Multisite phosphorylation networks as signal processors for Cdk1

Nat Struct Mol Biol. 2013 Dec;20(12):1415-24. doi: 10.1038/nsmb.2706. Epub 2013 Nov 3.


The order and timing of cell-cycle events is controlled by changing substrate specificity and different activity thresholds of cyclin-dependent kinases (CDKs). However, it is not understood how a single protein kinase can trigger hundreds of switches in a sufficiently time-resolved fashion. We show that cyclin-Cdk1-Cks1-dependent phosphorylation of multisite targets in Saccharomyces cerevisiae is controlled by key substrate parameters including distances between phosphorylation sites, distribution of serines and threonines as phosphoacceptors and positioning of cyclin-docking motifs. The component mediating the key interactions in this process is Cks1, the phosphoadaptor subunit of the cyclin-Cdk1-Cks1 complex. We propose that variation of these parameters within networks of phosphorylation sites in different targets provides a wide range of possibilities for differential amplification of Cdk1 signals, thus providing a mechanism to generate a wide range of thresholds in the cell cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / physiology
  • CDC2 Protein Kinase / metabolism
  • CDC2 Protein Kinase / physiology*
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology
  • Cyclin B / metabolism
  • Cyclin B / physiology
  • Cyclins / metabolism
  • Cyclins / physiology
  • Phosphorylation
  • Phosphoserine / chemistry
  • Phosphoserine / metabolism
  • Phosphothreonine / chemistry
  • Phosphothreonine / metabolism
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Saccharomyces cerevisiae Proteins / physiology
  • Signal Transduction


  • Adaptor Proteins, Signal Transducing
  • CKS1 protein, S cerevisiae
  • CLB5 protein, S cerevisiae
  • CLN2 protein, S cerevisiae
  • Cell Cycle Proteins
  • Cyclin B
  • Cyclins
  • Saccharomyces cerevisiae Proteins
  • Phosphothreonine
  • Phosphoserine
  • CDC2 Protein Kinase