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Polyanions provide selective control of APC/C interactions with the activator subunit

Transient interactions between the anaphase-promoting complex/cyclosome (APC/C) and its activator subunit Cdc20 or Cdh1 generate oscillations in ubiquitylation activity necessary to maintain the order of cell cycle events. Activator binds the APC/C with high affinity and exhibits negligible dissocia...

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Autores principales: Mizrak, Arda, Morgan, David O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925294/
https://www.ncbi.nlm.nih.gov/pubmed/31862931
http://dx.doi.org/10.1038/s41467-019-13864-1
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author Mizrak, Arda
Morgan, David O.
author_facet Mizrak, Arda
Morgan, David O.
author_sort Mizrak, Arda
collection PubMed
description Transient interactions between the anaphase-promoting complex/cyclosome (APC/C) and its activator subunit Cdc20 or Cdh1 generate oscillations in ubiquitylation activity necessary to maintain the order of cell cycle events. Activator binds the APC/C with high affinity and exhibits negligible dissociation kinetics in vitro, and it is not clear how the rapid turnover of APC/C-activator complexes is achieved in vivo. Here, we describe a mechanism that controls APC/C-activator interactions based on the availability of substrates. We find that APC/C-activator dissociation is stimulated by abundant cellular polyanions such as nucleic acids and polyphosphate. Polyanions also interfere with substrate ubiquitylation. However, engagement with high-affinity substrate blocks the inhibitory effects of polyanions on activator binding and APC/C activity. We propose that this mechanism amplifies the effects of substrate affinity on APC/C function, stimulating processive ubiquitylation of high-affinity substrates and suppressing ubiquitylation of low-affinity substrates.
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spelling pubmed-69252942019-12-22 Polyanions provide selective control of APC/C interactions with the activator subunit Mizrak, Arda Morgan, David O. Nat Commun Article Transient interactions between the anaphase-promoting complex/cyclosome (APC/C) and its activator subunit Cdc20 or Cdh1 generate oscillations in ubiquitylation activity necessary to maintain the order of cell cycle events. Activator binds the APC/C with high affinity and exhibits negligible dissociation kinetics in vitro, and it is not clear how the rapid turnover of APC/C-activator complexes is achieved in vivo. Here, we describe a mechanism that controls APC/C-activator interactions based on the availability of substrates. We find that APC/C-activator dissociation is stimulated by abundant cellular polyanions such as nucleic acids and polyphosphate. Polyanions also interfere with substrate ubiquitylation. However, engagement with high-affinity substrate blocks the inhibitory effects of polyanions on activator binding and APC/C activity. We propose that this mechanism amplifies the effects of substrate affinity on APC/C function, stimulating processive ubiquitylation of high-affinity substrates and suppressing ubiquitylation of low-affinity substrates. Nature Publishing Group UK 2019-12-20 /pmc/articles/PMC6925294/ /pubmed/31862931 http://dx.doi.org/10.1038/s41467-019-13864-1 Text en © The Author(s) 2019 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
Mizrak, Arda
Morgan, David O.
Polyanions provide selective control of APC/C interactions with the activator subunit
title Polyanions provide selective control of APC/C interactions with the activator subunit
title_full Polyanions provide selective control of APC/C interactions with the activator subunit
title_fullStr Polyanions provide selective control of APC/C interactions with the activator subunit
title_full_unstemmed Polyanions provide selective control of APC/C interactions with the activator subunit
title_short Polyanions provide selective control of APC/C interactions with the activator subunit
title_sort polyanions provide selective control of apc/c interactions with the activator subunit
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925294/
https://www.ncbi.nlm.nih.gov/pubmed/31862931
http://dx.doi.org/10.1038/s41467-019-13864-1
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