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    • Perhaps the discovery of this linkage has served

    2023-01-04

    Perhaps the discovery of this linkage has served to catapult much of the work on ABCA1, leaving its family member in need of a relationship with a defined human pathology. In this regard, there is by now a quite mature literature that suggests that ABCA2 may have been overlooked in terms of its importance to human metabolism. Some of the earliest reports detailed overexpression of ABCA2 through an amplification and gene duplication of a region of chromosome 9q34 in a human ovarian cancer cell line with resistance to the anticancer drug estramustine [5], an anti-microtubule chemotherapeutic, structurally similar to estradiol [6] used in the 1990s to treat hormone refractory prostate cancer [7]. Because estramustine is an estrogen-based therapeutic (although its cytotoxic properties are related to antimicrotubule activity) [8], this may have been a predication of the involvement of ABCA2 with sterol homeostasis. While there are numerous transporters involved in the efflux of small molecules, and ABCA2 has been shown to enhance sequestration of some agents into lysosomes [9], much of the more recent published material perhaps indicates a broader association of the transporter with CNS and Nexturastat A function, although this does not preclude other role(s) in oncology. The remainder of this article will detail some of the findings that may serve to invigorate interest in this transporter and its role in cellular homeostasis and human diseases.
    ABCA2: general information Initially, both ABCA1 and ABCA2 were co-isolated from embryonic mouse brain tissue [10]. They share the general protein structure of two transmembrane domains (TMD) and two nucleotide-binding domains (NBD) with an intervening highly hydrophobic loop domain (Fig. 1). The Abca2 gene locus mapped to chromosome 9q34 within a 21kb region [11], containing 48 exons encoding a polypeptide of 2436 residues [12], [13]. The minimal promoter region mapped 321 bp upstream of the translation start site [14] with the promoter containing consensus sequences for transcription factors HNF-3, c-myc and AP-1. In addition, it has two GC-boxes, encoding overlapping sites for the early growth response-1 (EGR-1) and Sp1 transcription factors [14]. ABCA2 is the largest of the ABC transporters, with a molecular mass of ∼270 kD [1]. Full length human ABCA2 was cloned and detailed tissue distribution studies confirmed high levels in brain, but also described expression patterns in ovary, leukocytes and macrophages [12], [13]. Temporal localization in oligodendrocytes in brain [15] and spinal cord [15] of the CNS, as well as Schwann cells in peripheral nerves [16], [17] has been found. Yeast two-hybrid studies revealed that within the hypothalamus, amygdala, cortex and selected brain stem nuclei ABCA2 colocalized with the orphan G protein-coupled receptor 50. This implies a link between functional aspects of G protein and neurotransmitter signaling strengthening a plausible role for this complex in stress response and energy homeostasis. (GPR50; [18]). Within the cell, fluorescent antibody studies revealed that ABCA2 primarily localizes to intracellular structures such as late endosomes/lysosomes, trans-Golgi and endoplasmic reticulum [19], although there are also indications of some expression at the cell membrane. Isoforms of 1A and 1B of ABCA2 are generated by alternative splicing [20], where exon 1 of isoform 1A encodes 22 amino acids, while that of isoform 1B, located 699 bp upstream contains a coding sequence for 52 amino acids. Both splice variants share similar tissue expression profiles and co-localize with lysosome-associated membrane proteins-1 and -2 (LAMP-1 and -2) [20]. Their specific functions in differentiation and/or development remain to be determined. Within the A sub-family ABCA2 shares amino acid sequence homology with ABCA1 (50), ABCA7 (44), ABCA3 (43), ABCA4 (40) and ABCA6 (32) [9]. With ABCA1, this includes two cytoplasmic NBDs and two conserved sequences in the N- and C-terminal domains (LLLWKN and VFVNFA, respectively). The LLLWKN (function unknown) sequence is present in all members except ABCA6 and 9 [9]. The VFVNFA motif is critical for apolipoprotein A-I binding and HDL cholesterol efflux in ABCA1 [21], obviously implying a similar function for ABCA2. A lipocalin signature sequence exists downstream of the first NBD and this is present in other proteins including, apolipoprotein D, prostaglandin D synthase, complement component C8 γ-chain and α-1-microglobulin [9]. Lipocalin motifs form a small pocket for binding to hydrophobic compounds, such as lipids and sterols. This is consistent with studies implicating small, hydrophobic compounds, such as estramustine as transport substrates for ABCA2 [22].