Q16526 (CRY1_HUMAN) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 109. History...
Names and origin
|Protein names||Recommended name:|
|Organism||Homo sapiens (Human) [Reference proteome]|
|Taxonomic identifier||9606 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo|
|Sequence length||586 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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 CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/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. More potent transcriptional repressor in cerebellum and liver than CRY2, though more effective in lengthening the period of the SCN oscillator. On its side, CRY2 seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY2, is dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. Interacts with CLOCK:BMAL1 independently of PER proteins and is found at CLOCK:BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK:BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1. May repress circadian target genes expression in collaboration with HDAC1 and HDAC2 through histone deacetylation. Mediates the clock-control activation of ATR and modulates ATR-mediated DNA damage checkpoint. In liver, mediates circadian regulation of cAMP signaling and gluconeogenesis by binding to membrane-coupled G proteins and blocking glucagon-mediated increases in intracellular cAMP concentrations and CREB1 phosphorylation. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). 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. Ref.5 Ref.6 Ref.11
Binds 1 FAD per subunit. Only a minority of the protein molecules contain bound FAD. Contrary to the situation in photolyases, the FAD is bound in a shallow, surface-exposed pocket.
Binds 1 5,10-methenyltetrahydrofolate non-covalently per subunit.
Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARNTL or ARNTL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts directly with TIMELESS. Interacts directly with PER1 and PER2 C-terminal domains. Interaction with PER2 inhibits its ubiquitination and vice versa. Interacts with FBXL21. Interacts with FBXL3. Interacts with PPP5C (via TPR repeats). Interacts with of the CLOCK-ARNTL/BMAL1 independently of PER2 and DNA. Interacts with HDAC1, HDAC2 and SIN3B. Interacts with nuclear receptors AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction with at least NR3C1/GR is ligand dependent. Interacts with PRKDC. Interacts with the G protein subunit alpha GNAS; the interaction may block GPCR-mediated regulation of cAMP concentrations. Ref.7 Ref.8 Ref.9 Ref.10 Ref.11
Expression is regulated by light and circadian rhythms and osicllates diurnally. Peak expression in the suprachiasma nucleus (SCN) and eye at the day/night transition (CT12). Levels decrease with ARNTL-CLOCK inhibition as part of the autoregulatory feedback loop.
Phosphorylation on Ser-247 by MAPK is important for the inhibition of CLOCK-ARNTL-mediated transcriptional activity. Phosphorylation by CSNK1E requires interaction with PER1 or PER2. Phosphorylation at Ser-71 and Ser-280 by AMPK decreases protein stability. Phosphorylation at Ser-568 exhibits a robust circadian rhythm with a peak at CT8, increases protein stability, prevents SCF(FBXL3)-mediated degradation and is antagonized by interaction with PRKDC By similarity.
Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes, regulating the balance between degradation and stabilization. The SCF(FBXL3) complex is mainly nuclear and mediates ubiquitination and subsequent degradation of CRY1. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY1 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by the SCF(FBXL21) complex but not by the SCF(FBXL3) complex. Ubiquitination may be inhibit by PER2. Ref.8
Belongs to the DNA photolyase class-1 family.
Contains 1 photolyase/cryptochrome alpha/beta domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 586||586||Cryptochrome-1||PRO_0000261140|
|Domain||3 – 132||130||Photolyase/cryptochrome alpha/beta|
|Nucleotide binding||387 – 389||3||FAD By similarity|
|Region||371 – 470||100||Required for inhibition of CLOCK-ARNTL-mediated transcription By similarity|
|Binding site||252||1||FAD; via amide nitrogen By similarity|
|Binding site||289||1||FAD By similarity|
|Binding site||355||1||FAD By similarity|
Amino acid modifications
|Modified residue||71||1||Phosphoserine; by AMPK By similarity|
|Modified residue||247||1||Phosphoserine; by MAPK By similarity|
|Modified residue||280||1||Phosphoserine; by AMPK By similarity|
|Modified residue||568||1||Phosphoserine By similarity|
|Cross-link||11||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|Cross-link||107||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|Cross-link||159||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|Cross-link||329||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|Cross-link||485||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|||"Putative human blue-light photoreceptors hCRY1 and hCRY2 are flavoproteins."|
Hsu D.S., Zhao X., Zhao S., Kazantsev A., Wang R.-P., Todo T., Wei Y.-F., Sancar A.
