TY - JOUR
T1 - Quaternary protein modeling to predict the function of DNA variation found in human mitochondrial cytochrome c oxidase
AU - Horan, Martin Patrick
AU - Rumbley, Jon N.
AU - Melvin, Richard G.
AU - Le Couteur, David G.
AU - Ballard, J. William O.
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
KW - COX
KW - functional prediction
KW - mitochondria
KW - modeling
KW - mtDNA mutation
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U2 - 10.1038/jhg.2012.144
DO - 10.1038/jhg.2012.144
M3 - Article
C2 - 23303385
AN - SCOPUS:84875460972
SN - 1434-5161
VL - 58
SP - 127
EP - 134
JO - Journal of Human Genetics
JF - Journal of Human Genetics
IS - 3
ER -