ATP-Binding Cassette Subfamily A Member 2
ATP-binding cassette (ABC) transporters are integral membrane proteins that cross the intracellular (organelles) and cytoplasmic membranes and are involved directly in the transport of substrates against a concentration gradient using ATP hydrolysis. The superfamily of human ABC transporters comprises 49 members and has a wide variety of functions. This family is divided into seven subfamilies from A to G, with the ABC “A” subfamily containing 13 members, such as ABCA1, ABCA2, and ABCA7, which transport sterols. The second member of the ABCA subfamily is named ABCA2. It is expressed at high levels in the white matter of the brain (Halene et al. 2016), as well as oligodendrocytes, schwann cells, excitatory and inhibitory neurons (Mack et al. 2012), brain capillary endothelial cells (Wolf et al. 2012), and glial cells (Macé et al. 2005) in the central and peripheral nervous systems. ABCA2 is also naturally expressed in some tissues of skin (Takenaka et al. 2013), heart, kidney, lung (Tarling et al. 2013), and reproductive organs (Mack et al. 2012), as well as blood cells such as macrophages, monocytes (Calpe-Berdiel et al. 2012), blood stem cells, and cancer cell lines (Aberuyi et al. 2014). ABCA2 is located on inner vesicles including late endosomes, lysosomes, trans-Golgi, and endoplasmic reticulum. This protein transports a variety of substrates that they have commonality with ABCA3 substrates (Aberuyi et al. 2014).
ABCA2 Gene Structure
ABCA2 Protein Structure
Function and Pathophysiological Role of ABCA2 Protein
ABCA2 imports toxic compounds and waste output from the cell’s cytoplasm to lysosomes for detoxification, regulates lipid metabolism, maintains cellular lipid homeostasis (Aberuyi et al. 2014; Davis 2015), and protects cells from reactive oxygen species (ROS) (Borel et al. 2012). The presence of a lipocalin signature motif suggests that the protein also binds and transports sterols and lipids such as sphingomyelin, phosphatidylethanolamine, and phosphatidylserine (Calpe-Berdiel et al. 2012; Davis 2015). Because of these functions, ABCA2 is involved in a number of important processes and its expression has been associated with development of diseases such as early atherosclerosis (Li et al. 2013), Alzheimer’s disease with early onset (Davis 2015), Tangier’s, and vestibular schwannoma (Mack et al. 2012).
One process where ABCA2 is known to be involved is the development of the nervous system. The presence of ABCA2 in neural tissues and oligodendrocytes especially at the time of myelin formation suggest a possible role in myelination and or other kings of metabolism in the central nervous system. (Hadzsiev et al. 2016). Furthermore, ABCA2 gene deficiency is known to cause a smaller body size and a shaking phenotype concomitant with changes in myelin ultrastructure or sphingolipid composition of neuronal tissues, further supporting the role of ABCA2 in the development/maintenance of myelin membrane and sphingolipid homeostasis in mouse (Mack et al. 2011).
ABCA2 overexpression has also been observed in multidrug resistance (MDR) (Rahgozar et al. 2014) and some human cancers including small cell lung cancer, acute myeloid leukemia (Barbet et al. 2012), liver (Borel et al. 2012), breast (Hlavác et al. 2013), ovarian (Barbet et al. 2012), prostate, and several neurological cancers (Mack et al. 2011). It has been reported that ABCA2 deficiency produces a delay in metastatic phenotype in prostate cancer and inhibits chemotactic migration (Mack et al. 2011).
ABCA2 Protein and Signaling Pathway in Alzheimer’s Disease
An E-box element is 49 base pairs upstream of the transcription start site of the APP promoter that binds the USF family of transcription factors, USF-1 and USF-2, to activate APP transcription. An increased presence of USF-1 and USF-2 has been observed in ABCA2-overexpressing cells, suggesting that ABCA2 can further increase APP expression by activation of the E-box. Therefore, targeting of ABCA2 expression may represent a novel approach to regulate PKC signaling cascades in improvement of AD pathology (Davis 2015).
ABCA2 is the second member of ABCA subfamily that is naturally expressed in some tissues, especially in the brain. This protein is located on inner vesicles including late endosomes, lysosomes, trans-Golgi, and endoplasmic reticulum and is responsible for transporting a variety of substrates. The ABCA2 gene is located on chromosome 9q34.3, near the ABCA1 gene and is contained within a CpG island. This gene has a total length of 21 kbp, with a 7.3 kbp coding region and 48 exons. Alternative splicing of ABCA2 leads to two transcripts called 1A and 1B which have different expression and tissue distribution, with the 1A isoform being more common. The promoter region of this gene is GC-rich (about 80%), TATA box-less, and has two GC boxes that are the binding site for several of the Sp-family factors and the EGR-1transcription factor which regulate transcription of the promoter. The Sp1 factor is a transcriptional activator while EGR-1 is a repressor of transcription for the human ABCA2 gene. The ABCA2 protein has 2436 amino acids and its molecular weight is approximately 250 kDa. It has the highest structural homology with ABCA1 and it is a “full transporter” that contains two symmetric halves, including TMD and NBD, with a long cytoplasmic regulator domain (HH1) in between. ABCA2 imports waste output of the cell and toxic compounds from the cytoplasm to the lysosomes and has a role in lipid transport, lipid metabolism regulation, maintenance of cellular lipid homeostasis, and cell protection from ROS. This protein has a lipocalin signature motif that binds and transports sterols and lipids. It is also involved in myelination and is associated with the development of the nervous system; however, further research will be needed to gain a more complete understanding of the mechanism of action of ABCA2 in this process. There is an association between ABCA2 and a number of diseases such as early atherosclerosis, AD with early onset, Tangier’s, vestibular schwannoma, MDR, and some human cancers such as T-cell acute lymphoblastic leukemia. The extent of the protein’s involvement in these diseases is an area with potential for future research. In the case of AD, ABCA2 has been shown to activate a signaling pathway that regulates APP transcription by PKC. ABCA2 overexpression reduces formation of the JDP-HDAC3 repressive complex and leads to transcriptional activation of APP by c-jun at the AP-1 site and USF family of transcription factors at the E-box element. Thus, a new approach in treating Alzheimer’s can be to regulate the PKC signaling pathway by targeting ABCA2 expression.
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