InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: CRY2

Summary

InnateDB Protein

IDBP-372142.4

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

CRY2

Protein Name

cryptochrome 2 (photolyase-like)

Synonyms

HCRY2; PHLL2;

Species

Homo sapiens

Ensembl Protein

ENSP00000397419

InnateDB Gene

IDBG-41167 (CRY2)

Protein Structure

UniProt Annotation

Function

Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time- keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCKNPAS2-ARNTL/BMAL1ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1, NR1D2, RORA, RORB and RORG, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. Less potent transcriptional repressor in cerebellum and liver than CRY1, though less effective in lengthening the period of the SCN oscillator. Seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY1, dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. May mediate circadian regulation of cAMP signaling and gluconeogenesis by blocking glucagon-mediated increases in intracellular cAMP concentrations and in CREB1 phosphorylation. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1. {ECO:0000269PubMed:10531061, ECO:0000269PubMed:14672706, ECO:0000269PubMed:16790549}.

Subcellular Localization

Cytoplasm {ECO:0000269PubMed:9801304}. Nucleus {ECO:0000269PubMed:9801304}. Note=Translocated to the nucleus through interaction with other Clock proteins such as PER2 or ARNTL.

Disease Associations

Tissue Specificity

Expressed in all tissues examined including fetal brain, fibroblasts, heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocytes. Highest levels in heart and skeletal muscle. {ECO:0000269PubMed:8909283, ECO:0000269PubMed:9801304}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 16 experimentally validated interaction(s) in this database.
They are also associated with 17 interaction(s) predicted by orthology.

Experimentally validated
Total	16 [view]
Protein-Protein	14 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	2 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	17 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0000976	transcription regulatory region sequence-specific DNA binding
GO:0000989	transcription factor binding transcription factor activity
GO:0003677	DNA binding
GO:0003684	damaged DNA binding
GO:0003697	single-stranded DNA binding
GO:0003913	DNA photolyase activity
GO:0005515	protein binding
GO:0009882	blue light photoreceptor activity
GO:0019902	phosphatase binding
GO:0043130	ubiquitin binding
GO:0071949	FAD binding

Biological Process

GO:0000122	negative regulation of transcription from RNA polymerase II promoter
GO:0006281	DNA repair
GO:0006351	transcription, DNA-templated
GO:0007623	circadian rhythm
GO:0009785	blue light signaling pathway
GO:0018298	protein-chromophore linkage
GO:0032515	negative regulation of phosphoprotein phosphatase activity
GO:0032922	circadian regulation of gene expression
GO:0042593	glucose homeostasis
GO:0042752	regulation of circadian rhythm
GO:0042754	negative regulation of circadian rhythm
GO:0043153	entrainment of circadian clock by photoperiod
GO:0045892	negative regulation of transcription, DNA-templated
GO:2000118	regulation of sodium-dependent phosphate transport
GO:2000323	negative regulation of glucocorticoid receptor signaling pathway