Biochemistry 35:13871-13877(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION.
|||"Cloning, tissue expression, and mapping of a human photolyase homolog with similarity to plant blue-light receptors."|
van der Spek P.J., Kobayashi K., Bootsma D., Takao M., Eker A.P.M., Yasui A.
Genomics 37:177-182(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
|||"Similarity among the Drosophila (6-4)photolyase, a human photolyase homolog, and the DNA photolyase-blue-light photoreceptor family."|
Todo T., Ryo H., Yamamoto K., Toh H., Inui T., Ayaki H., Nomura T., Ikenaga M.
Science 272:109-112(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
|||"Light-independent role of CRY1 and CRY2 in the mammalian circadian clock."|
Griffin E.A. Jr., Staknis D., Weitz C.J.
Science 286:768-771(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation."|
Kawamoto T., Noshiro M., Sato F., Maemura K., Takeda N., Nagai R., Iwata T., Fujimoto K., Furukawa M., Miyazaki K., Honma S., Honma K.I., Kato Y.
Biochem. Biophys. Res. Commun. 313:117-124(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"Posttranslational regulation of the mammalian circadian clock by cryptochrome and protein phosphatase 5."|
Partch C.L., Shields K.F., Thompson C.L., Selby C.P., Sancar A.
Proc. Natl. Acad. Sci. U.S.A. 103:10467-10472(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PPP5C.
|||"SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins."|
Busino L., Bassermann F., Maiolica A., Lee C., Nolan P.M., Godinho S.I., Draetta G.F., Pagano M.
Science 316:900-904(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY, UBIQUITINATION BY FBXL3, INTERACTION WITH FBXL3.
|||"Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis."|
Zhang E.E., Liu Y., Dentin R., Pongsawakul P.Y., Liu A.C., Hirota T., Nusinow D.A., Sun X., Landais S., Kodama Y., Brenner D.A., Montminy M., Kay S.A.
Nat. Med. 16:1152-1156(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH GNAS.
|||"Biochemical analysis of the canonical model for the mammalian circadian clock."|
Ye R., Selby C.P., Ozturk N., Annayev Y., Sancar A.
J. Biol. Chem. 286:25891-25902(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PER2.
|||"Cryptochromes mediate rhythmic repression of the glucocorticoid receptor."|
Lamia K.A., Papp S.J., Yu R.T., Barish G.D., Uhlenhaut N.H., Jonker J.W., Downes M., Evans R.M.
Nature 480:552-556(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS NR3C1 REPRESSOR, INTERACTION WITH AR; NR1D1; NR3C1; RORA AND RORC.
|||"Metabolism and the circadian clock converge."|
Eckel-Mahan K., Sassone-Corsi P.
Physiol. Rev. 93:107-135(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
|||"Molecular architecture of the mammalian circadian clock."|
Partch C.L., Green C.B., Takahashi J.S.
Trends Cell Biol. 24:90-99(2014) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
|+||Additional computationally mapped references.|
|D84657 mRNA. Translation: BAA12710.1.|
D83702 mRNA. Translation: BAA12068.1.
BC030519 mRNA. Translation: AAH30519.1.
|RefSeq||NP_004066.1. NM_004075.4. |
3D structure databases
|SMR||Q16526. Positions 3-489. |
Protein-protein interaction databases
|BioGrid||107797. 25 interactions.|
|IntAct||Q16526. 12 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENST00000008527; ENSP00000008527; ENSG00000008405. |
|UCSC||uc001tmi.4. human. |
|HGNC||HGNC:2384. CRY1. |
|MIM||601933. gene. |
Enzyme and pathway databases
|Reactome||REACT_24941. Circadian Clock. |
Gene expression databases
Family and domain databases
|Gene3D||184.108.40.2060. 1 hit. |
|InterPro||IPR006050. DNA_photolyase_N. |
|Pfam||PF00875. DNA_photolyase. 1 hit. |
PF03441. FAD_binding_7. 1 hit.
|SUPFAM||SSF48173. SSF48173. 1 hit. |
SSF52425. SSF52425. 1 hit.
|PROSITE||PS51645. PHR_CRY_ALPHA_BETA. 1 hit. |
|ChiTaRS||CRY1. human. |
|Accession||Primary (citable) accession number: Q16526|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
|Disclaimer||Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.|