ID CRY2_MOUSE Reviewed; 592 AA. AC Q9R194; O08706; Q6A024; DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 14-OCT-2015, entry version 120. DE RecName: Full=Cryptochrome-2; GN Name=Cry2; Synonyms=Kiaa0658; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi; OC Muroidea; Muridae; Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, INDUCTION, RP AND INTERACTION WITH PER1; PER2; PER3 AND TIMELESS. RC STRAIN=C57BL/6; RX PubMed=10428031; DOI=10.1016/S0092-8674(00)81014-4; RA Kume K., Zylka M.J., Sriram S., Shearman L.P., Weaver D.R., Jin X., RA Maywood E.S., Hastings M.H., Reppert S.M.; RT "mCRY1 and mCRY2 are essential components of the negative limb of the RT circadian clock feedback loop."; RL Cell 98:193-205(1999). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Embryo, Fetal brain, and Thymus; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., RA Davis M.J., Wilming L.G., Aidinis V., Allen J.E., RA Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., RA Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., RA Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., RA Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., RA di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., RA Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., RA Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., RA Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., RA Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., RA Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., RA Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., RA Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., RA Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., RA Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., RA Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., RA Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., RA Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., RA Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., RA Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., RA Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., RA Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., RA Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., RA Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., RA Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., RA Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., RA Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., RA Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., RA Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., RA Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., RA Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6, and CD-1; TISSUE=Brain, and Neural stem cell; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 9-592. RC TISSUE=Fetal brain; RX PubMed=15368895; DOI=10.1093/dnares/11.3.205; RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S., RA Saga Y., Seino S., Nishimura M., Kaisho T., Hoshino K., Kitamura H., RA Nagase T., Ohara O., Koga H.; RT "Prediction of the coding sequences of mouse homologues of KIAA gene: RT IV. The complete nucleotide sequences of 500 mouse KIAA-homologous RT cDNAs identified by screening of terminal sequences of cDNA clones RT randomly sampled from size-fractionated libraries."; RL DNA Res. 11:205-218(2004). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] OF 24-592, TISSUE SPECIFICITY, AND RP SUBCELLULAR LOCATION. RC TISSUE=Liver; RX PubMed=9801304; DOI=10.1093/nar/26.22.5086; RA Kobayashi K., Kanno S., Smit B., van der Horst G.T.J., Takao M., RA Yasui A.; RT "Characterization of photolyase/blue-light receptor homologs in mouse RT and human cells."; RL Nucleic Acids Res. 26:5086-5092(1998). RN [6] RP TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=10521578; DOI=10.1016/S0169-328X(99)00192-8; RA Miyamoto Y., Sancar A.; RT "Circadian regulation of cryptochrome genes in the mouse."; RL Brain Res. Mol. Brain Res. 