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Nature 414, 514-521 (29 November 2001) | doi:10.1038/35107009; Received 22 June 2001; Accepted 12 August 2001

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

Piers Nash1,2, Xiaojing Tang1,2, Stephen Orlicky1, Qinghua Chen3, Frank B. Gertler4, Michael D. Mendenhall3, Frank Sicheri1,5, Tony Pawson1,5 & Mike Tyers1,5

  1. Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
  2. L.P. Markey Cancer Center, Department of Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0096, USA
  3. Biology Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
  4. Department of Medical Genetics and Microbiology, University of Toronto, 1 Kings College Circle, Toronto M5S 1A8, Canada
  5. These authors contributed equally to this work

Correspondence to: Tony Pawson1,5Mike Tyers1,5 Correspondence and requests for materials should be addressed to T.P. (e-mail: Email: pawson@mshri.on.ca) or M.T. (e-mail: Email: tyers@mshri.on.ca). The protein interactions are available at the Biomolecular Interaction Network Database (accession numbers 1436, 1437 and 1438).

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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.

  1. Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada
  2. L.P. Markey Cancer Center, Department of Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0096, USA
  3. Biology Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
  4. Department of Medical Genetics and Microbiology, University of Toronto, 1 Kings College Circle, Toronto M5S 1A8, Canada
  5. These authors contributed equally to this work

Correspondence to: Tony Pawson1,5Mike Tyers1,5 Correspondence and requests for materials should be addressed to T.P. (e-mail: Email: pawson@mshri.on.ca) or M.T. (e-mail: Email: tyers@mshri.on.ca). The protein interactions are available at the Biomolecular Interaction Network Database (accession numbers 1436, 1437 and 1438).