Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

ATP-Binding Cassette Subfamily A Member 2

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101528

Synonyms

Historical Background

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

The ABCA2 gene is located near the ABCA1 gene, on chromosome 9q34.3 (Fig. 1) (Calpe-Berdiel et al. 2012). It is situated within a CpG island that is common for many housekeeping genes (Davis et al. 2003) and has an unexpectedly short length of 21 kbp when compared to the usual 23–250 kbp size of other transporters. The gene contains 48 exons and a coding region of 7.3 kbp (Aberuyi et al. 2014). The first exon is 699 bp upstream of the second, and alternative splicing of these two exons leads to two different transcripts called 1A and 1B. The 1A isoform N-terminal contains 22 amino acids and its transcript starts from exon II, while the 1B isoform N-terminal includes 52 amino acids, and exon I can be seen in its transcript (Mack et al. 2008). Similar to other genes, these two isoforms have different expression and tissue distribution, with the 1A isoform expressed ubiquitously while the 1B isoform’s expression is more restricted (Ile et al. 2004). The GC-rich (about 80%) and TATA-less (Davis et al. 2003) ABCA2 promoter, located 321 bp upstream of the gene’s translation initiation region, has potential binding sites for transcription factors that are associated with differentiation in neural and myeloid tissues (Mack et al. 2008). It has two GC boxes that are the binding sites for several of the Sp-family factors and the EGR-1 transcription factor which regulate the transcription of the promoter (Thiel et al. 2014). It has been shown that both the EGR-1 and Sp1 sites in GC-box 2 are required for the majority of promoter activity. The Sp1 factor functions as an activator of transcription while EGR-1 functions as a transcriptional repressor for the human ABCA2 promoter (Davis et al. 2003).
ATP-Binding Cassette Subfamily A Member 2, Fig. 1

A schematic picture of ABCA2 and ABCA1 gene locations on chromosome 9. The ABCA2 gene is located on chromosome 9q34.3, near the ABCA1 gene

ABCA2 Protein Structure

ABCA2 is a large symmetric membrane protein with a channel-like functional structure. This protein is a “full transporter” and its two symmetric halves contain a long cytoplasmic regulator domain in between which has a high hydrophobic sequence (HH1) that dips into the membrane (Fig. 2) (Aberuyi et al. 2014). Each symmetric half includes a hydrophobic multipass α-helical transmembrane domain (TMD) and a nucleotide-binding domain (NBD) that bind and hydrolyze ATP. The nucleotide-binding domains consist of the signature Walker A and Walker B motifs separated by an ABC “signature” motif that is characteristic of ABC transporters (Davis 2015). Overall, this protein contains 2436 amino acids and its molecular weight is approximately 250 kDa. The ABCA2 protein has the highest structural homology with ABCA1 due to duplication of the ancestral gene (Aberuyi et al. 2014) .
ATP-Binding Cassette Subfamily A Member 2, Fig. 2

ABCA2 gene (a) and protein (b) structure. There are two symmetric halves of this protein and each includes a membrane including a spanning domain (MSD) and a nucleotide-binding domain (NBD). High hydrophobic sequence (HH1) is a long cytoplasmic regulator domain between two symmetric halves (Aberuyi et al. 2014)

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

Overexpression and dysregulation of amyloid precursor protein (APP) leads to accumulation of amyloid β (Aβ) plaque in the brain which is centrally involved in Alzheimer’s disease (AD) etiology. ABCA2 activates a signaling pathway that regulates APP transcription, a possible mechanistic link between ABCA2 and AD. This transporter is localized to the late-endosomal/lysosomal compartment where acid ceramidase (ASAH1) resides and the Golgi complex where the predominant forms of alkaline ceramidase, ACER2 and ACER3, exist. ABCA2 may function to alter the transbilayer distribution of the sphingolipid ceramide in internal organelle membranes (Fig. 3). As a result, ceramide substrate is brought in proximity to the alkaline and acidic ceramidase enzymes to increase ceramidase activity and generate sphingosine. Sphingosine is a physiological inhibitor of protein kinase C (PKC), which in turn controls APP expression through DNA control elements in the APP promoter. The AP-1 site activator proteins, c-jun and c-fos, increase expression of the APP promoter while negative regulation at the AP-1 site in the APP promoter can be mediated by the JDP2 repressor protein. JDP2 binds to the AP-1 site, either as a JDP2 homodimer or a heterodimer with c-jun, and then recruits histone deacetylase HDAC3 to the promoter to inhibit p300-mediated histone acetylation and transcriptional activation by histone acetyltransferase (HAT). Thus, a repressive complex at the AP-1 site includes JDP-JDP-HDAC3 or c-jun-JDP-HDAC3. 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.
ATP-Binding Cassette Subfamily A Member 2, Fig. 3

ABCA2 overexpression leads to distribution of the sphingolipid ceramide (Cer) in internal organelle membranes, near the alkaline (ASAH1) and acidic ceramidase (ACER2/3) enzymes to increase ceramidase activity to generate sphingosine (Sph). Sphingosine inhibits protein kinase C (PKC) and decreases the in vivo binding of JDP2 and HDAC3 at AP-1 site in the amyloid precursor protein promoter. Amyloid precursor protein overexpression occurs by in vivo binding of the c-jun transcriptional activator at the AP-1 site which results in decreased formation of a transcription repressor complex, as well as increased in vivo binding of the USF-1 and USF-2 transcriptional activators at the E-box site. Thus, APP transcriptional regulation is mediated through PKC

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).

