Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Alessandro Paolini
  • Antonella Baldassarre
  • Andrea Masotti
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101533


Historical Background

Adenosine triphosphate (ATP)-binding cassette A3 transporter (ABCA3) is a member of the evolutionarily highly conserved family of ABC transporters. The ABCA3 gene (more than 80 kb length) maps to human chromosome 16 (16p13.3) and consists of 33 exons (30 of which are coding). ABCA3 encodes a 1704 amino acid (~150 kDa) protein (Dean 2005). ABCA3 is a lung-specific phospholipid transporter with a critical role in the intracellular surfactant synthesis and storage in lamellar bodies (LBs), which is organized into two tandem functional units (N-half and C-half), consisting in a TMD (α-helix motif) and a NBD for each half (Bruder et al. 2007; Park et al. 2010). The expression of ABCA3 is developmentally regulated, peaking prior to birth under the influence of steroids and transcription factors. Bi-allelic mutations of the ABCA3 gene represent the most frequent cause of congenital surfactant deficiency, indicating its critical role in lung function (Shulenin et al. 2004).

Functional Features of ABC Transporters

ATP-binding cassette (ABC) transporters constitute one of the largest known superfamilies of proteins highly conserved evolutionarily (Dean and Annilo 2005). They are transmembrane proteins which use the hydrolysis of ATP to drive the transport of a wide variety of substrates across cellular membranes. Substrates transported by ABC molecules include lipids, peptides, amino acids, carbohydrates, vitamins, ions, glucuronide and glutathione conjugates, and xenobiotics (Dean and Annilo 2005). ABC transporters are divided into three main functional categories: importers (i.e., in prokaryotes they mediate the uptake of nutrients into the cell), exporters (in eukaryotes and prokaryotes they export various types of molecules), and ABCs involved in translation and DNA repair processes. ABC importers and exporters have quite similar transport mechanisms (i.e., they open and close transmembrane domains and allow the transport of the substrate), and this also suggests that the structures should be quite similar (Davidson et al. 2008). The mechanism that describes the conformational changes associated with substrate binding is the alternating-access model. In this model, the substrate binding site alternates between outward- and inward-facing conformations. Briefly, the resting state of importers is characterized by an inwardly facing conformation, where the two NBDs are kept open by the TMDs that face outward (Fig. 1a). When the substrate enters the transporter, transmembrane domains change their conformation and ATP can bind to NBDs. These events allow the transporter to switch into an outward-facing conformation in which the TMDs have reoriented to receive the substrate from the binding protein. After hydrolysis of ATP into ADP and Pi, the NBD dimer opens, the substrate is released into the cytoplasm, and the transporter is again converted into the resting state (Davidson et al. 2008; Rees et al. 2009; Higgins et al. 2004). For exporters, the transport cycle begins with substrate binding to an inward-facing, open NBD conformation of the ABC transporter (Fig. 1b). This is followed by ATP-dependent closure of the NBDs, which concomitantly can shift the transporter to an outward-facing conformation and exposes the substrate for release on the other side of the membrane. Here, ATP hydrolysis leads to NBDs reopening and the transporter returns to the initial conformation (Rees et al. 2009, Linton KJ et al. 2007; ter Beek et al. 2014).
ABCA3, Fig. 1

A general mechanism of transport for ABC importers. (a) In the absence of substrate, the transporter is in a conformation in which the NBD dimer interface is open and the translocation pathway is exposed only to the cytoplasm. Interaction of substrate-bound BP with the closed extracellular side of the TMDs in the presence of ATP triggers a global conformational change in which the NBDs close and promote ATP hydrolysis, substrate-bound BP becomes tightly bound to the TMDs, and both BP and TMDs open at the periplasmic surface of the membrane to facilitate substrate transfer from the BP to a binding site in the membrane. Following ATP hydrolysis, which destabilizes the NBD dimer, the transporter returns to the inward facing state and the substrate completes its translocation across the membrane. (b) Proposed mechanism of transport for ABC exporters. Ligand binding to a high-affinity pocket formed by the TMDs induces a conformational change in the NBDs, resulting in a higher affinity for ATP. Two molecules of ATP bind to the NBDs. The energy released by the formation of the closed NBD dimer causes conformational change in the TMDs. ATP hydrolysis triggers dissolution of the closed NBD dimer, resulting in further conformational changes in the TMDs. Finally, phosphate and then ADP release restores the transporter to the open NBD dimer conformation ready for the subsequent cycle

In eukaryotes, ABC transporters are located in the plasma membrane, in the membranes of intracellular compartments such as the Golgi, endosome, multivesicular bodies, endoplasmic reticulum, peroxisome, and in mitochondria. To date, 48 members of the human family of ABC transporters have been identified. Based on their structural relatedness, these members are subdivided into seven families, designated ABC A–G (Dean and Annilo 2005).

