https://scholars.lib.ntu.edu.tw/handle/123456789/531423
標題: | Computational analysis of a novel mutation in ETFDH gene highlights its long-range effects on the FAD-binding motif | 作者: | Er T.-K. Chen C.-C. Liu Y.-Y. Chang H.-C. YIN-HSIU CHIEN Chang J.-G. Hwang J.-K. Jong Y.-J. |
公開日期: | 2011 | 卷: | 11 | 起(迄)頁: | 43 | 來源出版物: | BMC Structural Biology | 摘要: | Background: Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is an autosomal recessive disease caused by the defects in the mitochondrial electron transfer system and the metabolism of fatty acids. Recently, mutations in electron transfer flavoprotein dehydrogenase (ETFDH) gene, encoding electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) have been reported to be the major causes of riboflavin-responsive MADD. To date, no studies have been performed to explore the functional impact of these mutations or their mechanism of disrupting enzyme activity. Results: High resolution melting (HRM) analysis and sequencing of the entire ETFDH gene revealed a novel mutation (p.Phe128Ser) and the hotspot mutation (p.Ala84Thr) from a patient with MADD. According to the predicted 3D structure of ETF:QO, the two mutations are located within the flavin adenine dinucleotide (FAD) binding domain; however, the two residues do not have direct interactions with the FAD ligand. Using molecular dynamics (MD) simulations and normal mode analysis (NMA), we found that the p.Ala84Thr and p.Phe128Ser mutations are most likely to alter the protein structure near the FAD binding site as well as disrupt the stability of the FAD binding required for the activation of ETF:QO. Intriguingly, NMA revealed that several reported disease-causing mutations in the ETF:QO protein show highly correlated motions with the FAD-binding site. Conclusions: Based on the present findings, we conclude that the changes made to the amino acids in ETF:QO are likely to influence the FAD-binding stability. ? 2011 et al; licensee BioMed Central Ltd. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-80054735129&doi=10.1186%2f1472-6807-11-43&partnerID=40&md5=b7c6a65945e299a68b907e55aa51b2ba https://scholars.lib.ntu.edu.tw/handle/123456789/531423 |
ISSN: | 1472-6807 | DOI: | 10.1186/1472-6807-11-43 | SDG/關鍵字: | electron transfer flavoprotein dehydrogenase; flavine adenine nucleotide; oxidoreductase; ubiquinone derivative; ubiquinone oxidoreductase; unclassified drug; electron transferring flavoprotein; electron transferring flavoprotein dehydrogenase; electron-transferring-flavoprotein dehydrogenase; iron sulfur protein; oxidoreductase; article; binding site; case report; child; enzyme activity; female; gene mutation; gene sequence; high resolution melting analysis; human; molecular dynamics; multiple acyl CoA dehydrogenase deficiency; protein structure; school child; biology; chemistry; enzyme activation; genetics; metabolism; mutation; protein tertiary structure; Binding Sites; Child; Computational Biology; Electron-Transferring Flavoproteins; Enzyme Activation; Female; Flavin-Adenine Dinucleotide; Humans; Iron-Sulfur Proteins; Molecular Dynamics Simulation; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Mutation; Oxidoreductases Acting on CH-NH Group Donors; Protein Structure, Tertiary |
顯示於: | 醫學系 |
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