circadian locomoter output cycles kaput protein; hCLOCK; class E basic helix-loop-helix protein 8; bHLHe8 (CLOCK, BHLHE8, KIAA0334)

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Function

BMAL1-hCLOCK & BMAL2-hCLOCK heterodimers activate E-box element (3'-CACGTG-5') transcription of a number of proteins of the circadian clock
activates transcription of PER1 & PER2
transcription is inhibited in a feedback loop by PER proteins & CRY proteins
component of the circadian clock oscillator
efficient DNA binding requires dimerization with another bHLH protein
heterodimerization with BMAL1 is required for:
- E-box dependent transactivation
- hCLOCK nuclear translocation & degradation
- phosphorylation of both hCLOCK & BMAL1
interaction with PER proteins & CRY proteins requires translocation to the nucleus
interaction of the hCLOCK-BMAL1 heterodimer with PER or CRY inhibits transcription activation
binds weakly ARNT & ARNT2 to form heterodimers which bind poorly to the E-box motif
has intrinsic histone acetyltransferase activity that contributes to chromatin-remodeling events

cytoplasm, nucleus
shuttling between the cytoplasm & the nucleus is under circadian regulation & is BMAL1-dependent
phosphorylated form located in the nucleus

expressed in all tissues, including spleen, thymus, prostate, testis, ovary, small intestine, colon,leukocytes, heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas
highest levels in testis, skeletal muscle
low levels in thymus, lung, liver
expressed in all brain regions; highest levels in cerebellum, suprachiasmatic nucleus

CLOCK-BMAL1 double mutations within the PAS domains result in syngernistic desensitization to high levels of CRY on repression of CLOCK-BMAL1 transcriptional activity of PER1 & disrupt circadian rhythmicity