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, Mike Tyers

Research output: Contribution to journalArticlepeer-review

635 Scopus citations

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.

Original languageEnglish
Pages (from-to)514-521
Number of pages8
JournalNature
Volume414
Issue number6863
DOIs
StatePublished - Nov 29 2001

ASJC Scopus subject areas

  • General

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