The ABCA2 transporter: intracellular roles in trafficking and metabolism of LDL-derived cholesterol and sterol-related compounds

Abstract

ATP-binding cassette (ABC) transporters comprise a family of critical membrane bound proteins functioning in the translocation of molecules across cellular membranes. Substrates for transport include lipids, cholesterol and pharmacological agents. Mutations in ABC transporter genes cause a variety of human pathologies and elicit drug resistance phenotypes in cancer cells. ABCA2, the second member the A subfamily to be identified, was highly expressed in ovarian carcinoma cells resistant to the anti-cancer agent, estramustine, and more recently, in human vestibular schwannomas. Cells expressing elevated levels of ABCA2 show resistance to variety of compounds, including estradiol, mitoxantrone and a free radical initiator, 2,2'-azobis-(2-amidinopropane). ABCA2 is expressed in a variety of tissues, with greatest abundance in the central nervous system and macrophages. This transporter, along with other proteins that have a high degree of homology to ABCA2, including ABCA1 and ABCA7, are up-regulated in human macrophages during cholesterol import. Recent studies have shown ABCA2 also plays a role in the trafficking of low-density lipoprotein (LDL)-derived free cholesterol and to be coordinately expressed with sterol-responsive genes. A single nucleotide polymorphism in exon 14 of the ABCA2 gene was shown to be linked to early onset Alzheimer disease (AD) in humans, supporting an earlier study showing ABCA2 expression influences levels of APP and beta-amyloid peptide, the primary component of senile plaques. Studies thus far implicate ABCA2 as a sterol transporter, the deregulation of which may affect a cellular phenotype conducive to the pathogenesis of a variety of human diseases including AD, atherosclerosis and cancer.

Fig. (1).

Predicted membrane topology of the ABCA2 transporter. ABCA2 sequence data were applied to Kyle-Doolittle hydrophobicity analysis using Genetics Computer Group (version 9.1; Madison, WI) and McVector software (Oxford Molecular, Oxford, UK). Transmembrane domains were predicted using TopPred 2 analysis. Shown is a schematic of the predicted membrane topology of ABCA2 in the intraorganellar membrane. The extracellular and intracellular domains, respectively, are depicted above and below the horizontal lines representing a phospholipid bilayer. (Figure adapted from Vulevic et al. 2001[15]).

Fig. (2).

Alignment of ABCA transporters with high homology to ABCA2. The alignment is shown in descending order of homology with ABCA2 with (A) the conserved LLWKN motif at the N-terminus of unknown function, (B) a highly hydrophobic domain (residues 1457–1477 for ABCA2) and (C) highly conserved domain at the C-terminus. The sequence alignment was conducted using MultAlin software [119].

Fig. (3).

Putative substrates of ABCA2 transport.