Abstract
ABCA3 is a crucial protein of pulmonary surfactant biosynthesis, associated with recessive pulmonary disorders such as neonatal respiratory distress and interstitial lung disease. Mutations are mostly private, and accurate interpretation of variants is mandatory for genetic counseling and patient care. We used 3D structure information to complete the set of available bioinformatics tools dedicated to medical decision. Using the experimental structure of human ABCA4, we modeled 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. We focused and mapped known pathogenic missense variants on this model. We pinpointed amino-acids within the NBDs, the RDs and within the interfaces between the NBDs and TMDs intracellular helices (IHs), which are predicted to play key roles in the structure and/or the function of the ABCA3 transporter. This theoretical study also highlighted the possible impact of ABCA3 variants in the cytosolic part of the protein, such as the well-known p.Glu292Val and p.Arg288Lys variants.
Highlights
The pulmonary surfactant is a tensio-active film covering the air-liquid interface of the alveoli which prevents alveolar collapses at the end of expiration and has a protective role against pathogens [1]
This complex lipido-proteic mixture rich in phospholipids is synthetized by the alveolar type II cells and stored in lamellar bodies (LB), specific organelles that allow the transport of lipids and hydrophobic surfactant proteins B and C toward the air-liquid interface where surfactant is assembled into a stable film
No defined hotspot of mutations can be pinpointed in the ABCA3 gene as they are distributed throughout the protein
Summary
The pulmonary surfactant is a tensio-active film covering the air-liquid interface of the alveoli which prevents alveolar collapses at the end of expiration and has a protective role against pathogens [1]. A recent classification based on TMD folds defined ABCA proteins as type V ABC transporters (Figure S1) [9]. Their TMDs fold discretely, without swapping, and are devoid of long intracellular loops (ICLs), present in type IV exporters, but include four intracellular helices (IHs), before TM1/TM7 (IH1 and IH3) and between TM2TM3/TM8-TM9 (IH2-IH4) and two large extracellular domains (ECDs), the length of which largely vary among the different members of the ABCA family. Kinting and colleagues proposed a model of the TMDs-NBDs assembly based on the experimental 3D structure of human ABCA1 in which the NBDs are observed in an ATP-free conformation [10], with a spatial separation of the motifs constituting the ATP-binding sites [14]. We illuminate the possible impact of amino-acids that are currently not involved in pathology but are important for the structure and/or function of the protein
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