Identification of the adenovirus E4orf4 protein binding site on the B55α and Cdc55 regulatory subunits of PP2A: Implications for PP2A function, tumor cell killing and viral replication.

Adenovirus E4orf4 protein induces the death of human cancer cells and Saccharomyces cerevisiae. Binding of E4orf4 to the B/B55/Cdc55 regulatory subunit of protein phosphatase 2A (PP2A) is required, and such binding inhibits PP2A(B55) activity leading to dose-dependent cell death. We found that E4orf...

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Autores principales:	Melissa Z Mui, Michael Kucharski, Marie-Joëlle Miron, Woosuk Steve Hur, Albert M Berghuis, Paola Blanchette, Philip E Branton
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/2637b9d64caf436eb86d2f206acba4ae
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spelling	oai:doaj.org-article:2637b9d64caf436eb86d2f206acba4ae2021-11-18T06:07:20ZIdentification of the adenovirus E4orf4 protein binding site on the B55α and Cdc55 regulatory subunits of PP2A: Implications for PP2A function, tumor cell killing and viral replication.1553-73661553-737410.1371/journal.ppat.1003742https://doaj.org/article/2637b9d64caf436eb86d2f206acba4ae2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24244166/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Adenovirus E4orf4 protein induces the death of human cancer cells and Saccharomyces cerevisiae. Binding of E4orf4 to the B/B55/Cdc55 regulatory subunit of protein phosphatase 2A (PP2A) is required, and such binding inhibits PP2A(B55) activity leading to dose-dependent cell death. We found that E4orf4 binds across the putative substrate binding groove predicted from the crystal structure of B55α such that the substrate p107 can no longer interact with PP2A(B55α). We propose that E4orf4 inhibits PP2A(B55) activity by preventing access of substrates and that at high E4orf4 levels this inhibition results in cell death through the failure to dephosphorylate substrates required for cell cycle progression. However, E4orf4 is expressed at much lower and less toxic levels during a normal adenovirus infection. We suggest that in this context E4orf4 largely serves to recruit novel substrates such as ASF/SF2/SRSF1 to PP2A(B55) to enhance adenovirus replication. Thus E4orf4 toxicity probably represents an artifact of overexpression and does not reflect the evolutionary function of this viral product.Melissa Z MuiMichael KucharskiMarie-Joëlle MironWoosuk Steve HurAlbert M BerghuisPaola BlanchettePhilip E BrantonPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 11, p e1003742 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Melissa Z Mui Michael Kucharski Marie-Joëlle Miron Woosuk Steve Hur Albert M Berghuis Paola Blanchette Philip E Branton Identification of the adenovirus E4orf4 protein binding site on the B55α and Cdc55 regulatory subunits of PP2A: Implications for PP2A function, tumor cell killing and viral replication.
description	Adenovirus E4orf4 protein induces the death of human cancer cells and Saccharomyces cerevisiae. Binding of E4orf4 to the B/B55/Cdc55 regulatory subunit of protein phosphatase 2A (PP2A) is required, and such binding inhibits PP2A(B55) activity leading to dose-dependent cell death. We found that E4orf4 binds across the putative substrate binding groove predicted from the crystal structure of B55α such that the substrate p107 can no longer interact with PP2A(B55α). We propose that E4orf4 inhibits PP2A(B55) activity by preventing access of substrates and that at high E4orf4 levels this inhibition results in cell death through the failure to dephosphorylate substrates required for cell cycle progression. However, E4orf4 is expressed at much lower and less toxic levels during a normal adenovirus infection. We suggest that in this context E4orf4 largely serves to recruit novel substrates such as ASF/SF2/SRSF1 to PP2A(B55) to enhance adenovirus replication. Thus E4orf4 toxicity probably represents an artifact of overexpression and does not reflect the evolutionary function of this viral product.
format	article
author	Melissa Z Mui Michael Kucharski Marie-Joëlle Miron Woosuk Steve Hur Albert M Berghuis Paola Blanchette Philip E Branton
author_facet	Melissa Z Mui Michael Kucharski Marie-Joëlle Miron Woosuk Steve Hur Albert M Berghuis Paola Blanchette Philip E Branton
author_sort	Melissa Z Mui
title	Identification of the adenovirus E4orf4 protein binding site on the B55α and Cdc55 regulatory subunits of PP2A: Implications for PP2A function, tumor cell killing and viral replication.
title_short	Identification of the adenovirus E4orf4 protein binding site on the B55α and Cdc55 regulatory subunits of PP2A: Implications for PP2A function, tumor cell killing and viral replication.
title_full	Identification of the adenovirus E4orf4 protein binding site on the B55α and Cdc55 regulatory subunits of PP2A: Implications for PP2A function, tumor cell killing and viral replication.
title_fullStr	Identification of the adenovirus E4orf4 protein binding site on the B55α and Cdc55 regulatory subunits of PP2A: Implications for PP2A function, tumor cell killing and viral replication.
title_full_unstemmed	Identification of the adenovirus E4orf4 protein binding site on the B55α and Cdc55 regulatory subunits of PP2A: Implications for PP2A function, tumor cell killing and viral replication.
title_sort	identification of the adenovirus e4orf4 protein binding site on the b55α and cdc55 regulatory subunits of pp2a: implications for pp2a function, tumor cell killing and viral replication.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/2637b9d64caf436eb86d2f206acba4ae
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Identification of the adenovirus E4orf4 protein binding site on the B55α and Cdc55 regulatory subunits of PP2A: Implications for PP2A function, tumor cell killing and viral replication.

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