Summary

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.

See Also

References

  1. Aberuyi N, Rahgozar S, Moafi A. The role of ATP-binding cassette transporter A2 in childhood acute lymphoblastic leukemia multidrug resistance. Iran J Ped Hematol Oncol. 2014;4:118.PubMedCentralPubMedGoogle Scholar
  2. Barbet R, Peiffer I, Hutchins JR, Hatzfeld A, Garrido E, Hatzfeld JA. Expression of the 49 human ATP binding cassette (ABC) genes in pluripotent embryonic stem cells and in early-and late-stage multipotent mesenchymal stem cells: Possible role of ABC plasma membrane transporters in maintaining human stem cell pluripotency. Cell Cycle. 2012;11:1611–20.CrossRefPubMedGoogle Scholar
  3. Borel F, Han R, Visser A, Petry H, van Deventer SJ, Jansen PL, et al. Adenosine triphosphate-binding cassette transporter genes up-regulation in untreated hepatocellular carcinoma is mediated by cellular microRNAs. Hepatology. 2012;55:821–32.CrossRefPubMedGoogle Scholar
  4. Calpe-Berdiel L, Zhao Y, de Graauw M, Ye D, van Santbrink PJ, Mommaas AM, et al. Macrophage ABCA2 deletion modulates intracellular cholesterol deposition, affects macrophage apoptosis, and decreases early atherosclerosis in LDL receptor knockout mice. Atherosclerosis. 2012;223:332–41.CrossRefPubMedGoogle Scholar
  5. Davis Jr W. The ATP-binding cassette transporter-2 (ABCA2) overexpression modulates sphingosine levels and transcription of the amyloid precursor protein (APP) gene. Curr Alzheimer Res. 2015;12:847.PubMedCentralCrossRefPubMedGoogle Scholar
  6. Davis Jr W, Chen ZJ, Ile KE, Tew KD. Reciprocal regulation of expression of the human adenosine 5′-triphosphate binding cassette, sub-family A, transporter 2 (ABCA2) promoter by the early growth response-1 (EGR-1) and Sp-family transcription factors. Nucleic Acids Res. 2003;31:1097–107.PubMedCentralCrossRefPubMedGoogle Scholar
  7. Hadzsiev K, Komlosi K, Czako M, Duga B, Szalai R, Szabo A, et al. Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype. Mol Cytogenet. 2016;9:1.CrossRefGoogle Scholar
  8. Halene TB, Kozlenkov A, Jiang Y, Mitchell AC, Javidfar B, Dincer A, et al. NeuN+ neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure. Schizophrenia Research. 2016;170(2–3):235–44.Google Scholar
  9. Hlavác V, Brynychová V, Václavíková R, Ehrlichová M, Vrána D, Pecha V, et al. The expression profile of ATP-binding cassette transporter genes in breast carcinoma. Pharmacogenomics. 2013;14:515–29.CrossRefPubMedGoogle Scholar
  10. Ile KE, Davis W, Boyd JT, Soulika AM, Tew KD. Identification of a novel first exon of the human ABCA2 transporter gene encoding a unique N-terminus. Biochim Biophys Acta. 2004;1678:22–32.CrossRefPubMedGoogle Scholar
  11. Li G, Gu HM, Zhang DW. ATP-binding cassette transporters and cholesterol translocation. IUBMB life. 2013.Google Scholar
  12. Macé S, Cousin E, Ricard S, Génin E, Spanakis E, Lafargue-Soubigou C, et al. ABCA2 is a strong genetic risk factor for early-onset Alzheimer’s disease. Neurobiol Dis. 2005;18:119–25.CrossRefPubMedGoogle Scholar
  13. Mack JT, Brown CB, Tew KD. ABCA2 as a therapeutic target in cancer and nervous system disorders. Expert Opin Ther Targets. 2008;12:491–504.CrossRefPubMedGoogle Scholar
  14. Mack JT, Helke KL, Normand G, Green C, Townsend DM, Tew KD. ABCA2 transporter deficiency reduces incidence of TRAMP prostate tumor metastasis and cellular chemotactic migration. Cancer Lett. 2011;300:154–61.CrossRefPubMedGoogle Scholar
  15. Rahgozar S, Moafi A, Abedi M, Entezar-E-Ghaem M, Moshtaghian J, Ghaedi K, Esmaeili A, Montazeri F. mRNA expression profile of multidrug-resistant genes in acute lymphoblastic leukemia of children, a prognostic value for ABCA3 and ABCA2. 2014;15:35–41.Google Scholar
  16. Takenaka S, Itoh T, Fujiwara R. Expression pattern of human ATP-binding cassette transporters in skin. Pharmacol Res Perspect. 2013;1Google Scholar
  17. Tarling EJ, de Aguiar Vallim TQ, Edwards PA. Role of ABC transporters in lipid transport and human disease. Trends Endocrinol Metabol. 2013;24:342–50.CrossRefGoogle Scholar
  18. Thiel G, Müller I, Rössler OG. Expression, signaling and function of Egr transcription factors in pancreatic β-cells and insulin-responsive tissues. Mol Cell Endocrinol. 2014;388:10–9.CrossRefPubMedGoogle Scholar
  19. Wolf A, Bauer B, Hartz A. ABC transporters and the Alzheimer’s disease enigma. Front Psychiat. 2012;3:54.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of BiologyUniversity of IsfahanIsfahanIran
  2. 2.University of IsfahanIsfahanIran
  3. 3.University of British ColumbiaVancouverCanada