Mitochondrial disease-related mutations at the cytochrome b-iron-sulfur protein (ISP) interface : molecular effects on the large-scale motion of ISP and superoxide generation studied in Rhodobacter capsulatus cytochrome bc_{1}
| Autor: | Robert Ekiert, Arkadiusz Borek, Patryk Kuleta, Justyna Czernek, Artur Osyczka |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Iron-Sulfur Proteins
Models Molecular WT wild type 0301 basic medicine EPR electron paramagnetic resonance Cytochrome domain movement Gene Expression Biochemistry Protein Structure Secondary Rhodobacter capsulatus Electron Transport Complex III DBH2 2 3-dimethoxy-5-methyl-6-decyl-1 4-benzohydroquinone Cytochrome C1 Superoxides cytochrome bc_{1} reactive oxygen species mitochondrial diseases biology Cytochrome bc1 Cytochrome b Chemistry Mitochondrial complex III Cytochrome c ISP iron–sulfur protein Cytochrome P450 reductase electron transfer Mitochondria ISP-HD head domain of ISP Mitochondrial Membranes Oxidation-Reduction Stereochemistry ETC electron transport chain Biophysics Mitochondrial diseases Article Electron Transport Electron transfer 03 medical and health sciences ROS reactive oxygen species SOD superoxide dismutase Humans Cytochrome c oxidase Protein Interaction Domains and Motifs 030102 biochemistry & molecular biology CW continuous wave Cell Biology Kinetics Protein Subunits 030104 developmental biology mitochondrial complex III Coenzyme Q – cytochrome c reductase Mutation biology.protein Domain movement Reactive oxygen species |
| Zdroj: | Biochimica et Biophysica Acta |
| Popis: | One of the important elements of operation of cytochrome bc1 (mitochondrial respiratory complex III) is a large scale movement of the head domain of iron–sulfur protein (ISP-HD), which connects the quinol oxidation site (Qo) located within the cytochrome b, with the outermost heme c1 of cytochrome c1. Several mitochondrial disease-related mutations in cytochrome b are located at the cytochrome b-ISP-HD interface, thus their molecular effects can be associated with altered motion of ISP-HD. Using purple bacterial model, we recently showed that one of such mutations — G167P shifts the equilibrium position of ISP-HD towards positions remote from the Qo site as compared to the native enzyme [Borek et al., J. Biol. Chem. 290 (2015) 23781-23792]. This resulted in the enhanced propensity of the mutant to generate reactive oxygen species (ROS) which was explained on the basis of the model evoking “semireverse” electron transfer from heme bL to quinone. Here we examine another mutation from that group — G332D (G290D in human), finding that it also shifts the equilibrium position of ISP-HD in the same direction, however displays less of the enhancement in ROS production. We provide spectroscopic indication that G332D might affect the electrostatics of interaction between cytochrome b and ISP-HD. This effect, in light of the measured enzymatic activities and electron transfer rates, appears to be less severe than structural distortion caused by proline in G167P mutant. Comparative analysis of the effects of G332D and G167P confirms a general prediction that mutations located at the cytochrome b-ISP-HD interface influence the motion of ISP-HD and indicates that “pushing” ISP-HD away from the Qo site is the most likely outcome of this influence. It can also be predicted that an increase in ROS production associated with the “pushing” effect is quite sensitive to overall severity of this change with more active mutants being generally more protected against elevated ROS. This article is part of a Special Issue entitled ‘EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2–6, 2016’, edited by Prof. Paolo Bernardi. Highlights • Several mitochondrial mutations are located at the cytochrome b-ISP interface. • We compare molecular effects of two mutations from that group. • In both mutants ISP is shifted away from the Qo catalytic site. • This effect is generally associated with increased ROS production. • More active mutants are more protected against elevated ROS. |
| Databáze: | OpenAIRE |
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