Quaternary protein modeling to predict the function of DNA variation found in human mitochondrial cytochrome c oxidase
Autor: | Jon N. Rumbley, David G. Le Couteur, Martin Horan, Richard G. Melvin, J. William O. Ballard |
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Rok vydání: | 2013 |
Předmět: |
Male
Models Molecular Protein subunit DNA Mutational Analysis Mitochondrion Biology medicine.disease_cause DNA Mitochondrial Electron Transport Complex IV 03 medical and health sciences 0302 clinical medicine Databases Genetic Protein Interaction Mapping Genetics medicine Animals Humans Cytochrome c oxidase Protein Structure Quaternary Genetics (clinical) Aged 030304 developmental biology Aged 80 and over 0303 health sciences Oxidase test Mutation Protein structure prediction Mitochondria Amino Acid Substitution biology.protein Cattle 030217 neurology & neurosurgery Function (biology) |
Zdroj: | Journal of Human Genetics. 58:127-134 |
ISSN: | 1435-232X 1434-5161 |
DOI: | 10.1038/jhg.2012.144 |
Popis: | Cytochrome c oxidase (COX) of the electron transport system is thought to be the rate-limiting step in cellular respiration and is found mutated in numerous human pathologies. Here, we employ quaternary three-dimensional (3-D) modeling to construct a model for human COX. The model was used to predict the functional consequences of amino-acid mutations based on phylogenetic conservation of amino acids together with volume and/or steric perturbations, participation in subunit-subunit interfaces and non-covalent energy loss or incompatibilities. These metrics were combined and interpreted for potential functional impact. A notable strength of the 3-D model is that it can interpret and predict the structural consequences of amino-acid variation in all 13 protein subunits. Importantly, the influence of compensatory changes can also be modeled. We examine mutations listed in the human mutation database Mitomap, and in 100 older men, and compare the results from the 3-D model against the automated MutPred web application tool. In combination, these comparisons suggest that the 3-D model predicts more functionally significant mutations than does MutPred. We conclude that the model has useful functional prediction capability but may need modification as functional data on specific mutations becomes known. |
Databáze: | OpenAIRE |
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