Dynamic circadian protein-protein interaction networks predict temporal organization of cellular functions

PLoS Genet. 2013 Mar;9(3):e1003398. doi: 10.1371/journal.pgen.1003398. Epub 2013 Mar 28.


Essentially all biological processes depend on protein-protein interactions (PPIs). Timing of such interactions is crucial for regulatory function. Although circadian (~24-hour) clocks constitute fundamental cellular timing mechanisms regulating important physiological processes, PPI dynamics on this timescale are largely unknown. Here, we identified 109 novel PPIs among circadian clock proteins via a yeast-two-hybrid approach. Among them, the interaction of protein phosphatase 1 and CLOCK/BMAL1 was found to result in BMAL1 destabilization. We constructed a dynamic circadian PPI network predicting the PPI timing using circadian expression data. Systematic circadian phenotyping (RNAi and overexpression) suggests a crucial role for components involved in dynamic interactions. Systems analysis of a global dynamic network in liver revealed that interacting proteins are expressed at similar times likely to restrict regulatory interactions to specific phases. Moreover, we predict that circadian PPIs dynamically connect many important cellular processes (signal transduction, cell cycle, etc.) contributing to temporal organization of cellular physiology in an unprecedented manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • CLOCK Proteins* / genetics
  • CLOCK Proteins* / metabolism
  • Cell Cycle / genetics
  • Cell Cycle / physiology
  • Circadian Clocks / genetics*
  • Circadian Rhythm / genetics*
  • ErbB Receptors / metabolism
  • HEK293 Cells
  • Humans
  • Protein Interaction Maps / genetics*
  • Protein Phosphatase 1 / genetics
  • Protein Phosphatase 1 / metabolism
  • Signal Transduction


  • ARNTL Transcription Factors
  • ARNTL protein, human
  • CLOCK Proteins
  • EGFR protein, human
  • ErbB Receptors
  • Protein Phosphatase 1

Grant support

This study was supported by grants of the BMBF (NGFN1/2, GO-Bio), EU (EuroSpin and SynSys), as well as the Helmholtz Association (MSBN, HelMA) to EEW; the Portuguese Fundação para a Ciência e a Tecnologia to MEF and RKRK (IBB/CBME, LA; SFRH/BPD/70718/2010); and the Deutsche Forschungsgemeinschaft (SFB740, SFB618) to AK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.