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Abstract
Regulation of mitochondrial 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.
Highlights
Regulation of mitochondrial 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
To understand how phosphorylation affects the structure of human cytochrome c (Cc), we tackled the challenge of fully characterizing the phosphomimetic mutant Y48pCMF Cc in its reduced form, which is the redox state of Cc donating electrons to cytochrome c oxidase (CcO) in homeostasis and is essential for its apoptotic activity, because Cc becomes highly reduced upon its release from the mitochondria to the cytosol [32]
A recent spectroscopic analysis of Y48pCMF Cc showed a singular shift of the typical alkaline transition pKa to physiological pH values [31], as is the case with the Y48E Cc mutant [26, 27]
Summary
Regulation of mitochondrial 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. We used biochemical assays to show that the Y48pCMF mutation impairs Cc channeling between cytochrome bc1 (Cbc1) and CcO, enhances peroxidase activity, and induces an antiapoptotic function of Cc. Phosphorylation of Tyr48 Induces Local Structural Changes in Cytochrome c.
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