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Proc Natl Acad Sci U S A. 2017 Apr 11;114(15):E3041-E3050. doi: 10.1073/pnas.1618008114. Epub 2017 Mar 27.

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

Author information

1
Instituto de Investigaciones Químicas, cicCartuja, Universidad de Sevilla-Spanish National Scientific Council (CSIC), 41092 Seville, Spain.
2
Magnetic Resonance Center (CERM), Department of Chemistry, University of Florence, 50019 Sesto Fiorentino, Florence, Italy.
3
Diamond Light Source, Didcot, Oxfordshire OX11 0DE, United Kingdom.
4
Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC, 41013 Seville, Spain.
5
Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit BIFI-Instituto Química-Física Rocasolano (CSIC), Universidad de Zaragoza, 50018 Zaragoza, Spain.
6
Instituto de Investigaciones Químicas, cicCartuja, Universidad de Sevilla-Spanish National Scientific Council (CSIC), 41092 Seville, Spain; idiazmoreno@us.es.

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.

KEYWORDS:

cytochrome c; mitochondrial dysfunction; nuclear magnetic resonance; phosphorylation; respiratory supercomplexes

PMID:
28348229
PMCID:
PMC5393209
DOI:
10.1073/pnas.1618008114
[Indexed for MEDLINE]
Free PMC Article

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