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12 results on '"Moreno-Beltrán, Blas"'

6. Structural basis of mitochondrial dysfunction in response to cytochromecphosphorylation at tyrosine 48

Author

Moreno-Beltrán, Blas, Guerra-Castellano, Alejandra, Díaz-Quintana, Antonio, Del Conte, Rebecca, García-Mauriño, Sofía M., Díaz-Moreno, Sofía, González-Arzola, Katiuska, Santos-Ocaña, Carlos, Velázquez-Campoy, Adrián, De la Rosa, Miguel A., Turano, Paola, and Díaz-Moreno, Irene

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-methylL-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

Published
2017

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

Author

Ministerio de Economía y Competitividad (España), European Commission, Fundación Ramón Areces, Junta de Andalucía, Consejo Superior de Investigaciones Científicas (España), Ministerio de Educación (España), Moreno-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, Ministerio de Economía y Competitividad (España), European Commission, Fundación Ramón Areces, Junta de Andalucía, Consejo Superior de Investigaciones Científicas (España), Ministerio de Educación (España), Moreno-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, and Díaz-Moreno, Irene

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.

Published
2017

9. Mimicking Tyrosine Phosphorylation in Human Cytochrome cby the Evolved tRNA Synthetase Technique

Author

Guerra-Castellano, Alejandra, primary, Díaz-Quintana, Antonio, additional, Moreno-Beltrán, Blas, additional, López-Prados, Javier, additional, Nieto, Pedro M., additional, Meister, Wiebke, additional, Staffa, Jana, additional, Teixeira, Miguel, additional, Hildebrandt, Peter, additional, De la Rosa, Miguel A., additional, and Díaz-Moreno, Irene, additional

Published
2015
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12. Mimicking Tyrosine Phosphorylation in Human Cytochrome c by the Evolved tRNA Synthetase Technique.

Author

Guerra ‐ Castellano, Alejandra, Díaz ‐ Quintana, Antonio, Moreno ‐ Beltrán, Blas, López ‐ Prados, Javier, Nieto, Pedro M., Meister, Wiebke, Staffa, Jana, Teixeira, Miguel, Hildebrandt, Peter, De la Rosa, Miguel A., and Díaz ‐ Moreno, Irene

Subjects
TYROSINE, PHOSPHORYLATION, CYTOCHROME c, CHEMICAL reactions, AMINO acids
Abstract

Phosphorylation of tyrosine 48 of cytochrome c is related to a wide range of human diseases due to the pleiotropic role of the heme-protein in cell life and death. However, the structural conformation and physicochemical properties of phosphorylated cytochrome c are difficult to study as its yield from cell extracts is very low and its kinase remains unknown. Herein, we report a high-yielding synthesis of a close mimic of phosphorylated cytochrome c, developed by optimization of the synthesis of the non-canonical amino acid p-carboxymethyl- L-phenylalanine ( pCMF) and its efficient site-specific incorporation at position 48. It is noteworthy that the Y48 pCMF mutation significantly destabilizes the FeMet bond in the ferric form of cytochrome c, thereby lowering the p Ka value for the alkaline transition of the heme-protein. This finding reveals the differential ability of the phosphomimic protein to drive certain events. This modified cytochrome c might be an important tool to investigate the role of the natural protein following phosphorylation. [ABSTRACT FROM AUTHOR]

Published
2015
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