A polymorphic position in electron transfer flavoprotein modulates kinetic stability as evidenced by thermal stress |
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Authors: | Henriques Bárbara J Fisher Mark T Bross Peter Gomes Cláudio M |
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Affiliation: | aInstituto Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal;bDepartment Biochemistry and Molecular Biology, University Kansas Medical Center, KS, USA;cResearch Unit for Molecular Medicine, Aarhus University Hospital, Skejby, Aarhus, Denmark |
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Abstract: | The electron transfer flavoprotein (ETF) is a hub interacting with at least 11 mitochondrial flavoenzymes and linking them to the respiratory chain. Here we report the effect of the ETFα-T/I171 polymorphism on protein conformation and kinetic stability under thermal stress. Although variants have comparable thermodynamic stabilities, kinetically their behavior is rather distinct as ETFα-T171 displays increased susceptibility to cofactor flavin adenine dinucleotide (FAD) loss and enhanced kinetics of inactivation during thermal stress. Mimicking a fever episode yields substantial activity loss. However, the presence of substoichiometric concentrations of GroEL is sufficient to act as an effective buffer against long-term thermal denaturation. Our investigations are compatible with the notion that the ETFα-T171 variant displays an altered conformational landscape that results in reduced protein function under thermal stress. |
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Keywords: | Abbreviations: ETF, electron transfer flavoprotein SAP&rsquo s, single amino acid polymorphisms FAD, flavin adenine dinucleotide AMP, adenosine 5&prime monophosphate MADD, multiple acyl-CoA dehydrogenase deficiency CD, circular dichroism Tm, midpoint transition temperature |
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