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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8508924 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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