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Structural basis of mitochondrial dysfunction in response to cytochrome c phosphorylation at tyrosine 48

AuthorsMoreno-Beltrán, Blas ; Guerra-Castellano, Alejandra ; Díaz-Quintana, Antonio; Conte, Rebecca del; García-Mauriño, Sofía M.; Díaz-Moreno, Sofía; González-Arzola, Katiuska ; Santos-Ocaña, Carlos ; Velázquez-Campoy, Adrián; Rosa, Miguel A. de la ; Turano, Paola; Díaz-Moreno, Irene
Issue Date2017
PublisherNational Academy of Sciences (U.S.)
CitationProceedings of the National Academy of Sciences 114(15): E3041–E3050 (2017)
AbstractRegulation 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.
Publisher version (URL)htpp://dx.doi.org/10.1073/pnas.1618008114
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