances ABCA1 degradation by ubiquitin-proteasome and lysosomal pathways in macrophages
2018, Journal of Diabetes and its Complications
Advanced glycation end products (AGEs) induce cellular oxidative/endoplasmic reticulum stress and inflammation. We investigated its underlying mechanisms for atherogenesis focusing on regulation of ABCA1 protein decay in macrophages.
The ABCA1 decay rate was evaluated in macrophages after treatment with LXR agonist and by incubation with control (C) or AGE-albumin concomitant or not with cycloheximide, MG-132, ammonium chloride and calpain inhibitors were utilized to inhibit, respectively, proteasome, lysosome and ABCA1 proteolysis at cell surface. ABCA1 was determined by immunoblot and the protein decay rate calculated along time by the slope of the linear regression. Ubiquitination level was determined in ABCA1 immunoprecipitated from whole cell lysate or bulk cell membrane. AGE effect was also analyzed in THP-1 cells transfected with siRNA-RAGE. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/MS. One-way ANOVA and Student t test were utilized to compare results.
CML and PYR-albumin were higher in AGE-albumin as compared to C. AGE-albumin reduced ABCA1 in J774 and THP-1 macrophages (20–30%) and induced a higher ABCA1 ubiquitination and a faster protein decay rate that was dependent on the presence of AGE during the kinetics of measurement in the presence of cycloheximide. Proteasomal inhibition restored and lysosomal inhibition partially recovered ABCA1 in cells treated with AGE-albumin. Calpain inhibition was not able to rescue ABCA1. RAGE knockdown prevented the reduction in ABCA1 elicited by AGE.
AGE-albumin diminishes ABCA1 by accelerating its degradation through the proteasomal and lysosomal systems. This may increase lipid accumulation in macrophages by diminishing cholesterol efflux via RAGE signaling contributing to atherosclerosis in diabetes mellitus.
Structure of the Human Lipid Exporter ABCA1
2017, Cell
Citation Excerpt :
The ABCA1-mediated lipid export and loading to apoA-I represents the rate-controlling step in HDL biogenesis (Lee and Parks, 2005; Oram and Lawn, 2001; Oram et al., 2000; Smith et al., 2004). ABCA1, cloned in 1994 and originally named as ABC1 (Luciani et al., 1994), was identified to be the disease-causing gene for Tangier disease (TD), a rare genetic disorder that exhibits severe reduction of HDL and high incidence of premature CVD (Bodzioch et al., 1999; Brooks-Wilson et al., 1999; Rust et al., 1999). Mutations of ABCA1 have also been detected in less severe familial HDL deficiency (Brooks-Wilson et al., 1999; Marcil et al., 1999).
ABCA1, an ATP-binding cassette (ABC) subfamily A exporter, mediates the cellular efflux of phospholipids and cholesterol to the extracellular acceptor apolipoprotein A-I (apoA-I) for generation of nascent high-density lipoprotein (HDL). Mutations of human ABCA1 are associated with Tangier disease and familial HDL deficiency. Here, we report the cryo-EM structure of human ABCA1 with nominal resolutions of 4.1 Å for the overall structure and 3.9 Å for the massive extracellular domain. The nucleotide-binding domains (NBDs) display a nucleotide-free state, while the two transmembrane domains (TMDs) contact each other through a narrow interface in the intracellular leaflet of the membrane. In addition to TMDs and NBDs, two extracellular domains of ABCA1 enclose an elongated hydrophobic tunnel. Structural mapping of dozens of disease-related mutations allows potential interpretation of their diverse pathogenic mechanisms. Structural-based analysis suggests a plausible “lateral access” mechanism for ABCA1-mediated lipid export that may be distinct from the conventional alternating-access paradigm.

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Regular ArticleCloning of Two Novel ABC Transporters Mapping on Human Chromosome 9

Abstract

Regular Article
Cloning of Two Novel ABC Transporters Mapping on Human Chromosome 9