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

Moreno-Beltrán, B. ; Guerra-Castellano, A. ; Díaz-Quintana, A. ; Conte, R.D. ; García-Mauriño, S.M. ; Díaz-Moreno, S. ; González-Arzola, K. ; Santos-Ocaña, C. ; Velázquez-Campoy, A. (Universidad de Zaragoza) ; De la Rosa, M.A. ; Turano, P. ; Díaz-Moreno, I.

Resumen: 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.

Idioma: Inglés

DOI: 10.1073/pnas.1618008114

Año: 2017

Publicado en: Proceedings of the National Academy of Sciences 114, 15 (2017), E3041-E3050
ISSN: 0027-8424

Factor impacto JCR: 9.504 (2017)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 5 / 64 = 0.078 (2017) - Q1 - T1

Factor impacto SCIMAGO: 6.092 - Multidisciplinary (Q1)

Financiación: info:eu-repo/grantAgreement/EC/FP7/261863/EU/NMR for Structural Biology/BIO-NMR
Financiación: info:eu-repo/grantAgreement/EC/FP7/312284/EU/Coordinated Access to Lightsources to Promote Standards and Optimization/CALIPSO
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2015-19451-BMC
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2015-71017-P-BMC

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)