Moreno-Beltran B, Guerra-Castellano A, Diaz-Quintana A, Del Conte R, Garcia-Maurino SM, Diaz-Moreno S, Gonzalez-Arzola K, Santos-Ocana C, Velazquez-Campoy A, De la Rosa MA, Diaz-Moreno I.
Proc Natl Acad Sci U S A 2017 Apr.; 114: E3041.
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.
PubMed: 28348229. Doi: 10.1073/pnas.1618008114. free PMC article