Research Article

Crystal Structure of the Heterodimeric CLOCK:BMAL1 Transcriptional Activator Complex

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Science  31 May 2012:
1222804
DOI: 10.1126/science.1222804

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Abstract

The circadian clock in mammals is driven by an autoregulatory transcriptional feedback mechanism that takes about 24 hours to complete. A key component of this mechanism is a heterodimeric transcriptional activator consisting of two bHLH-PAS domain protein subunits, CLOCK and BMAL1. Here, we report the crystal structure of a complex containing the mouse CLOCK:BMAL1 bHLH-PAS domains at 2.3 Å resolution. The structure reveals an unusual asymmetric heterodimer with the three domains in each of the two subunits, bHLH, PAS-A and PAS-B tightly intertwined and involved in dimerization interactions, resulting in three distinct protein interfaces. Mutations that perturb the observed heterodimer interfaces affect the stability and activity of the CLOCK:BMAL1 complex as well as the periodicity of the circadian oscillator. The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock.

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