71:238-243(1999). RN [7] RP PHOSPHORYLATION AT SER-265 AND SER-557, AND MUTAGENESIS OF SER-265 AND RP SER-557. RX PubMed=15298678; DOI=10.1111/j.1356-9597.2004.00758.x; RA Sanada K., Harada Y., Sakai M., Todo T., Fukada Y.; RT "Serine phosphorylation of mCRY1 and mCRY2 by mitogen-activated RT protein kinase."; RL Genes Cells 9:697-708(2004). RN [8] RP INTERACTION WITH PER1 AND PER2, PHOSPHORYLATION, AND SUBCELLULAR RP LOCATION. RX PubMed=11875063; DOI=10.1074/jbc.M111466200; RA Eide E.J., Vielhaber E.L., Hinz W.A., Virshup D.M.; RT "The circadian regulatory proteins BMAL1 and cryptochromes are RT substrates of casein kinase Iepsilon."; RL J. Biol. Chem. 277:17248-17254(2002). RN [9] RP INTERACTION WITH PER1; PER2 AND PER3. RX PubMed=14701732; DOI=10.1128/MCB.24.2.584-594.2004; RA Lee C., Weaver D.R., Reppert S.M.; RT "Direct association between mouse PERIOD and CKIepsilon is critical RT for a functioning circadian clock."; RL Mol. Cell. Biol. 24:584-594(2004). RN [10] RP PHOSPHORYLATION AT SER-557, AND SUBCELLULAR LOCATION. RX PubMed=15980066; DOI=10.1074/jbc.M506225200; RA Harada Y., Sakai M., Kurabayashi N., Hirota T., Fukada Y.; RT "Ser-557-phosphorylated mCRY2 is degraded upon synergistic RT phosphorylation by glycogen synthase kinase-3 beta."; RL J. Biol. Chem. 280:31714-31721(2005). RN [11] RP INTERACTION WITH CLOCK-ARNTL COMPLEX, AND FUNCTION. RX PubMed=16628007; RA Kondratov R.V., Kondratova A.A., Lee C., Gorbacheva V.Y., RA Chernov M.V., Antoch M.P.; RT "Post-translational regulation of circadian transcriptional RT CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES."; RL Cell Cycle 5:890-895(2006). RN [12] RP INTERACTION WITH CLOCK AND ARNTL. RX PubMed=16717091; DOI=10.1074/jbc.M603722200; RA Etchegaray J.P., Yang X., DeBruyne J.P., Peters A.H., Weaver D.R., RA Jenuwein T., Reppert S.M.; RT "The polycomb group protein EZH2 is required for mammalian circadian RT clock function."; RL J. Biol. Chem. 281:21209-21215(2006). RN [13] RP INTERACTION WITH NFIL3. RX PubMed=17274955; DOI=10.1016/j.bbrc.2007.01.084; RA Ohno T., Onishi Y., Ishida N.; RT "The negative transcription factor E4BP4 is associated with circadian RT clock protein PERIOD2."; RL Biochem. Biophys. Res. Commun. 354:1010-1015(2007). RN [14] RP INTERACTION WITH FBXL3, AND UBIQUITINATION. RX PubMed=17462724; DOI=10.1016/j.cell.2007.04.030; RA Siepka S.M., Yoo S.H., Park J., Song W., Kumar V., Hu Y., Lee C., RA Takahashi J.S.; RT "Circadian mutant Overtime reveals F-box protein FBXL3 regulation of RT cryptochrome and period gene expression."; RL Cell 129:1011-1023(2007). RN [15] RP FUNCTION. RX PubMed=17310242; DOI=10.1038/ncb1539; RA Zhao W.N., Malinin N., Yang F.C., Staknis D., Gekakis N., Maier B., RA Reischl S., Kramer A., Weitz C.J.; RT "CIPC is a mammalian circadian clock protein without invertebrate RT homologues."; RL Nat. Cell Biol. 9:268-275(2007). RN [16] RP INTERACTION WITH ARNTL AND CLOCK, AND INDUCTION. RX PubMed=19917250; DOI=10.1016/j.molcel.2009.10.012; RA Chen R., Schirmer A., Lee Y., Lee H., Kumar V., Yoo S.H., RA Takahashi J.S., Lee C.; RT "Rhythmic PER abundance defines a critical nodal point for negative RT feedback within the circadian clock mechanism."; RL Mol. Cell 36:417-430(2009). RN [17] RP FUNCTION. RX PubMed=19299583; DOI=10.1126/science.1171641; RA Ramsey K.M., Yoshino J., Brace C.S., Abrassart D., Kobayashi Y., RA Marcheva B., Hong H.K., Chong J.L., Buhr E.D., Lee C., Takahashi J.S., RA Imai S., Bass J.; RT "Circadian clock feedback cycle through NAMPT-mediated NAD+ RT biosynthesis."; RL Science 324:651-654(2009). RN [18] RP INTERACTION WITH ARNTL AND PER2, SUBCELLULAR LOCATION, AND MUTAGENESIS RP OF ARG-501 AND LYS-503. RX PubMed=20840750; DOI=10.1186/1471-2199-11-69; RA Ozber N., Baris I., Tatlici G., Gur I., Kilinc S., Unal E.B., RA Kavakli I.H.; RT "Identification of two amino acids in the C-terminal domain of mouse RT CRY2 essential for PER2 interaction."; RL BMC Mol. Biol. 