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Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death

High-risk human papillomavirus (HR-HPV) E2 protein, the master regulator of viral life cycle, induces apoptosis of host cell that is independent of its virus-associated regulatory functions. E2 protein of HR-HPV18 has been found to be involved in novel FADD-independent activation of caspase-8, howev...

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Autores principales: Singh, Nitu, Senapati, Sanjib, Bose, Kakoli
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764946/
https://www.ncbi.nlm.nih.gov/pubmed/26906543
http://dx.doi.org/10.1038/srep21408
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author Singh, Nitu
Senapati, Sanjib
Bose, Kakoli
author_facet Singh, Nitu
Senapati, Sanjib
Bose, Kakoli
author_sort Singh, Nitu
collection PubMed
description High-risk human papillomavirus (HR-HPV) E2 protein, the master regulator of viral life cycle, induces apoptosis of host cell that is independent of its virus-associated regulatory functions. E2 protein of HR-HPV18 has been found to be involved in novel FADD-independent activation of caspase-8, however, the molecular basis of this unique non-death-fold E2-mediated apoptosis is poorly understood. Here, with an interdisciplinary approach that involves in silico, mutational, biochemical and biophysical probes, we dissected and characterized the E2-procasapse-8 binding interface. Our data demonstrate direct non-homotypic interaction of HPV18 E2 transactivation domain (TAD) with α2/α5 helices of procaspase-8 death effector domain-B (DED-B). The observed interaction mimics the homotypic DED-DED complexes, wherein the conserved hydrophobic motif of procaspase-8 DED-B (F122/L123) occupies a groove between α2/α3 helices of E2 TAD. This interaction possibly drives DED oligomerization leading to caspase-8 activation and subsequent cell death. Furthermore, our data establish a model for E2-induced apoptosis in HR-HPV types and provide important clues for designing E2 analogs that might modulate procaspase-8 activation and hence apoptosis.
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spelling pubmed-47649462016-03-02 Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death Singh, Nitu Senapati, Sanjib Bose, Kakoli Sci Rep Article High-risk human papillomavirus (HR-HPV) E2 protein, the master regulator of viral life cycle, induces apoptosis of host cell that is independent of its virus-associated regulatory functions. E2 protein of HR-HPV18 has been found to be involved in novel FADD-independent activation of caspase-8, however, the molecular basis of this unique non-death-fold E2-mediated apoptosis is poorly understood. Here, with an interdisciplinary approach that involves in silico, mutational, biochemical and biophysical probes, we dissected and characterized the E2-procasapse-8 binding interface. Our data demonstrate direct non-homotypic interaction of HPV18 E2 transactivation domain (TAD) with α2/α5 helices of procaspase-8 death effector domain-B (DED-B). The observed interaction mimics the homotypic DED-DED complexes, wherein the conserved hydrophobic motif of procaspase-8 DED-B (F122/L123) occupies a groove between α2/α3 helices of E2 TAD. This interaction possibly drives DED oligomerization leading to caspase-8 activation and subsequent cell death. Furthermore, our data establish a model for E2-induced apoptosis in HR-HPV types and provide important clues for designing E2 analogs that might modulate procaspase-8 activation and hence apoptosis. Nature Publishing Group 2016-02-24 /pmc/articles/PMC4764946/ /pubmed/26906543 http://dx.doi.org/10.1038/srep21408 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Singh, Nitu
Senapati, Sanjib
Bose, Kakoli
Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death
title Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death
title_full Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death
title_fullStr Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death
title_full_unstemmed Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death
title_short Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death
title_sort insights into the mechanism of human papillomavirus e2-induced procaspase-8 activation and cell death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764946/
https://www.ncbi.nlm.nih.gov/pubmed/26906543
http://dx.doi.org/10.1038/srep21408
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