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Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1

The antagonism between cyclin-dependent kinases (Cdks) and the ubiquitin ligase APC/C-Cdh1 is central to eukaryotic cell cycle control. APC/C-Cdh1 targets cyclin B and other regulatory proteins for degradation, whereas Cdks disable APC/C-Cdh1 through phosphorylation of the Cdh1 activator protein at...

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Autores principales: Höckner, Sebastian, Neumann-Arnold, Lea, Seufert, Wolfgang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945139/
https://www.ncbi.nlm.nih.gov/pubmed/27226481
http://dx.doi.org/10.1091/mbc.E15-11-0787
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author Höckner, Sebastian
Neumann-Arnold, Lea
Seufert, Wolfgang
author_facet Höckner, Sebastian
Neumann-Arnold, Lea
Seufert, Wolfgang
author_sort Höckner, Sebastian
collection PubMed
description The antagonism between cyclin-dependent kinases (Cdks) and the ubiquitin ligase APC/C-Cdh1 is central to eukaryotic cell cycle control. APC/C-Cdh1 targets cyclin B and other regulatory proteins for degradation, whereas Cdks disable APC/C-Cdh1 through phosphorylation of the Cdh1 activator protein at multiple sites. Budding yeast Cdh1 carries nine Cdk phosphorylation sites in its N-terminal regulatory domain, most or all of which contribute to inhibition. However, the precise role of individual sites has remained unclear. Here, we report that the Cdk phosphorylation sites of yeast Cdh1 are organized into autonomous subgroups and act through separate mechanisms. Cdk sites 1–3 had no direct effect on the APC/C binding of Cdh1 but inactivated a bipartite nuclear localization sequence (NLS) and thereby controlled the partitioning of Cdh1 between cytoplasm and nucleus. In contrast, Cdk sites 4–9 did not influence the cell cycle–regulated localization of Cdh1 but prevented its binding to the APC/C. Cdk sites 4–9 reside near two recently identified APC/C interaction motifs in a pattern conserved with the human Cdh1 orthologue. Thus a Cdk-inhibited NLS goes along with Cdk-inhibited APC/C binding sites in yeast Cdh1 to relay the negative control by Cdk1 phosphorylation of the ubiquitin ligase APC/C-Cdh1.
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spelling pubmed-49451392016-09-30 Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1 Höckner, Sebastian Neumann-Arnold, Lea Seufert, Wolfgang Mol Biol Cell Articles The antagonism between cyclin-dependent kinases (Cdks) and the ubiquitin ligase APC/C-Cdh1 is central to eukaryotic cell cycle control. APC/C-Cdh1 targets cyclin B and other regulatory proteins for degradation, whereas Cdks disable APC/C-Cdh1 through phosphorylation of the Cdh1 activator protein at multiple sites. Budding yeast Cdh1 carries nine Cdk phosphorylation sites in its N-terminal regulatory domain, most or all of which contribute to inhibition. However, the precise role of individual sites has remained unclear. Here, we report that the Cdk phosphorylation sites of yeast Cdh1 are organized into autonomous subgroups and act through separate mechanisms. Cdk sites 1–3 had no direct effect on the APC/C binding of Cdh1 but inactivated a bipartite nuclear localization sequence (NLS) and thereby controlled the partitioning of Cdh1 between cytoplasm and nucleus. In contrast, Cdk sites 4–9 did not influence the cell cycle–regulated localization of Cdh1 but prevented its binding to the APC/C. Cdk sites 4–9 reside near two recently identified APC/C interaction motifs in a pattern conserved with the human Cdh1 orthologue. Thus a Cdk-inhibited NLS goes along with Cdk-inhibited APC/C binding sites in yeast Cdh1 to relay the negative control by Cdk1 phosphorylation of the ubiquitin ligase APC/C-Cdh1. The American Society for Cell Biology 2016-07-15 /pmc/articles/PMC4945139/ /pubmed/27226481 http://dx.doi.org/10.1091/mbc.E15-11-0787 Text en © 2016 Höckner et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Höckner, Sebastian
Neumann-Arnold, Lea
Seufert, Wolfgang
Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1
title Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1
title_full Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1
title_fullStr Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1
title_full_unstemmed Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1
title_short Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1
title_sort dual control by cdk1 phosphorylation of the budding yeast apc/c ubiquitin ligase activator cdh1
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945139/
https://www.ncbi.nlm.nih.gov/pubmed/27226481
http://dx.doi.org/10.1091/mbc.E15-11-0787
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