11:69-69(2010). RN [19] RP PHOSPHORYLATION AT SER-553 AND SER-557, AND MUTAGENESIS OF SER-553 AND RP SER-557. RX PubMed=20123978; DOI=10.1128/MCB.01047-09; RA Kurabayashi N., Hirota T., Sakai M., Sanada K., Fukada Y.; RT "DYRK1A and glycogen synthase kinase 3beta, a dual-kinase mechanism RT directing proteasomal degradation of CRY2 for circadian timekeeping."; RL Mol. Cell. Biol. 30:1757-1768(2010). RN [20] RP FUNCTION IN GLUCONEOGENESIS, AND DISRUPTION PHENOTYPE. RX PubMed=20852621; DOI=10.1038/nm.2214; RA Zhang E.E., Liu Y., Dentin R., Pongsawakul P.Y., Liu A.C., Hirota T., RA Nusinow D.A., Sun X., Landais S., Kodama Y., Brenner D.A., RA Montminy M., Kay S.A.; RT "Cryptochrome mediates circadian regulation of cAMP signaling and RT hepatic gluconeogenesis."; RL Nat. Med. 16:1152-1156(2010). RN [21] RP FUNCTION AS NR3C1 REPRESSOR, INTERACTION WITH AR AND NR3C1, AND RP DISRUPTION PHENOTYPE. RX PubMed=22170608; DOI=10.1038/nature10700; RA Lamia K.A., Papp S.J., Yu R.T., Barish G.D., Uhlenhaut N.H., RA Jonker J.W., Downes M., Evans R.M.; RT "Cryptochromes mediate rhythmic repression of the glucocorticoid RT receptor."; RL Nature 480:552-556(2011). RN [22] RP FUNCTION AS TRANSCRIPTIONAL REPRESSOR, INTERACTION WITH PER1, AND RP TISSUE SPECIFICITY. RX PubMed=24154698; DOI=10.1152/ajprenal.00472.2013; RA Richards J., Cheng K.Y., All S., Skopis G., Jeffers L., Lynch I.J., RA Wingo C.S., Gumz M.L.; RT "A role for the circadian clock protein Per1 in the regulation of RT aldosterone levels and renal Na+ retention."; RL Am. J. Physiol. 305:F1697-F1704(2013). RN [23] RP FUNCTION IN METABOLISM, AND DISRUPTION PHENOTYPE. RX PubMed=23531614; DOI=10.1152/ajpendo.00512.2012; RA Barclay J.L., Shostak A., Leliavski A., Tsang A.H., Johren O., RA Muller-Fielitz H., Landgraf D., Naujokat N., van der Horst G.T., RA Oster H.; RT "High-fat diet-induced hyperinsulinemia and tissue-specific insulin RT resistance in Cry-deficient mice."; RL Am. J. Physiol. 304:E1053-E1063(2013). RN [24] RP UBIQUITINATION BY THE SCF(FBXL3) AND SCF(FBXL21) COMPLEXES, AND RP INTERACTION WITH FBXL3 AND FBXL21. RX PubMed=23452855; DOI=10.1016/j.cell.2013.01.055; RA Yoo S.H., Mohawk J.A., Siepka S.M., Shan Y., Huh S.K., Hong H.K., RA Kornblum I., Kumar V., Koike N., Xu M., Nussbaum J., Liu X., Chen Z., RA Chen Z.J., Green C.B., Takahashi J.S.; RT "Competing E3 ubiquitin ligases govern circadian periodicity by RT degradation of CRY in nucleus and cytoplasm."; RL Cell 152:1091-1105(2013). RN [25] RP UBIQUITINATION BY THE SCF(FBXL3) AND SCF(FBXL21) COMPLEXES, RP UBIQUITINATION AT LYS-125; LYS-241; LYS-347; LYS-474 AND LYS-503, AND RP INTERACTION WITH FBXL3 AND FBXL21. RX PubMed=23452856; DOI=10.1016/j.cell.2013.01.054; RA Hirano A., Yumimoto K., Tsunematsu R., Matsumoto M., Oyama M., RA Kozuka-Hata H., Nakagawa T., Lanjakornsiripan D., Nakayama K.I., RA Fukada Y.; RT "FBXL21 regulates oscillation of the circadian clock through RT ubiquitination and stabilization of cryptochromes."; RL Cell 152:1106-1118(2013). RN [26] RP INTERACTION WITH PRKDC. RX PubMed=24158435; DOI=10.1074/jbc.M113.509604; RA Gao P., Yoo S.H., Lee K.J., Rosensweig C., Takahashi J.S., Chen B.P., RA Green C.B.; RT "Phosphorylation of the cryptochrome 1 C-terminal tail regulates RT circadian period length."; RL J. Biol. Chem. 288:35277-35286(2013). RN [27] RP FUNCTION IN CIRCADIAN CLOCK, AND DISRUPTION PHENOTYPE. RX PubMed=23616524; DOI=10.1523/JNEUROSCI.4950-12.2013; RA Anand S.N., Maywood E.S., Chesham J.E., Joynson G., Banks G.T., RA Hastings M.H., Nolan P.M.; RT "Distinct and separable roles for endogenous CRY1 and CRY2 within the RT circadian molecular clockwork of the suprachiasmatic nucleus, as RT revealed by the Fbxl3(Afh) mutation."; RL J. Neurosci. 33:7145-7153(2013). RN [28] RP FUNCTION IN CIRCADIAN RHYTHM MAINTENANCE. RX PubMed=23575670; DOI=10.1038/ncomms2670; RA Ono D., Honma S., Honma K.; RT "Cryptochromes are critical for the development of coherent circadian RT rhythms in the mouse suprachiasmatic nucleus."; RL Nat. Commun. 