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

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. O...

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Autores principales: Elena-Real, Carlos A., Díaz-Quintana, Antonio, González-Arzola, Katiuska, Velázquez-Campoy, Adrián, Orzáez, Mar, López-Rivas, Abelardo, Gil-Caballero, Sergio, De la Rosa, Miguel Á., Díaz-Moreno, Irene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840378/
https://www.ncbi.nlm.nih.gov/pubmed/29511177
http://dx.doi.org/10.1038/s41419-018-0408-1
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author Elena-Real, Carlos A.
Díaz-Quintana, Antonio
González-Arzola, Katiuska
Velázquez-Campoy, Adrián
Orzáez, Mar
López-Rivas, Abelardo
Gil-Caballero, Sergio
De la Rosa, Miguel Á.
Díaz-Moreno, Irene
author_facet Elena-Real, Carlos A.
Díaz-Quintana, Antonio
González-Arzola, Katiuska
Velázquez-Campoy, Adrián
Orzáez, Mar
López-Rivas, Abelardo
Gil-Caballero, Sergio
De la Rosa, Miguel Á.
Díaz-Moreno, Irene
author_sort Elena-Real, Carlos A.
collection PubMed
description 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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spelling pubmed-58403782018-03-08 Cytochrome c speeds up caspase cascade activation by blocking 14-3-3ε-dependent Apaf-1 inhibition Elena-Real, Carlos A. Díaz-Quintana, Antonio González-Arzola, Katiuska Velázquez-Campoy, Adrián Orzáez, Mar López-Rivas, Abelardo Gil-Caballero, Sergio De la Rosa, Miguel Á. Díaz-Moreno, Irene Cell Death Dis Article 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. Nature Publishing Group UK 2018-03-06 /pmc/articles/PMC5840378/ /pubmed/29511177 http://dx.doi.org/10.1038/s41419-018-0408-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Elena-Real, Carlos A.
Díaz-Quintana, Antonio
González-Arzola, Katiuska
Velázquez-Campoy, Adrián
Orzáez, Mar
López-Rivas, Abelardo
Gil-Caballero, Sergio
De la Rosa, Miguel Á.
Díaz-Moreno, Irene
Cytochrome c speeds up caspase cascade activation by blocking 14-3-3ε-dependent Apaf-1 inhibition
title Cytochrome c speeds up caspase cascade activation by blocking 14-3-3ε-dependent Apaf-1 inhibition
title_full Cytochrome c speeds up caspase cascade activation by blocking 14-3-3ε-dependent Apaf-1 inhibition
title_fullStr Cytochrome c speeds up caspase cascade activation by blocking 14-3-3ε-dependent Apaf-1 inhibition
title_full_unstemmed Cytochrome c speeds up caspase cascade activation by blocking 14-3-3ε-dependent Apaf-1 inhibition
title_short Cytochrome c speeds up caspase cascade activation by blocking 14-3-3ε-dependent Apaf-1 inhibition
title_sort cytochrome c speeds up caspase cascade activation by blocking 14-3-3ε-dependent apaf-1 inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840378/
https://www.ncbi.nlm.nih.gov/pubmed/29511177
http://dx.doi.org/10.1038/s41419-018-0408-1
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