Clock News

Two interesting new papers in PLoS Biology today:

A Role for the PERIOD:PERIOD Homodimer in the Drosophila Circadian Clock:

The current models of circadian clocks in flies and mammals involve the formation of complexes between clock proteins in the cytoplasm. These complexes are usually heterodimers (that is, made up of two different clock proteins) and appear to enter the nucleus at certain times of the circadian day in order to shut down their own gene expression by deactivating specific transcription factors. After progressive phosphorylation the repressor proteins eventually are degraded so that a new cycle of transcription can begin. Here we present evidence that in addition to heterodimeric complexes, the clock protein PERIOD (PER) also forms homodimers (pairs of identical proteins). Based on a structural model a PER mutant was designed, which is not able to form homodimers but can still bind to its partner TIMELESS (TIM). Flies expressing this mutant PER protein show abnormal clock function in regard to PER nuclear translocation, repressor activity, and behavioral rhythms. The circadian clock model in flies therefore needs to be extended by adding the PER:PER homodimer as a functional unit. Recent structural studies with mammalian PER proteins suggest that homodimers between clock proteins are an important general feature of eukaryotic clocks.

Structural and Functional Analyses of PAS Domain Interactions of the Clock Proteins Drosophila PERIOD and Mouse PERIOD2:

Most organisms have daily activity cycles (circadian rhythms), which are generated by circadian clocks. Circadian periodicity is produced by specific clock protein interactions and posttranslational modifications as well as changes in their cellular localization, expression, and stability. To learn more about the molecular processes underlying circadian clock operation in fruit flies and mouse, we analysed the homo- and heterodimeric interactions of the clock proteins Drosophila PERIOD (dPER) and mouse PERIOD2 (mPER2). We show that dPER and mPER2 use different interaction surfaces for homodimer formation, which are associated with different dimerization affinities. In addition, we present a structure-based biochemical analysis of the heterodimeric interaction of dPER with its partner Drosophila TIMELESS (dTIM). We identify a versatile molecular surface of the PERIOD proteins, which mediates homodimer formation of mPER2 but is used for dPER-dTIM heterodimer formation in Drosophila. Our results reveal quantitative and qualitative differences in the molecular interactions of PERIOD clock proteins in flies and mammals, allowing them to adjust to their different binding partners and regulatory functions in these different organisms.