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Nitration of tyrosine 74 prevents human cytochrome c to play a key role in apoptosis signaling by blocking caspase-9 activation

IBVF/IIQ

José M. García-Heredia, Irene Díaz-Moreno, Pedro M. Nieto, Mar Orzáez, Stella Kocanis, Miguel Teixeira, Enrique Pérez-Payá, Antonio Díaz-Quintana, Miguel A. De la Rosa Biochimica et Biophysica Acta 2010, Vol. 1797, 981–993

Tyrosine nitration is one of the most common post-transcriptional modifications of proteins, so affecting their structure and function. Human cytochrome c, with five tyrosine residues, is an excellent case study as it is a well-known protein playing a double physiological role in different cell compartments. On one hand, it acts as electron carrier within the mitochondrial respiratory electron transport chain, and on the other hand, it serves as a cytoplasmic apoptosis-triggering agent. In a previous paper, we reported the effect of nitration on physicochemical and kinetic features of monotyrosine cytochrome c mutants. Here, we analyse the nitration-induced changes in secondary structure, thermal stability, haem environment, alkaline transition and molecular dynamics of three of such monotyrosine mutants – the so-called h-Y67, h-Y74 and h-Y97 –which have four tyrosines replaced by phenylalanines and just keep the tyrosine residue giving its number to the mutant. The resulting data, along with the functional analyses of the three mutants, indicate that it is the specific nitration of solvent-exposed Tyr74 which enhances the peroxidase activity and blocks the ability of Cc to activate caspase-9, thereby preventing the apoptosis signaling pathway.

(Lea la entrevista con José Manuel García-Heredia acerca de este artículo)

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