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Structure-Based Understanding of ABCA3 Variants

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 ca...

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Detalles Bibliográficos
Autores principales: Onnée, Marion, Fanen, Pascale, Callebaut, Isabelle, de Becdelièvre, Alix
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508924/
https://www.ncbi.nlm.nih.gov/pubmed/34638622
http://dx.doi.org/10.3390/ijms221910282
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author Onnée, Marion
Fanen, Pascale
Callebaut, Isabelle
de Becdelièvre, Alix
author_facet Onnée, Marion
Fanen, Pascale
Callebaut, Isabelle
de Becdelièvre, Alix
author_sort Onnée, Marion
collection PubMed
description 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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spelling pubmed-85089242021-10-13 Structure-Based Understanding of ABCA3 Variants Onnée, Marion Fanen, Pascale Callebaut, Isabelle de Becdelièvre, Alix Int J Mol Sci Article 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. MDPI 2021-09-24 /pmc/articles/PMC8508924/ /pubmed/34638622 http://dx.doi.org/10.3390/ijms221910282 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Onnée, Marion
Fanen, Pascale
Callebaut, Isabelle
de Becdelièvre, Alix
Structure-Based Understanding of ABCA3 Variants
title Structure-Based Understanding of ABCA3 Variants
title_full Structure-Based Understanding of ABCA3 Variants
title_fullStr Structure-Based Understanding of ABCA3 Variants
title_full_unstemmed Structure-Based Understanding of ABCA3 Variants
title_short Structure-Based Understanding of ABCA3 Variants
title_sort structure-based understanding of abca3 variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508924/
https://www.ncbi.nlm.nih.gov/pubmed/34638622
http://dx.doi.org/10.3390/ijms221910282
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