Q49AN0 (CRY2_HUMAN) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 87. 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||593 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. 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). Ref.7 Ref.9
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 By similarity.
Binds 1 5,10-methenyltetrahydrofolate non-covalently per subunit By similarity.
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 PER1 and PER2 C-terminal domains. Interaction with PER2 inhibits its ubiquitination and vice versa. Interacts with NFIL3. Interacts with FBXL3 and FBXL21. FBXL3, PER2 and the cofactor FAD compete for overlapping binding sites. FBXL3 cannot bind CRY2 that interacts already with PER2 or that contains bound FAD. Interacts with PPP5C (via TPR repeats); the interaction downregulates the PPP5C phosphatase activity on CSNK1E. AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction, at least, with NR3C1/GR is ligand dependent. Interacts with PRKDC. Ref.9 Ref.10
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. Ref.1 Ref.6
Phosphorylation on Ser-266 by MAPK is important for the inhibition of CLOCK-ARNTL-mediated transcriptional activity. Phosphorylation by CSKNE requires interaction with PER1 or PER2. Phosphorylated in a circadian manner at Ser-554 and Ser-558 in the suprachiasmatic nucleus (SCN) and liver. Phosphorylation at Ser-558 by DYRK1A promotes subsequent phosphorylation at Ser-554 by GSK3-beta: the two-step phosphorylation at the neighboring Ser residues leads to its proteasomal degradation 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 CRY2. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY2 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. The SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser-554 and Ser-558. Ubiquitination may be inhibited by PER2.
Belongs to the DNA photolyase class-1 family.
Contains 1 photolyase/cryptochrome alpha/beta domain.
The sequence AAH35161.1 differs from that shown. Reason: Probable cloning artifact. Aberrant splice sites.
The sequence BAG57993.1 differs from that shown. Reason: Erroneous translation. Wrong choice of CDS.
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: Q49AN0-1) |
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform 2 (identifier: Q49AN0-2) |
The sequence of this isoform differs from the canonical sequence as follows:
1-72: MAATVATAAA...SSSVGINRWR → MPAPPGRTHTW
|Note: No experimental confirmation available.|
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 593||593||Cryptochrome-2||PRO_0000261148|
|Domain||22 – 151||130||Photolyase/cryptochrome alpha/beta|
|Nucleotide binding||406 – 408||3||FAD By similarity|
|Region||390 – 489||100||Required for inhibition of CLOCK-ARNTL-mediated transcription By similarity|
|Binding site||271||1||FAD; via amide nitrogen By similarity|
|Binding site||308||1||FAD By similarity|
|Binding site||374||1||FAD By similarity|
Amino acid modifications
|Modified residue||266||1||Phosphoserine; by MAPK By similarity|
|Modified residue||554||1||Phosphoserine; by GSK3-beta By similarity|
|Modified residue||558||1||Phosphoserine; by DYRK1A and MAPK By similarity|
|Cross-link||126||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|Cross-link||242||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|Cross-link||348||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|Cross-link||475||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|Cross-link||504||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity|
|Alternative sequence||1 – 72||72||MAATV…INRWR → MPAPPGRTHTW in isoform 2.||VSP_038970|
|Sequence conflict||422||1||S → G in AAH35161. Ref.4|
|Sequence conflict||9||1||H → L in BAG57993. Ref.2|
|||"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] (ISOFORM 1), CHARACTERIZATION, TISSUE SPECIFICITY.
Tissue: Fetal brain.
|||"Complete sequencing and characterization of 21,243 full-length human cDNAs."|
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
|||"Human chromosome 11 DNA sequence and analysis including novel gene identification."|
Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. Sakaki Y.
Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"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] (ISOFORM 1).
|||"Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro."|
Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.
DNA Res. 5:169-176(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 5-593 (ISOFORM 1).
|||"Characterization of photolyase/blue-light receptor homologs in mouse and human cells."|
Kobayashi K., Kanno S., Smit B., van der Horst G.T.J., Takao M., Yasui A.
Nucleic Acids Res. 26:5086-5092(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
|||"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.
|||"Nucleocytoplasmic shuttling and mCRY-dependent inhibition of ubiquitylation of the mPER2 clock protein."|
Yagita K., Tamanini F., Yasuda M., Hoeijmakers J.H., van der Horst G.T., Okamura H.
EMBO J. 21:1301-1314(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION.
|||"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: FUNCTION, 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.
|||"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.|
|AK294904 mRNA. Translation: BAG57993.1. Sequence problems.|
AC068385 Genomic DNA. No translation available.
BC035161 mRNA. Translation: AAH35161.1. Sequence problems.
BC041814 mRNA. Translation: AAH41814.1.
AB014558 mRNA. Translation: BAA31633.1.
|RefSeq||NP_001120929.1. NM_001127457.2. [Q49AN0-2]|
3D structure databases
|SMR||Q49AN0. Positions 22-513. |
Protein-protein interaction databases
|BioGrid||107798. 16 interactions.|
|IntAct||Q49AN0. 3 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENST00000417225; ENSP00000397419; ENSG00000121671. [Q49AN0-2]|
|UCSC||uc009ykw.3. human. [Q49AN0-2]|
uc010rgo.2. human. [Q49AN0-1]
|HGNC||HGNC:2385. CRY2. |
|MIM||603732. gene. |
Enzyme and pathway databases
|Reactome||REACT_24941. Circadian Clock. |
Gene expression databases
Family and domain databases
|Gene3D||126.96.36.1990. 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. |
|Accession||Primary (citable) accession number: Q49AN0|
Secondary accession number(s): B4DH32, O75148, Q8IV71
|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.|