Molecular Playground/CLOCK:BMAL1 heterodimer complex

The is a vital regulatory component of the circadian rhythm protein regulation system.The binding between CLOCK and BMAL1 involves the N-terminal bHLH, PAS-A and PAS-B domains of both proteins. Each domain binds to its corresponding equivalent domain in the other protein. Though both proteins contain the same types of domains with similar primary amino acid sequences in each, the overall heterodimer is surprisingly asymmetrical due to differences in the spatial orientation of the domains in each protein. Since this heterodimer complex involves the binding of all of the major domains in both participating proteins, the overall binding affinity is very high.

CLOCK

is a protein central to the regulation of the mammalian circadian rhythm system. CLOCK is a helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) protein that regulates the circadian rhythm by forming heterodimers with other circadian rhythm proteins to activate the transcription of other proteins.^[1] consists of 12 alpha-helixes and 8 beta-sheets. In between the helixes and sheets, there are many flexible loops, which are the main contributions to the CLOCK:BMAL1 interactions.

BMAL1

Circadian Rhythm

The circadian rhythm is the 24 hour protein regulation system found in most mammalian species. The circadian rhythm causes certain proteins to be expressed during the day and then downregulated during the night. The circadian rhythm originates in the suprachiasmatic nucleus (SCN), which is located in the hypothalamus. The SCN controls the expression of of proteins in a time dependent manner through a genetic feedback loop initiated by light passing through the eye. The CLOCK:BMAL1 heterodimer complex is a vital component of this system as this heterodimer binds to the E-box promoter region of other circadian rhythm proteins and trigger the transcription of those proteins. These proteins then repress their own transcription in order to regulate the protein content to the appropriate levels. ^[2]

Disease

Mutated forms of CLOCK exist which do not regulate protein expression correctly and thereby result in altered circadian rhythms. CLOCK-delta19 is a mutant form of CLOCK which binds to BMAL1 normally but the resulting heterodimer does not activate transcription of certain other circadian rhythm proteins. Mutant mice carrying this altered CLOCK protein have shown abnormal circadian rhythms as a result. ^[3]

It has been shown in recent years that people who have lifestyles which involve light exposure that is different than the normal 12 hours of daylight/12 hours of night have significantly increased chances of developing cancer. This indicates that disruption of the normal circadian rhythm gene regulation cycle has severe downstream effects on the host's genetic makeup. Additionally, it has been shown that cancer tissues often have distorted circadian rhythms, showing the significance of circadian rhythms to cancer progression. ^[4]

Structural highlights