Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 15, Pages E3041-E3050Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1618008114
Keywords
cytochrome c; mitochondrial dysfunction; nuclear magnetic resonance; phosphorylation; respiratory supercomplexes
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Funding
- FRISBI [ANR-10-INSB-05-02]
- GRAL within the Grenoble Partnership for Structural Biology [ANR-10-LABX-49-01]
- Spanish Ministry of Economy and Competitiveness [BFU2015-71017-P/BMC, BFU2015-19451/BMC]
- European Union [Bio-NMR-00130, CALIPSO-312284]
- Ramon Areces Foundation
- Andalusian Government [BIO198]
- Spanish Ministry of Education [AP2009-4092]
- European Bio-NMR Project
- CSIC [JaePre-2011-01248]
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Regulation ofmitochondrial activity allows cells to adapt to changing conditions and to control oxidative stress, and its dysfunction can lead to hypoxia-dependent pathologies such as ischemia and cancer. Although cytochrome c phosphorylation-in particular, at tyrosine 48-is a key modulator of mitochondrial signaling, its action and molecular basis remain unknown. Here we mimic phosphorylation of cytochrome c by replacing tyrosine 48 with p-carboxy-methyl-L-phenylalanine (pCMF). The NMR structure of the resulting mutant reveals significant conformational shifts and enhanced dynamics around pCMF that could explain changes observed in its functionality: The phosphomimetic mutation impairs cytochrome c diffusion between respiratory complexes, enhances hemeprotein peroxidase and reactive oxygen species scavenging activities, and hinders caspase-dependent apoptosis. Our findings provide a framework to further investigate the modulation of mitochondrial activity by phosphorylated cytochrome c and to develop novel therapeutic approaches based on its prosurvival effects.
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