期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：15
页码：E3041-E3050
DOI：10.1073/pnas.1618008114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 ( p CMF). The NMR structure of the resulting mutant reveals significant conformational shifts and enhanced dynamics around p CMF 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.
关键词：cytochrome c ; mitochondrial dysfunction ; nuclear magnetic resonance ; phosphorylation ; respiratory supercomplexes
