Crystal structure of the heterodimeric CLOCK: BMAL1 transcriptional activator complex

N Huang, Y Chelliah, Y Shan, CA Taylor, SH Yoo… - Science, 2012 - science.org
N Huang, Y Chelliah, Y Shan, CA Taylor, SH Yoo, C Partch, CB Green, H Zhang…
Science, 2012science.org
The circadian clock in mammals is driven by an autoregulatory transcriptional feedback
mechanism that takes approximately 24 hours to complete. A key component of this
mechanism is a heterodimeric transcriptional activator consisting of two basic helix-loop-
helix PER-ARNT-SIM (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 circadian clock in mammals is driven by an autoregulatory transcriptional feedback mechanism that takes approximately 24 hours to complete. A key component of this mechanism is a heterodimeric transcriptional activator consisting of two basic helix-loop-helix PER-ARNT-SIM (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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