Crystal structure of the heterodimeric CLOCK: BMAL1 transcriptional activator complex

Nian Huang, Yogarany Chelliah, Yongli Shan, Clinton A. Taylor, Seung Hee Yoo, Carrie Partch, Carla B. Green, Hong Zhang, Joseph S. Takahashi

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)189-194
Number of pages6
JournalScience
Volume337
Issue number6091
DOIs
StatePublished - Jul 13 2012

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Circadian Clocks
Protein Subunits
Dimerization
Periodicity
Mammals
Mutation
Proteins

ASJC Scopus subject areas

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Huang, N., Chelliah, Y., Shan, Y., Taylor, C. A., Yoo, S. H., Partch, C., ... Takahashi, J. S. (2012). Crystal structure of the heterodimeric CLOCK: BMAL1 transcriptional activator complex. Science, 337(6091), 189-194. https://doi.org/10.1126/science.1222804

Crystal structure of the heterodimeric CLOCK : BMAL1 transcriptional activator complex. / Huang, Nian; Chelliah, Yogarany; Shan, Yongli; Taylor, Clinton A.; Yoo, Seung Hee; Partch, Carrie; Green, Carla B.; Zhang, Hong; Takahashi, Joseph S.

In: Science, Vol. 337, No. 6091, 13.07.2012, p. 189-194.

Research output: Contribution to journalArticle

Huang, N, Chelliah, Y, Shan, Y, Taylor, CA, Yoo, SH, Partch, C, Green, CB, Zhang, H & Takahashi, JS 2012, 'Crystal structure of the heterodimeric CLOCK: BMAL1 transcriptional activator complex', Science, vol. 337, no. 6091, pp. 189-194. https://doi.org/10.1126/science.1222804
Huang N, Chelliah Y, Shan Y, Taylor CA, Yoo SH, Partch C et al. Crystal structure of the heterodimeric CLOCK: BMAL1 transcriptional activator complex. Science. 2012 Jul 13;337(6091):189-194. https://doi.org/10.1126/science.1222804
Huang, Nian ; Chelliah, Yogarany ; Shan, Yongli ; Taylor, Clinton A. ; Yoo, Seung Hee ; Partch, Carrie ; Green, Carla B. ; Zhang, Hong ; Takahashi, Joseph S. / Crystal structure of the heterodimeric CLOCK : BMAL1 transcriptional activator complex. In: Science. 2012 ; Vol. 337, No. 6091. pp. 189-194.
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