Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase

Detalhes bibliográficos
Autor(a) principal: Madeira, Catarina A.
Data de Publicação: 2023
Outros Autores: Anselmo, Carolina, Costa, João M., Bonito, Cátia A., Ferreira, Ricardo J., Santos, Daniel J.V.A., Wanders, Ronald J., Vicente, João B., Ventura, Fátima V., Leandro, Paula
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10362/158646
Resumo: Funding Information: This work was supported by FEDER and Fundação para a Ciência e a Tecnologia , I. P. through iMed.ULisboa (Projects UIDB/04138/2020 and UIDP/04138/2020 ), iNOVA4Health ( UIDB/04462/2020 , UIDP/04462/2020 ) and LS4FUTURE Associated Laboratory ( LA/P/0087/2020 ) and research project PTDC/BIA-BQM/29570/2017 . Publisher Copyright: © 2023 The Author(s)
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spelling Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenaseDisease-causing mutationsElectron transferring flavoproteinFlavin adenine dinucleotideInborn metabolic disordersMedium chain acyl-CoA dehydrogenase deficiencyProtein misfoldingMolecular MedicineMolecular BiologyFunding Information: This work was supported by FEDER and Fundação para a Ciência e a Tecnologia , I. P. through iMed.ULisboa (Projects UIDB/04138/2020 and UIDP/04138/2020 ), iNOVA4Health ( UIDB/04462/2020 , UIDP/04462/2020 ) and LS4FUTURE Associated Laboratory ( LA/P/0087/2020 ) and research project PTDC/BIA-BQM/29570/2017 . Publisher Copyright: © 2023 The Author(s)Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is associated with ACADM gene mutations, leading to an impaired function and/or structure of MCAD. Importantly, after import into the mitochondria, MCAD must incorporate a molecule of flavin adenine dinucleotide (FAD) per subunit and assemble into tetramers. However, the effect of MCAD amino acid substitutions on FAD incorporation has not been investigated. Herein, the commonest MCAD variant (p.K304E) and 11 additional rare variants (p.Y48C, p.R55G, p.A88P, p.Y133C, p.A140T, p.D143V, p.G224R, p.L238F, p.V264I, p.Y372N, and p.G377V) were functionally and structurally characterized. Half of the studied variants presented a FAD content <65 % compared to the wild-type. Most of them were recovered as tetramers, except the p.Y372N (mainly as dimers). No correlation was found between the levels of tetramers and FAD content. However, a correlation between FAD content and the cofactor's affinity, proteolytic stability, thermostability, and thermal inactivation was established. We showed that the studied amino acid changes in MCAD may alter the substrate chain-length dependence and the interaction with electron-transferring-flavoprotein (ETF) necessary for a proper functioning electron transfer thus adding additional layers of complexity to the pathological effect of ACADM missense mutations. Although the majority of the variant MCADs presented an impaired capacity to retain FAD during their synthesis, some of them were structurally rescued by cofactor supplementation, suggesting that in the mitochondrial environment the levels and activity of those variants may be dependent of FAD's availability thus contributing for the heterogeneity of the MCADD phenotype found in patients presenting the same genotype.Instituto de Tecnologia Química e Biológica António Xavier (ITQB)RUNMadeira, Catarina A.Anselmo, CarolinaCosta, João M.Bonito, Cátia A.Ferreira, Ricardo J.Santos, Daniel J.V.A.Wanders, Ronald J.Vicente, João B.Ventura, Fátima V.Leandro, Paula2023-10-03T22:18:42Z2023-102023-10-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/158646eng0925-4439PURE: 72614789https://doi.org/10.1016/j.bbadis.2023.166766info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T05:41:11Zoai:run.unl.pt:10362/158646Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:57:14.781491Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase
title Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase
spellingShingle Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase
Madeira, Catarina A.
Disease-causing mutations
Electron transferring flavoprotein
Flavin adenine dinucleotide
Inborn metabolic disorders
Medium chain acyl-CoA dehydrogenase deficiency
Protein misfolding
Molecular Medicine
Molecular Biology
title_short Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase
title_full Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase
title_fullStr Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase
title_full_unstemmed Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase
title_sort Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase
author Madeira, Catarina A.
author_facet Madeira, Catarina A.
Anselmo, Carolina
Costa, João M.
Bonito, Cátia A.
Ferreira, Ricardo J.
Santos, Daniel J.V.A.
Wanders, Ronald J.
Vicente, João B.
Ventura, Fátima V.
Leandro, Paula
author_role author
author2 Anselmo, Carolina
Costa, João M.
Bonito, Cátia A.
Ferreira, Ricardo J.
Santos, Daniel J.V.A.
Wanders, Ronald J.
Vicente, João B.
Ventura, Fátima V.
Leandro, Paula
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Tecnologia Química e Biológica António Xavier (ITQB)
RUN
dc.contributor.author.fl_str_mv Madeira, Catarina A.
Anselmo, Carolina
Costa, João M.
Bonito, Cátia A.
Ferreira, Ricardo J.
Santos, Daniel J.V.A.
Wanders, Ronald J.
Vicente, João B.
Ventura, Fátima V.
Leandro, Paula
dc.subject.por.fl_str_mv Disease-causing mutations
Electron transferring flavoprotein
Flavin adenine dinucleotide
Inborn metabolic disorders
Medium chain acyl-CoA dehydrogenase deficiency
Protein misfolding
Molecular Medicine
Molecular Biology
topic Disease-causing mutations
Electron transferring flavoprotein
Flavin adenine dinucleotide
Inborn metabolic disorders
Medium chain acyl-CoA dehydrogenase deficiency
Protein misfolding
Molecular Medicine
Molecular Biology
description Funding Information: This work was supported by FEDER and Fundação para a Ciência e a Tecnologia , I. P. through iMed.ULisboa (Projects UIDB/04138/2020 and UIDP/04138/2020 ), iNOVA4Health ( UIDB/04462/2020 , UIDP/04462/2020 ) and LS4FUTURE Associated Laboratory ( LA/P/0087/2020 ) and research project PTDC/BIA-BQM/29570/2017 . Publisher Copyright: © 2023 The Author(s)
publishDate 2023
dc.date.none.fl_str_mv 2023-10-03T22:18:42Z
2023-10
2023-10-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10362/158646
url http://hdl.handle.net/10362/158646
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 0925-4439
PURE: 72614789
https://doi.org/10.1016/j.bbadis.2023.166766
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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