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Open Access Highly Accessed Research article

Computational analysis of a novel mutation in ETFDH gene highlights its long-range effects on the FAD-binding motif

Tze-Kiong Er12, Chih-Chieh Chen3, Yen-Yi Liu3, Hui-Chiu Chang2, Yin-Hsiu Chien4, Jan-Gowth Chang167, Jenn-Kang Hwang3* and Yuh-Jyh Jong125*

Author Affiliations

1 Division of Molecular Diagnostics, Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., Kaohsiung, 80708, Taiwan

2 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., Kaohsiung, 80708, Taiwan

3 Institute of Bioinformatics and Systems Biology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 30068, Taiwan

4 Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, 8 Chung-Shan South Road, Taipei, 10041, Taiwan

5 Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., Kaohsiung, 80708, Taiwan

6 Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., Kaohsiung, 80708, Taiwan

7 Center for Excellence in Environmental Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., Kaohsiung, 80708, Taiwan

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BMC Structural Biology 2011, 11:43  doi:10.1186/1472-6807-11-43

Published: 21 October 2011

Abstract

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.