title: Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1.
abstract: 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.
authors.affiliation: Department of Genetics, University of Regensburg, D-93040 Regensburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Höckner
authors.affiliation: Department of Genetics, University of Regensburg, D-93040 Regensburg, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Neumann-Arnold
authors.affiliation: Department of Genetics, University of Regensburg, D-93040 Regensburg, Germany Wolfgang.Seufert@ur.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Seufert
mesh_terms: D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D064200:Cdh1 Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D008938:Mitosis / Q000502:physiology; D010766:Phosphorylation; D004718:Saccharomycetales / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
chemical_list: D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D019926:Cyclin B; D043743:Ubiquitin-Protein Ligase Complexes; D016203:CDC2 Protein Kinase