Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication
SCF ubiquitin ligases target phosphorylated substrates for ubiquitin-dependent proteolysis by means of adapter subunits called F-box proteins. The F-box protein Cdc4 captures phosphorylated forms of the cyclin-dependent kinase inhibitor Sic1 for ubiquitination in late G1 phase, an event necessary fo...
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| Published in | Nature (London) Vol. 414; no. 6863; pp. 514 - 521 |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
London
Nature Publishing
29.11.2001
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| Abstract | SCF ubiquitin ligases target phosphorylated substrates for ubiquitin-dependent proteolysis by means of adapter subunits called F-box proteins. The F-box protein Cdc4 captures phosphorylated forms of the cyclin-dependent kinase inhibitor Sic1 for ubiquitination in late G1 phase, an event necessary for the onset of DNA replication. The WD40 repeat domain of Cdc4 binds with high affinity to a consensus phosphopeptide motif (the Cdc4 phospho-degron, CPD), yet Sic1 itself has many sub-optimal CPD motifs that act in concert to mediate Cdc4 binding. The weak CPD sites in Sic1 establish a phosphorylation threshold that delays degradation in vivo, and thereby establishes a minimal G1 phase period needed to ensure proper DNA replication. Multisite phosphorylation may be a more general mechanism to set thresholds in regulated protein-protein interactions. |
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| AbstractList | SCF ubiquitin ligases target phosphorylated substrates for ubiquitin-dependent proteolysis by means of adapter subunits called F-box proteins. The F-box protein Cdc4 captures phosphorylated forms of the cyclin-dependent kinase inhibitor Sic1 for ubiquitination in late G1 phase, an event necessary for the onset of DNA replication. The WD40 repeat domain of Cdc4 binds with high affinity to a consensus phosphopeptide motif (the Cdc4 phospho-degron, CPD), yet Sic1 itself has many sub-optimal CPD motifs that act in concert to mediate Cdc4 binding. The weak CPD sites in Sic1 establish a phosphorylation threshold that delays degradation in vivo, and thereby establishes a minimal G1 phase period needed to ensure proper DNA replication. Multisite phosphorylation may be a more general mechanism to set thresholds in regulated protein-protein interactions. SCF ubiquitin ligases target phosphorylated substrates for ubiquitin-dependent proteolysis by means of adapter subunits called F-box proteins. The F-box protein Cdc4 captures phosphorylated forms of the cyclin-dependent kinase inhibitor Sic1 for ubiquitination in late G1 phase, an event necessary for the onset of DNA replication. |
| Audience | Academic |
| Author | Sicheri, Frank Nash, Piers Pawson, Tony Tang, Xiaojing Chen, Qinghua Tyers, Mike Orlicky, Stephen Mendenhall, Michael D Gertler, Frank B |
| Author_xml | – sequence: 1 givenname: Tony surname: Pawson fullname: Pawson, Tony organization: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital Department of Medical Genetics and Microbiology, University of Toronto – sequence: 2 givenname: Mike surname: Tyers fullname: Tyers, Mike organization: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital Department of Medical Genetics and Microbiology, University of Toronto – sequence: 3 givenname: Piers surname: Nash fullname: Nash, Piers organization: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital – sequence: 4 givenname: Xiaojing surname: Tang fullname: Tang, Xiaojing organization: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital – sequence: 5 givenname: Stephen surname: Orlicky fullname: Orlicky, Stephen organization: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital – sequence: 6 givenname: Qinghua surname: Chen fullname: Chen, Qinghua organization: L.P. Markey Cancer Center, Department of Biochemistry, University of Kentucky – sequence: 7 givenname: Frank B surname: Gertler fullname: Gertler, Frank B organization: Biology Department, Massachusetts Institute of Technology – sequence: 8 givenname: Michael D surname: Mendenhall fullname: Mendenhall, Michael D organization: L.P. Markey Cancer Center, Department of Biochemistry, University of Kentucky – sequence: 9 givenname: Frank surname: Sicheri fullname: Sicheri, Frank organization: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital Department of Medical Genetics and Microbiology, University of Toronto |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14159585$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/11734846$$D View this record in MEDLINE/PubMed |
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| CODEN | NATUAS |
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| SubjectTerms | Binding Sites Biological and medical sciences Cdc4 protein Cell Cycle Cell Cycle Proteins - antagonists & inhibitors Cell Cycle Proteins - metabolism Consensus Sequence Cyclin-Dependent Kinase Inhibitor Proteins cyclin-dependent kinase inhibitors Deoxyribonucleic acid DNA DNA Replication - physiology DNA, Fungal - biosynthesis Enzyme Inhibitors F-box protein F-Box Proteins Fundamental and applied biological sciences. Psychology Fungal Proteins - antagonists & inhibitors Fungal Proteins - metabolism Fungal Proteins - physiology Molecular and cellular biology Molecular biology Phosphorylation Protein Structure, Tertiary Proteins Saccharomyces cerevisiae Proteins Sic1 protein Substrate Specificity Ubiquitin - metabolism ubiquitin ligase Ubiquitin-Protein Ligases ubiquitination |
| Title | Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication |
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