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Open Access Highly Accessed Research article

Interaction of circadian clock proteins PER2 and CRY with BMAL1 and CLOCK

Sonja Langmesser1, Tiziano Tallone12, Alain Bordon13, Sandro Rusconi14 and Urs Albrecht1*

Author Affiliations

1 Department of Medicine, Division of Biochemistry, University of Fribourg, Rue du Musée 5, 1700 Fribourg, Switzerland

2 PolyGene AG, Riedmattstrasse 9, 8153 Rümlang, Switzerland

3 Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Maulbeerstrasse 66, CH-4058 Basel, Switzerland

4 Dipartimento dell’educazione, della cultura e dello sport, Divisione della cultura e degli studi universitari, Viale S. Franscini 30a, 6501 Bellinzona, Switzerland

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BMC Molecular Biology 2008, 9:41  doi:10.1186/1471-2199-9-41

Published: 22 April 2008



Circadian oscillation of clock-controlled gene expression is mainly regulated at the transcriptional level. Heterodimers of CLOCK and BMAL1 act as activators of target gene transcription; however, interactions of PER and CRY proteins with the heterodimer abolish its transcriptional activation capacity. PER and CRY are therefore referred to as negative regulators of the circadian clock. To further elucidate the mechanism how positive and negative components of the clock interplay, we characterized the interactions of PER2, CRY1 and CRY2 with BMAL1 and CLOCK using a mammalian two-hybrid system and co-immunoprecipitation assays.


Both PER2 and the CRY proteins were found to interact with BMAL1 whereas only PER2 interacts with CLOCK. CRY proteins seem to have a higher affinity to BMAL1 than PER2. Moreover, we provide evidence that PER2, CRY1 and CRY2 bind to different domains in the BMAL1 protein.


The regulators of clock-controlled transcription PER2, CRY1 and CRY2 differ in their capacity to interact with each single component of the BMAL1-CLOCK heterodimer and, in the case of BMAL1, also in their interaction sites. Our data supports the hypothesis that CRY proteins, especially CRY1, are stronger repressors than PER proteins.