4:1666-1666(2013). RN [29] RP REVIEW. RX PubMed=23303907; DOI=10.1152/physrev.00016.2012; RA Eckel-Mahan K., Sassone-Corsi P.; RT "Metabolism and the circadian clock converge."; RL Physiol. Rev. 93:107-135(2013). RN [30] RP INTERACTION WITH CIART. RX PubMed=24736997; DOI=10.1371/journal.pbio.1001839; RA Goriki A., Hatanaka F., Myung J., Kim J.K., Yoritaka T., Tanoue S., RA Abe T., Kiyonari H., Fujimoto K., Kato Y., Todo T., Matsubara A., RA Forger D., Takumi T.; RT "A novel protein, CHRONO, functions as a core component of the RT mammalian circadian clock."; RL PLoS Biol. 12:E1001839-E1001839(2014). RN [31] RP REVIEW. RX PubMed=23916625; DOI=10.1016/j.tcb.2013.07.002; RA Partch C.L., Green C.B., Takahashi J.S.; RT "Molecular architecture of the mammalian circadian clock."; RL Trends Cell Biol. 24:90-99(2014). RN [32] RP X-RAY CRYSTALLOGRAPHY (1.94 ANGSTROMS) OF 1-512 IN COMPLEX WITH RP UBIQUITIN LIGASE SYNTHETIC INHIBITOR. RX PubMed=24080726; DOI=10.1038/cr.2013.136; RA Nangle S., Xing W., Zheng N.; RT "Crystal structure of mammalian cryptochrome in complex with a small RT molecule competitor of its ubiquitin ligase."; RL Cell Res. 23:1417-1419(2013). RN [33] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-512 IN COMPLEXES WITH FAD; RP SKP1 AND FBXL3, IDENTIFICATION IN A COMPLEX WITH SKP1 AND FBXL3, RP COFACTOR, IDENTIFICATION BY MASS SPECTROMETRY, AND MUTAGENESIS OF RP TRP-310; ASP-339; ARG-376; PHE-428; ILE-499 AND LEU-517. RX PubMed=23503662; DOI=10.1038/nature11964; RA Xing W., Busino L., Hinds T.R., Marionni S.T., Saifee N.H., Bush M.F., RA Pagano M., Zheng N.; RT "SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor RT pocket."; RL Nature 496:64-68(2013). CC -!- FUNCTION: Transcriptional repressor which forms a core component CC of the circadian clock. The circadian clock, an internal time- CC keeping system, regulates various physiological processes through CC the generation of approximately 24 hour circadian rhythms in gene CC expression, which are translated into rhythms in metabolism and CC behavior. It is derived from the Latin roots 'circa' (about) and CC 'diem' (day) and acts as an important regulator of a wide array of CC physiological functions including metabolism, sleep, body CC temperature, blood pressure, endocrine, immune, cardiovascular, CC and renal function. Consists of two major components: the central CC clock, residing in the suprachiasmatic nucleus (SCN) of the brain, CC and the peripheral clocks that are present in nearly every tissue CC and organ system. Both the central and peripheral clocks can be CC reset by environmental cues, also known as Zeitgebers (German for CC 'timegivers'). The predominant Zeitgeber for the central clock is CC light, which is sensed by retina and signals directly to the SCN. CC The central clock entrains the peripheral clocks through neuronal CC and hormonal signals, body temperature and feeding-related cues, CC aligning all clocks with the external light/dark cycle. Circadian CC rhythms allow an organism to achieve temporal homeostasis with its CC environment at the molecular level by regulating gene expression CC to create a peak of protein expression once every 24 hours to CC control when a particular physiological process is most active CC with respect to the solar day. Transcription and translation of CC core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, CC PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm CC generation, whereas delays imposed by post-translational CC modifications (PTMs) are important for determining the period CC (tau) of the rhythms (tau refers to the period of a rhythm and is CC the length, in time, of one complete cycle). A diurnal rhythm is CC synchronized with the day/night cycle, while the ultradian and CC infradian rhythms have a period shorter and longer than 24 hours, CC