'Linnea Saunders/Sandbox 1 CLOCK:BMAL1 Transcriptional Activator Complex'
Overview
The circadian locomotor output cycles protein kaput and brain-muscle-arnt-like (CLOCK:BMAL1) transcriptional activator complex is an important protein involved in the regulation of our circadian rhythm. The protein shown at the right is a crystallized structure of this complex from Mus musculus. This protein is a heterodimer of CLOCK and BMAL1. Its main function is to interact with DNA at regulatory elements to upregulate the production of proteins period (PER) and cryptochrome (CRY) during the day. These proteins (PER and CRY) heterodimerize at night and interact with CLOCK:BMAL1 to repress the transcription of PER and CRY.1 They are then degraded, allowing their transcription to occur again. This process takes approximately 24 hours and is the main mechanism of the circadian rhythm, and CLOCK:BMAL1 lies at the heart of this process.2
In addition to regulating PER and CRY, CLOCK:BMAL1 regulates the transcription of Rev-erbα, which is a nuclear hormone receptor).3 Rev-erbα once transcribed, inhibits the transcription of BMAL1.
CLOCK:BMAL1 contains two necessary domain structures to facilitate its function in the cell, as well as sites for phosphorylation, acetylation, O-glycosylation, sumoylation, and ubiquitination, which allow for dimerization, increasing transcriptional activity, and degradation of the complex.
Disease
CLOCK:BMAL1 is known to be a factor in hormone-related breast cancer by contributing to cell growth. Estrogen receptor-α (ERα), when stimulated by estrogen, interacts with CLOCK to increase transcriptional activity at genes regulated by CLOCK:BMAL1. This is achieved by promoting sumoylation of CLOCK at .4 When transcriptional activity of these genes is increased, cell growth is stimulated, and more cells are promoted to the S phase of the cell cycle.
Structural highlights
The main domains of interest within the CLOCK:BMAL1 complex are the , which are necessary for dimerization, and the , which allows the complex to interact with DNA. Each subunit contains two PAS domains, which interact with the PAS domains of the other subunit to maintain the structure of the complex.
