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

Function: 1) BMAL1-hCLOCK & BMAL2-hCLOCK heterodimers activate E-box element (3'-CACGTG-5') transcription of a number of proteins of the circadian clock 2) activates transcription of PER1 & PER2 3) transcription is inhibited in a feedback loop by PER proteins & CRY proteins 4) component of the circadian clock oscillator 5) efficient DNA binding requires dimerization with another bHLH protein 6) heterodimerization with BMAL1 is required for: a) E-box dependent transactivation b) hCLOCK nuclear translocation & degradation c) phosphorylation of both hCLOCK & BMAL1 7) interaction with PER proteins & CRY proteins requires translocation to the nucleus 8) interaction of the hCLOCK-BMAL1 heterodimer with PER or CRY inhibits transcription activation 9) binds weakly ARNT & ARNT2 to form heterodimers which bind poorly to the E-box motif 10) has intrinsic histone acetyltransferase activity that contributes to chromatin-remodeling events Compartment: - cytoplasm, nucleus - shuttling between the cytoplasm & the nucleus is under circadian regulation & is BMAL1-dependent - phosphorylated form located in the nucleus Expression: - 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 Pathology: - 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

General

basic helix loop helix (bHLH) family transcription factor histone acetyltransferase phosphoprotein

Properties

SIZE: entity length = 846 aa MW = 95 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: DNA-binding motif SITE: 35-47 helix-loop-helix NAME: helix-loop-helix SITE: 48-85 FOR-BINDING-VIA: helix-loop-helix PAS domain {107-177} PAS domain {262-332} MOTIF: Tyr phosphorylation site {Y331} PAC domain {336-379} Ser phosphorylation site {S408} active site basic helix-loop-helix MOTIF: basic DNA-binding motif helix-loop-helix NAME: helix-loop-helix FOR-BINDING-VIA: helix-loop-helix FOR-BINDING-OF: DNA motif FOR-BINDING-VIA: helix-loop-helix Implicated in the circadian rhythmicity {514-564} glutamine-rich region {744-760} MOTIF: glutamine residue (SEVERAL) glutamine-rich region {819-828} MOTIF: glutamine residue (SEVERAL)

Database Correlations

OMIM 601851 UniProt O15516 PFAM correlations Entrez Gene 9575 Kegg hsa:9575 ENZYME 2.3.1.48

References

UniProt :accession O15516