respectively. Disruptions in the circadian rhythms contribute to CC the pathology of cardiovascular diseases, cancer, metabolic CC syndromes and aging. A transcription/translation feedback loop CC (TTFL) forms the core of the molecular circadian clock mechanism. CC Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or CC ARNTL2/BMAL2, form the positive limb of the feedback loop, act in CC the form of a heterodimer and activate the transcription of core CC clock genes and clock-controlled genes (involved in key metabolic CC processes), harboring E-box elements (5'-CACGTG-3') within their CC promoters. The core clock genes: PER1/2/3 and CRY1/2 which are CC transcriptional repressors form the negative limb of the feedback CC loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 CC heterodimer inhibiting its activity and thereby negatively CC regulating their own expression. This heterodimer also activates CC nuclear receptors NR1D1/2 and RORA/B/G, which form a second CC feedback loop and which activate and repress ARNTL/BMAL1 CC transcription, respectively. CRY1 and CRY2 have redundant CC functions but also differential and selective contributions at CC least in defining the pace of the SCN circadian clock and its CC circadian transcriptional outputs. Less potent transcriptional CC repressor in cerebellum and liver than CRY1, though less effective CC in lengthening the period of the SCN oscillator. Seems to play a CC critical role in tuning SCN circadian period by opposing the CC action of CRY1. With CRY1, dispensable for circadian rhythm CC generation but necessary for the development of intercellular CC networks for rhythm synchrony. May mediate circadian regulation of CC cAMP signaling and gluconeogenesis by blocking glucagon-mediated CC increases in intracellular cAMP concentrations and in CREB1 CC phosphorylation. Besides its role in the maintenance of the CC circadian clock, is also involved in the regulation of other CC processes. Plays a key role in glucose and lipid metabolism CC modulation, in part, through the transcriptional regulation of CC genes involved in these pathways, such as LEP or ACSL4. Represses CC glucocorticoid receptor NR3C1/GR-induced transcriptional activity CC by binding to glucocorticoid response elements (GREs). Represses CC the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1 and CC NAMPT. {ECO:0000269|PubMed:10428031, ECO:0000269|PubMed:16628007, CC ECO:0000269|PubMed:17310242, ECO:0000269|PubMed:19299583, CC ECO:0000269|PubMed:20852621, ECO:0000269|PubMed:22170608, CC ECO:0000269|PubMed:23531614, ECO:0000269|PubMed:23575670, CC ECO:0000269|PubMed:23616524, ECO:0000269|PubMed:24154698}. CC -!- COFACTOR: CC Name=FAD; Xref=ChEBI:CHEBI:57692; CC Evidence={ECO:0000269|PubMed:23503662}; CC Note=Binds 1 FAD per subunit. Only a minority of the protein CC molecules contain bound FAD. Contrary to the situation in CC photolyases, the FAD is bound in a shallow, surface-exposed CC pocket. {ECO:0000269|PubMed:23503662}; CC -!- COFACTOR: CC Name=5,10-methylenetetrahydrofolate; Xref=ChEBI:CHEBI:12071; CC Evidence={ECO:0000250}; CC Note=Binds 1 5,10-methenyltetrahydrofolate non-covalently per CC subunit. {ECO:0000250}; CC -!- SUBUNIT: Component of the circadian core oscillator, which CC includes the CRY proteins, CLOCK or NPAS2, ARNTL/BMAL1 or CC ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER CC proteins. Interacts directly with PER1 and PER2 C-terminal CC domains. Interaction with PER2 inhibits its ubiquitination and CC vice versa. Interacts with NFIL3. Interacts with FBXL3 and FBXL21. CC FBXL3, PER2 and the cofactor FAD compete for overlapping binding CC sites. FBXL3 cannot bind CRY2 that interacts already with PER2 or CC that contains bound FAD. Interacts with PPP5C (via TPR repeats); CC the interaction downregulates the PPP5C phosphatase activity on CC CSNK1E. AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction, at CC least, with NR3C1/GR is ligand dependent. Interacts with PRKDC and CC CIART. {ECO:0000269|PubMed:10428031, ECO:0000269|PubMed:11875063, CC ECO:0000269|PubMed:14701732, ECO:0000269|PubMed:16628007, CC ECO:0000269|PubMed:16717091, ECO:0000269|PubMed:17274955, CC ECO:0000269|PubMed:17462724, ECO:0000269|PubMed:19917250, CC ECO:0000269|PubMed:20840750, ECO:0000269|PubMed:22170608, CC ECO:0000269|PubMed:23452855, ECO:0000269|PubMed:23452856, CC ECO:0000269|PubMed:23503662, ECO:0000269|PubMed:24080726, CC ECO:0000269|PubMed:24154698, ECO:0000269|PubMed:24158435, CC ECO:0000269|PubMed:24736997}. CC -!