期刊
SCIENCE
卷 337, 期 6091, 页码 189-194出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1222804
关键词
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资金
- Howard Hughes Medical Institute
- American Heart Association [10GRNT4310090]
- NIH [R01 GM090247, R01 GM081875]
- National Institute of General Medical Sciences
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]
- U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
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 angstrom 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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