Metherell, LA;
Guerra-Assunção, JA;
Sternberg, MJ;
David, A;
(2016)
Three-Dimensional Model of Human Nicotinamide Nucleotide Transhydrogenase (NNT) and Sequence-Structure Analysis of its Disease-Causing Variations.
Human Mutation
, 37
(10)
pp. 1074-1084.
10.1002/humu.23046.
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Abstract
Defective mitochondrial proteins are emerging as major contributors to human disease. Nicotinamide nucleotide transhydrogenase (NNT), a widely expressed mitochondrial protein, has a crucial role in the defence against oxidative stress. NNT variations have recently been reported in patients with familial glucocorticoid deficiency (FGD) and in patients with heart failure. Moreover, knockout animal models suggest that NNT has a major role in diabetes mellitus and obesity. In this study, we used experimental structures of bacterial transhydrogenases to generate a structural model of human NNT (H-NNT). Structure-based analysis allowed the identification of H-NNT residues forming the NAD binding site, the proton canal and the large interaction site on the H-NNT dimer. In addition, we were able to identify key motifs that allow conformational changes adopted by domain III in relation to its functional status, such as the flexible linker between domains II and III and the salt bridge formed by H-NNT Arg882 and Asp830. Moreover, integration of sequence and structure data allowed us to study the structural and functional effect of deleterious amino acid substitutions causing FGD and left ventricular non-compaction cardiomyopathy. In conclusion, interpretation of the function-structure relationship of H-NNT contributes to our understanding of mitochondrial disorders.
Type: | Article |
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Title: | Three-Dimensional Model of Human Nicotinamide Nucleotide Transhydrogenase (NNT) and Sequence-Structure Analysis of its Disease-Causing Variations |
Location: | United States |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1002/humu.23046 |
Publisher version: | http://dx.doi.org/10.1002/humu.23046 |
Language: | English |
Additional information: | Copyright © 2016 The Authors. Human Mutation published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | NNT, familial glucocorticoid deficiency, mitochondrial disease, protein structure, variations |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
URI: | https://discovery.ucl.ac.uk/id/eprint/1507844 |
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