Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication

Piers Nash, Xiaojing Tang, Stephen Orlicky, Qinghua Chen, Frank B. Gertler, Michael D. Mendenhall, Frank Sicheri, Tony Pawson () and Mike Tyers ()
Additional contact information
Piers Nash: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Xiaojing Tang: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Stephen Orlicky: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Qinghua Chen: L.P. Markey Cancer Center, University of Kentucky
Frank B. Gertler: Massachusetts Institute of Technology
Michael D. Mendenhall: L.P. Markey Cancer Center, University of Kentucky
Frank Sicheri: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Tony Pawson: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Mike Tyers: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Nature, 2001, vol. 414, issue 6863, 514-521

Abstract: 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.

Date: 2001
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DOI: 10.1038/35107009

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