Reference

Proc Natl Acad Sci USA (2018). doi: 10.1073/pnas.1806833115. Imagen revista

Authors

Alejandra Guerra-Castellano, Antonio Díaz-Quintana, Gonzalo Pérez-Mejías, Carlos A. Elena-Real, Katiuska González-Arzola, Sofía M. García-Mauriño, Miguel A. De la Rosa, and Irene Díaz-Moreno.

Abstract

Respiratory cytochrome c has been found to be phosphorylated at tyrosine 97 in the postischemic brain upon neuroprotective insulin treatment, but how such posttranslational modification affects mitochondrial metabolism is unclear. Here, we report the structural features and functional behavior of a phosphomimetic cytochrome c mutant, which was generated by site-specific incorporation at position 97 of p-carboxymethyl-L-phenylalanine using the evolved tRNA synthetase method. We found that the point mutation does not alter the overall folding and heme environment of cytochrome c, but significantly affects the entire oxidative phosphorylation process. In fact, the electron donation rate of the mutant heme protein to cytochrome c oxidase, or complex IV, within respiratory supercomplexes was higher than that of the wild-type species, in agreement with the observed decrease in reactive oxygen species production. Direct contact of cytochrome c with the respiratory supercomplex factor HIGD1A (hypoxia-inducible domain family member 1A) is reported here, with the mutant heme protein exhibiting a lower affinity than the wild-type species. Interestingly, phosphomimetic cytochrome c also exhibited a lower caspase-3 activation activity. Altogether, these findings yield a better understanding of the molecular basis for mitochondrial metabolism in acute diseases, such as brain ischemia, and thus could allow the use of phosphomimetic cytochrome c as a neuroprotector with therapeutic applications.

 

Description

El presente trabajo describe como la disminución en la muerte neuronal post-isquemia se debe a cambios sustanciales en el metabolismo mitocondrial (incluida la menor producción de especies reactivas de oxígeno) y la homeostasis celular inducida por la fosforilación del citocromo c. Estos hallazgos, por lo tanto, proporcionan las bases para comprender el mecanismo molecular y el uso potencial de especies fosfomiméticas de citocromo c, lo que ofrece nuevas oportunidades para desarrollar terapias más eficientes contra inducidas por hipoxia aguda.

 

 

Imagen Grupo Biointeractomica

 

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo Biointeractómica centra sus esfuerzos en el análisis estructural y funcional de las macromoléculas biológicas, así como de sus interacciones, que son claves en una amplia variedad de procesos celulares. También profundiza en el estudio de las modificaciones post-traduccionales de las proteínas y, en particular, del citocromo c, proteína que juega un doble papel en la vida y muerte celular.

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