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Comparison of the structural dynamic and mitochondrial electron-transfer properties of the proapoptotic human cytochrome c variants, G41S, Y48H and A51V
- Source :
- Journal of Inorganic Biochemistry. 203:110924
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Mitochondrial cytochrome c is associated with electron transfer in the respiratory chain and in apoptosis. Four cytochrome c variants have been identified in families that suffer from mild autosomal dominant thrombocytopenia, a platelet disorder associated with increased apoptosis. Three out of the four substitutions, G41S, Y48H and A51V are located on the 40–57 Ω-loop. The G41S and Y48H variants perturb key physicochemical and dynamic properties that result in enhanced functional features associated with apoptotic activity. Herein we characterise the ferric A51V variant. We show by chemical denaturation that this variant causes the native state to be destabilized. Through azide binding kinetics, the population of a pentacoordinate heme form, whereby the Met80 axial ligand is dissociated, is estimated to be of equal magnitude to that found in the Y48H variant. This pentacoordinate form gives rise to peroxidase activity, which despite the similar pentacoordinate population of the A51V variant to that of the Y48H variant, the peroxidase activity of the A51V variant is suppressed. Far-UV circular dichroism spectroscopy and pH jump studies, suggest that a combination of structural and dynamic features in addition to the population of the pentacoordinate form regulate peroxidase activity in these disease variants. Additionally, the steady-state ratio of ferric/ferrous cytochrome c when in turnover with cytochrome c oxidase has been investigated for all 40–57 Ω-loop variants. These studies show that the lower pKa of the alkaline transition for the disease causing variants increases the ferric to ferrous heme ratio, indicating a possible influence on respiration in vivo.
- Subjects :
- Circular dichroism
Iron
Platelet disorder
Cell Respiration
Population
Mutation, Missense
Respiratory chain
Apoptosis
Electrons
Heme
Molecular Dynamics Simulation
010402 general chemistry
01 natural sciences
Biochemistry
Inorganic Chemistry
chemistry.chemical_compound
Animals
Humans
Cytochrome c oxidase
education
Peroxidase
education.field_of_study
biology
010405 organic chemistry
Cytochrome c
Cytochromes c
Thrombocytopenia
0104 chemical sciences
chemistry
biology.protein
Biophysics
Cattle
Subjects
Details
- ISSN :
- 01620134
- Volume :
- 203
- Database :
- OpenAIRE
- Journal :
- Journal of Inorganic Biochemistry
- Accession number :
- edsair.doi.dedup.....5845ff33da5537788d30bfa4fc17be4c