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Cell Death Dis. 2018 Mar 6;9(3):365. doi: 10.1038/s41419-018-0408-1.

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

Author information

1
Instituto de Investigaciones Químicas (IIQ) - Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla - Consejo Superior de Investigaciones Científicas (CSIC), Sevilla, Spain.
2
Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit IQFR-CSIC-BIFI, Universidad de Zaragoza, Zaragoza, Spain.
3
Centro de Investigación Príncipe Felipe, Valencia, Spain.
4
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Sevilla, Spain.
5
Instituto de Investigaciones Químicas (IIQ) - Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla - Consejo Superior de Investigaciones Científicas (CSIC), Sevilla, Spain. marosa@us.es.
6
Instituto de Investigaciones Químicas (IIQ) - Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla - Consejo Superior de Investigaciones Científicas (CSIC), Sevilla, Spain. idiazmoreno@us.es.

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 14-3-3ε (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 to block 14-3-3ε-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 / 14-3-3ε complex. Overall, these findings suggest an additional cytochrome c-mediated mechanism to modulate apoptosome formation, shedding light onto the rigorous apoptotic regulation network.

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