Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex.
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.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Nian
N
Huang
Yogarany
Y
Chelliah
Yongli
Y
Shan
Clinton A
CA
Taylor
Seung-Hee
SH
Yoo
Carrie
C
Partch
Carla B
CB
Green
Hong
H
Zhang
Joseph S
JS
Takahashi
D056930:ARNTL Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D056926:CLOCK Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002940:Circadian Rhythm; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D057809:HEK293 Cells; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D015533:Transcriptional Activation
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D050505:Mutant Proteins; D021122:Protein Subunits; D004247:DNA; D056926:CLOCK Proteins; C538944:Clock protein, mouse