3.A.1.211.5
The surfactant-secreting porter, ABCA3 (exports lipids and proteins into lamellar bodies). Fatal surfactant deficiency (FSD) can result from mutations in ABCA3, causing abnormal intracellular localization (type I) or decreased ATP hydrolysis (type II). Other mutations cause pediatric interstitial lung disease (pILD) (Matsumura et al. 2008).  ABCA3 is found in lamellar bodies of lung alveolar type II cells where it probably secretes surfactants (mixture of lipids; e.g., PC) and proteins (e.g., surfactant proteins A, B, C and D) stored in lamellar bodies and exocytosed (Matsumura et al., 2006). ABCA3 plays an essential role in pulmonary surfactant lipid metabolism and lamellar body biogenesis, probably by transporting these lipids as substrates (Ban et al., 2007). Cheong et al., 2007 have shown that ABCA3 is critical for lamellar body biogenesis in mice. They suggested it functions in surfactant-protein B processing and lung development late in gestation. Lymphoma exosomes shield target cells from antibody attack, and exosome biogenesis is modulated by lysosome-associated ABCA3 which mediates resistance to chemotherapy. Silencing ABCA3 enhances susceptability of target cells to antibody-mediated lysis. Mechanisms of cancer cell resistance to drugs and antibodies are linked in an ABCA3-dependent pathway of exosome secretion (Aung et al., 2011). Onnée et al. 2021 used the experimental structure of human ABCA4, to model at atomic resolution the human ABCA3 3D structure including transmembrane domains (TMDs), nucleotide-binding domains (NBDs), and regulatory domains (RDs) in an ATP-bound conformation. They mapped known pathogenic missense variants on this model, pinpointing amino-acids within the NBDs, the RDs and the interfaces between the NBDs and TMDs intracellular helices, which are predicted to play key roles in the structure and/or the function of the ABCA3 transporter (Onnée et al. 2021). The cryo-EM structures of human ABCA3 in two distinct conformations, both at resolution of 3.3 A, have been solved (Xie et al. 2022). In the absence of ATP, ABCA3 adopts a "lateral-opening" conformation with the lateral surfaces of TMSs exposed to the membrane and features two positively charged cavities within the TMSs as potential substrate binding sites. ATP binding induces pronounced conformational changes, resulting in the collapse of the potential substrate binding cavities. These results help to rationalize the disease-causing mutations in human ABCA3 and suggest a conserved "lateral access and extrusion" mechanism for both lipid export and import mediated by ABCA transporters (Xie et al. 2022). Cigarette smoke extract combined with LPS reduces ABCA3 expression in chronic pulmonary inflammation, and this may be related to PPARgamma/ P38 MAPK signaling pathway (Zhang et al. 2022). ABCA3 is unstable (Onnée et al. 2022).