期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 19, 页码 -出版社
MDPI
DOI: 10.3390/ijms221910282
关键词
ABCA3; mutation; nucleotide-binding domain (NBD); regulatory domain (RD); 3D modeling
资金
- Institut National de la Sante et de la Recherche Medicale (INSERM), Universite Paris-Est Creteil
- Centre national de la recherche scientifique (CNRS)
ABCA3 protein plays a crucial role in pulmonary surfactant biosynthesis and is associated with recessive pulmonary disorders. Using 3D structure information, researchers modeled the protein and pinpointed known pathogenic missense variants, providing insights into the possible impact of these variants in the protein's structure and function.
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.
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