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Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis

The BCL-2 family protein BAK is a key regulator of mitochondrial apoptosis. BAK activation first involves N-terminal conformational changes that lead to the transient exposure of the BAK BH3 domain that then inserts into a hydrophobic groove on another BAK molecule to form symmetric dimers. We showe...

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Detalles Bibliográficos
Autores principales: Azad, Abul, Fox, Joanna, Leverrier, Sabrina, Storey, Alan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506661/
https://www.ncbi.nlm.nih.gov/pubmed/23189150
http://dx.doi.org/10.1371/journal.pone.0049601
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author Azad, Abul
Fox, Joanna
Leverrier, Sabrina
Storey, Alan
author_facet Azad, Abul
Fox, Joanna
Leverrier, Sabrina
Storey, Alan
author_sort Azad, Abul
collection PubMed
description The BCL-2 family protein BAK is a key regulator of mitochondrial apoptosis. BAK activation first involves N-terminal conformational changes that lead to the transient exposure of the BAK BH3 domain that then inserts into a hydrophobic groove on another BAK molecule to form symmetric dimers. We showed recently that post-translational modifications are important in the regulation of BAK conformational change and multimerization, with dephosphorylation at tyrosine 108 constituting an initial step in the BAK activation process. We now show that dephosphorylation of serine 117 (S117), located in the BAK hydrophobic groove, is also critical for BAK activation to proceed to completion. Phosphorylation of BAK at S117 has two important regulatory functions: first, it occludes the binding of BH3-containing peptides that bind to BAK causing activation and cytochrome c release from mitochondria; second, it prevents BAK-BH3:BAK-Groove interactions that nucleate dimer formation for subsequent multimerization. Hence, BH3-mediated BAK conformational change and subsequent BAK multimerization for cytochrome c release and cell death is intimately linked to, and dependent on, dephosphorylation at S117. Our study reveals important novel mechanistic and structural insights into the temporal sequence of events governing the process of BAK activation in commitment to cell death and how they are regulated.
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spelling pubmed-35066612012-11-27 Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis Azad, Abul Fox, Joanna Leverrier, Sabrina Storey, Alan PLoS One Research Article The BCL-2 family protein BAK is a key regulator of mitochondrial apoptosis. BAK activation first involves N-terminal conformational changes that lead to the transient exposure of the BAK BH3 domain that then inserts into a hydrophobic groove on another BAK molecule to form symmetric dimers. We showed recently that post-translational modifications are important in the regulation of BAK conformational change and multimerization, with dephosphorylation at tyrosine 108 constituting an initial step in the BAK activation process. We now show that dephosphorylation of serine 117 (S117), located in the BAK hydrophobic groove, is also critical for BAK activation to proceed to completion. Phosphorylation of BAK at S117 has two important regulatory functions: first, it occludes the binding of BH3-containing peptides that bind to BAK causing activation and cytochrome c release from mitochondria; second, it prevents BAK-BH3:BAK-Groove interactions that nucleate dimer formation for subsequent multimerization. Hence, BH3-mediated BAK conformational change and subsequent BAK multimerization for cytochrome c release and cell death is intimately linked to, and dependent on, dephosphorylation at S117. Our study reveals important novel mechanistic and structural insights into the temporal sequence of events governing the process of BAK activation in commitment to cell death and how they are regulated. Public Library of Science 2012-11-26 /pmc/articles/PMC3506661/ /pubmed/23189150 http://dx.doi.org/10.1371/journal.pone.0049601 Text en © 2012 Azad et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Azad, Abul
Fox, Joanna
Leverrier, Sabrina
Storey, Alan
Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis
title Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis
title_full Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis
title_fullStr Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis
title_full_unstemmed Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis
title_short Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis
title_sort blockade of the bak hydrophobic groove by inhibitory phosphorylation regulates commitment to apoptosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506661/
https://www.ncbi.nlm.nih.gov/pubmed/23189150
http://dx.doi.org/10.1371/journal.pone.0049601
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