Structural Features of ABCA3

Adenosine triphosphate (ATP)-binding cassette A3 transporter (ABCA3) is a transmembrane lipid carrier that belongs to the ABC transporter family. Twelve human ABC transporter genes belonging to the A-subfamily (ABCA1–10, ABCA12, and ABCA13) and two pseudogenes (ABCA11P and ABCA17P) are known so far (Dean 2005; Paolini et al. 2015; Piehler et al. 2006). ABCA3 is a 150 kDa, 1704 amino acid protein encoded by an 80 kb gene composed of 33 exons, only 30 of which are transcribed, located at the 16p13.3 genomic locus. ABCA3 is organized into two tandem functional units (N-half and C-half), consisting in a TMD (α-helix motif) and a NBD for each half (Bruder et al. 2007; Park et al. 2010). Both N- and C-halves of ABCA3 have been predicted to contain a TMD formed by six hydrophobic membrane-spanning α-helices connected by a long loop (156–220 aa) connecting the first and the second α-helix and by short hydrophilic loops (8–53 aa length) linking the remaining helices of the TMS. The extracellular domain (ECD) loops and the TMDs constitute the main substrate binding site that allows the trafficking of lipid molecules. As in other ABCA proteins, ABCA3 presents a short (~22 aa) N-terminal protein segment of positively charged residues, which is followed by the first α-helix of the transmembrane motif: a domain rich in hydrophobic amino acids such as valine and leucine. The extracellular domains (ECDs) between the first α-helix (N- and C-half) and the rest of the TMD domain protrude in the extracellular compartment. However, in ABCA3 protein, the function of these two extracellular loops is still unknown (Vedhachalam et al. 2007).

Most of the members of ABC transporters have a similar domain organization except for the number of transmembrane domains that may vary (i.e., ABCB2, ABCC1, etc.) or the different length of the loops that connect them. The ABCA3 nucleotide binding domains (NBD1 and NBD2) consist of 153 and 154 amino acids, respectively, and are generally conserved in many other species (Higgins 1992).

Expression, Regulation, and Function of ABCA3

The ABCA3 protein can be readily detected by 26–27 weeks of gestation in normal fetuses, but as early as 23–24 weeks when lung inflammation is present. Its expression increases in the presence of lung infection and bronchopulmonary dysplasia (Stahlman et al. 2007; Yoshida et al. 2004). Several factors and hormones regulate ABCA3 expression. Among the most important, we recall the glucocorticoids, such as dexamethasone (Yoshida et al. 2004), thyroid transcription factor 1 (TTF-1) which play a switch role in epithelial maturation and surfactant synthesis inducing the expression of ABCA3, SP-A, SP-B, and SP-C (Stahlman et al. 2007; Yoshida et al. 2004; Kolla et al. 2007) and STAT3 (signal transducer and activator of transcription 3) that induces ABCA3 expression and possibly mediates its response to inflammation (Matsuzaki et al. 2008). Other enhancing ABCA3 transcription factors include FOXA2 (forkhead box A2), GATA6 (GATA-binding protein 6), and NFATc3 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 3) (Besnard et al. 2007). Finally, ABCA3 transcription is also inducible by SREBP1a and SREBP1c (sterol regulatory element-binding transcription factor 1a/c) proteins that contain several sterol-responsive elements and are involved in lamellar bodies formation (Besnard et al. 2007).

ABCA3 expression was detected at highest levels in type II alveolar epithelial cells, but it was also found in other organs including liver, stomach, kidney, adrenal, pancreas, trachea, and brain. Specifically, ABCA3 has been localized predominantly to the limiting membrane of lamellar bodies, lipid-rich organelles associated with the production, storage, and secretion of pulmonary surfactant (Yamano et al. 2001). Vesicular structures observed in HEK293 cells exogenously expressing ABCA3 suggest the involvement of ABCA3 protein in the generation of lamellar body-like structures (Nagata et al. 2004). Further evidence supporting the hypothesis that ABCA3 might be involved in assembly of lung surfactant were provided by in vitro studies, suggesting that ABCA3 transport of phospholipids and cholesterol is essential for lamellar body formation, a key step in assembly of lung surfactant, in primary cultures of human AT2 cells and the human carcinoma A549 cell line (Cheong et al. 2006).

