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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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Cascades of multisite phosphorylation control Sic1 destruction at the onset of S phase

Mardo Kõivomägi1, Ervin Valk, Rainis Venta

  • 1Institute of Technology, University of Tartu, Tartu 50411, Estonia.

Nature
|October 14, 2011
PubMed

Insights

Multisite protein phosphorylation transforms graded signals into switch-like responses. This study reveals how cyclin-dependent kinase (Cdk) cascades and docking interactions regulate Sic1 destruction, controlling cell cycle transitions.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Multisite protein phosphorylation is theorized to create ultrasensitive biological switches from graded signals.
  • The precise dynamics and sequence of phosphorylation events in multisite phosphorylation remain poorly understood.
  • In Saccharomyces cerevisiae, Sic1 inhibition of Clb5-Cdk1 is critical for S phase initiation, involving extensive Sic1 phosphorylation for degradation.

Purpose of the Study:

  • To investigate the dynamics and sequence of multisite phosphorylation events in Sic1 regulation.
  • To elucidate the roles of Cln2-Cdk1 and Clb5-Cdk1 in Sic1 phosphorylation cascades.
  • To uncover the mechanisms governing the switch-like destruction of Sic1 and cell cycle control.

Main Methods:

  • Utilized Saccharomyces cerevisiae as a model organism.
  • Investigated protein kinase signaling pathways, specifically focusing on Cdk1 complexes and their substrates.
  • Analyzed phosphorylation events, protein degradation, and regulatory interactions, including docking motifs and phospho-adaptors.

Main Results:

  • Sic1 destruction is mediated by processive multiphosphorylation cascades involving both Cln2-Cdk1 and Clb5-Cdk1.
  • Specific phosphodegrons within Sic1 are targeted by these phosphorylation cascades.
  • Cyclin-specific docking interactions and Cks1 (a phospho-adaptor) dictate the routes of these phosphorylation cascades.
  • Clb5-Cdk1-dependent phosphorylation creates positive feedback crucial for switch-like Sic1 destruction.
  • A docking network within phosphorylation site clusters reveals novel complexity in Cdk1 regulation.

Conclusions:

  • Sic1 destruction is a complex, regulated process involving coordinated action of multiple Cdk complexes and specific docking interactions.
  • The findings reveal a new layer of complexity in Cdk1-dependent cell cycle regulation through multisite phosphorylation.
  • This study has broad implications for understanding how multisite phosphorylation regulates diverse cellular processes.

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