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Cytochrome c speeds up caspase cascade activation by blocking 14-3-3?-dependent Apaf-1 inhibition.


ABSTRACT: Apoptosis is a highly regulated form of programmed cell death, essential to the development and homeostasis of multicellular organisms. Cytochrome c is a central figure in the activation of the apoptotic intrinsic pathway, thereby activating the caspase cascade through its interaction with Apaf-1. Our recent studies have revealed 14-3-3? (a direct inhibitor of Apaf-1) as a cytosolic cytochrome c target. Here we explore the cytochrome c / 14-3-3? interaction and show the ability of cytochrome c to block 14-3-3?-mediated Apaf-1 inhibition, thereby unveiling a novel function for cytochrome c as an indirect activator of caspase-9/3. We have used calorimetry, NMR spectroscopy, site mutagenesis and computational calculations to provide an insight into the structural features of the cytochrome c / 14-3-3? complex. Overall, these findings suggest an additional cytochrome c-mediated mechanism to modulate apoptosome formation, shedding light onto the rigorous apoptotic regulation network.

SUBMITTER: Elena-Real CA 

PROVIDER: S-EPMC5840378 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Cytochrome c speeds up caspase cascade activation by blocking 14-3-3ε-dependent Apaf-1 inhibition.

Elena-Real Carlos A CA   Díaz-Quintana Antonio A   González-Arzola Katiuska K   Velázquez-Campoy Adrián A   Orzáez Mar M   López-Rivas Abelardo A   Gil-Caballero Sergio S   De la Rosa Miguel Á MÁ   Díaz-Moreno Irene I  

Cell death & disease 20180306 3


Apoptosis is a highly regulated form of programmed cell death, essential to the development and homeostasis of multicellular organisms. Cytochrome c is a central figure in the activation of the apoptotic intrinsic pathway, thereby activating the caspase cascade through its interaction with Apaf-1. Our recent studies have revealed 14-3-3ε (a direct inhibitor of Apaf-1) as a cytosolic cytochrome c target. Here we explore the cytochrome c / 14-3-3ε interaction and show the ability of cytochrome c t  ...[more]

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