ABCA3 Deficiency and Mechanisms of Disease

ABCA3 deficiency is appearing to be one of the most common cause of inborn errors of surfactant metabolism. More than 180 distinct mutations including multiple-missense, splice-site, and frameshift mutations in the gene encoding ABCA3 have been found in children with severe neonatal respiratory disease and adolescents with some forms of interstitial lung disease (Shulenin et al. 2004). In humans, mutations in the ABCA3 gene are associated with decreased surfactant phosphatidylcholine content and increased surface tension of the lung lavage fluid, also suggesting that ABCA3 plays an important role in pulmonary surfactant phospholipid homeostasis (Garmany et al. 2006). Since the phenotype of mice with targeted disruption of the ABCA3 gene was similar to that of humans with functional or trafficking mutations in the ABCA3 gene, the use of animal models has contributed to increase the knowledge regarding the physiologic transport function of ABCA3. Engineered Abca3−/− mice that completely lack ABCA3 expression die of respiratory failure as a result of an inability to secrete pulmonary surfactant into the alveolar space (Fitzgerald et al. 2007). Furthermore, it has been recently demonstrated that adult mice with ABCA3 haplo-insufficiency are more susceptible to the deleterious effects of lung injury by hyperoxia or mechanical ventilation (Herber-Jonat et al. 2013). However, the wide spectrum of mutations in the ABCA3 gene well correlate with different phenotype forms of severe respiratory distress, such as persistent or recurrent tachypnea in newborns (Kinane et al. 2011; Prestridge et al. 2006), and mutations associated with milder clinical forms, such as ILD (interstitial lung disease), desquamative interstitial pneumonitis presenting in childhood (Whitsett et al. 2010), and idiopathic pulmonary fibrosis or emphysema in adults (Epaud et al. 2014). ABCA3 deficiency was characterized to variable histopathology showing combinations of alveolar epithelial type 2 cells (AEC2) hyperplasia, intraalveolar eosinophilic material, alveolar macrophages, desquamated epithelial cells, interalveolar septa thickening, fibrosis, and inflammation (Brasch et al. 2006; Citti et al. 2013). Ultrastructural anomalies, observed following TEM analysis, put in evidence a profound disruption of surfactant composition and function due to decreased amount of phosphatidylcholine and other phospholipids that induce high alveolar surface tension values compared with controls and to surfactant protein B (SP-B) deficiency (Garmany et al. 2006; Edwards et al. 2005). Moreover, altered SP-B and surfactant protein C (SP-C) processing and routing occur also in ABCA3 deficiency and probably contribute to surfactant homoeostasis disruption and respiratory symptoms.

This pathological scenario has become more complex, and recently several studies have demonstrated that the surfactant dysfunction and respiratory disease not only correlate with mutations located in the exons or the immediate intron-exon boundaries, but also with noncoding regions, resulting in aberrant ABCA3 mRNA splicing and expression (Agrawal et al. 2012).

At the protein level, many deleterious mutations found in humans generally cluster on extracellular domain 1 (ECD1) and NBD2, highlighting the functional relevance of these domains (Fig. 2). Mutagenesis experiments (of severe phenotypes) showed that proteins with ECD1, ECD4, and C-terminus mutations remained located in the endoplasmic reticulum (ER) and exhibited impaired glycosylation, whereas NBD1 and NBD2 mutant proteins led to decreased ATP binding and/or hydrolysis (Matsumura et al. 2006). NBD2 mutants fail to accumulate phosphatidylcholine into organelles, which supports the critical role of ATP binding and hydrolysis in the active lipid transport mechanism (Cheong et al. 2007). Certain ECD1 mutants determined an ER stress response by activating chaperone proteins of the HSP70 (heat shock protein 70) complex and triggered apoptosis, which may represents an additional lung injury mechanism in the complex pathogenesis of ABCA3 deficiency (Weichert et al. 2011). Another potential mechanism, typically observed in pediatric or adult interstitial lung disease and lung fibrosis, is the epithelial-mesenchymal transition (EMT). In experiments with particular lung epithelial cell line having two common human ABCA3 mutations, disruption of certain epithelial markers and induction of mesenchymal markers, a gradually change in fibroblast-like aspect and behavior was observed (Kaltenborn et al. 2012) miming a phenomenon that probably accounts for the intense interstitial cell proliferation and fibrosis observed in most ABCA3 mutation carriers.
ABCA3, Fig. 2

Distribution of amino acid mutations in ABCA3. ABCA3 protein model with two transmembrane domains (TMD1, TMD2) each containing six transmembrane domains and two hypothesized inner-membrane domains (Paolini et al. 2015), and two nucleotide-binding domains (NBD1, NBD2) with two Walker domains A and B. Over 180 published amino acid variations have been reported. These mutations are distributed throughout the protein sequence but are mainly enriched on extracellular domain 1 (ECD1) and NBD2, highlighting the functional importance of these two domains. The colored points in the picture indicate the most important mutations in pediatric interstitial lung disease (Peca et al. 2015)


The uniqueness and variability of ABCA3 variants overlapped to other surfactant-related genetic diseases strongly support the use of high-throughput approaches, such as next generation sequencing or whole-exome sequencing to get a more comprehensive picture of ABCA3 deficiencies (Wambach et al. 2014). Mutation type and position, in silico validation tools, human variation database, species conservation databases, and inheritance patterns should be complemented by strict phenotypical characterization. Although lung transplantation remains the only option for end-stage lung disease, given its poor long-term prognosis, some less severe forms of ILD may benefit from pharmacological treatment. Inflammatory modulating agents, such as pulse methylprednisolone, hydroxychloroquine, and azithromycin, are used occasionally either individually or in combination (Flamein et al. 2012), although their use has not been validated by proper clinical trials. A deeper understanding of the pathogenic mechanisms could lead to the development of mutation-specific drugs, such as proteasome inhibitors in mutations affecting glycosylation site (Beers et al. 2013) or chemical chaperones in those affecting intracellular trafficking (Cheong et al. 2006).


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Alessandro Paolini
    • 1
  • Antonella Baldassarre
    • 1
  • Andrea Masotti
    • 1
  1. 1.Gene Expression - Microarrays LaboratoryBambino Gesù Children’s Hospital, IRCCSRomeItaly