- INTERACTION: CC Q9WTL8:Arntl; NbExp=6; IntAct=EBI-1266619, EBI-644534; CC Q8BFZ4:Fbxl21; NbExp=4; IntAct=EBI-1266619, EBI-6898235; CC Q8C4V4:Fbxl3; NbExp=6; IntAct=EBI-1266619, EBI-1266589; CC O54943:Per2; NbExp=4; IntAct=EBI-1266619, EBI-1266779; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocated to the CC nucleus through interaction with other Clock proteins such as PER2 CC or ARNTL. CC -!- TISSUE SPECIFICITY: Expressed in all tissues examined including CC heart, brain, spleen, lung, liver, skeletal muscle, kidney and CC testis. Weak expression in spleen. {ECO:0000269|PubMed:10521578, CC ECO:0000269|PubMed:24154698, ECO:0000269|PubMed:9801304}. CC -!- INDUCTION: Shows no clear circadian oscillation pattern in testis, CC cerebellum nor liver. In skeletal muscle, under constant darkness CC and 12 hours light:12 hours dark conditions, levels peak between CC ZT6 and ZT9. {ECO:0000269|PubMed:10428031, CC ECO:0000269|PubMed:10521578, ECO:0000269|PubMed:19917250}. CC -!- PTM: Phosphorylation on Ser-265 by MAPK is important for the CC inhibition of CLOCK-ARNTL-mediated transcriptional activity. CC Phosphorylation by CSKNE requires interaction with PER1 or PER2. CC Phosphorylated in a circadian manner at Ser-553 and Ser-557 in the CC suprachiasmatic nucleus (SCN) and liver. Phosphorylation at Ser- CC 557 by DYRK1A promotes subsequent phosphorylation at Ser-553 by CC GSK3-beta: the two-step phosphorylation at the neighboring Ser CC residues leads to its proteasomal degradation. CC {ECO:0000269|PubMed:11875063, ECO:0000269|PubMed:15298678, CC ECO:0000269|PubMed:15980066, ECO:0000269|PubMed:20123978}. CC -!- PTM: Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes, CC regulating the balance between degradation and stabilization. The CC SCF(FBXL3) complex is mainly nuclear and mediates ubiquitination CC and subsequent degradation of CRY2. In contrast, cytoplasmic CC SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CC CRY2 and counteract the activity of the SCF(FBXL3) complex. The CC SCF(FBXL3) and SCF(FBXL21) complexes probably mediate CC ubiquitination at different Lys residues. The SCF(FBXL3) complex CC recognizes and binds CRY2 phosphorylated at Ser-553 and Ser-557. CC Ubiquitination may be inhibited by PER2. CC {ECO:0000269|PubMed:15298678, ECO:0000269|PubMed:15980066, CC ECO:0000269|PubMed:17462724, ECO:0000269|PubMed:20123978, CC ECO:0000269|PubMed:23452855, ECO:0000269|PubMed:23452856}. CC -!- DISRUPTION PHENOTYPE: Animals show longer circadian periods. CC Double knockouts of CRY1 and CRY2 show slightly decrease body CC weight and lose the cycling rhythmicity of feeding behavior, CC energy expenditure and glucocorticorids expression. Glucose CC homeostasis is severely disrupted and animals exhibit elevated CC blood glucose in response to acute feeding after an overnight fast CC as well as severely impaired glucose clearance in a glucose CC tolerance test. When challenged with high-fat diet, animals CC rapidly gain weight and surpass that of wild-type mice, despite CC displaying hypophagia. They exhibit hyperinsulinemia and selective CC insulin resistance in the liver and muscle but show high insulin CC sensitivity in adipose tissue and consequent increased lipid CC uptake. Mice display enlarged gonadal, subcutaneous and perirenal CC fat deposits with adipocyte hypertrophy and increased lipied CC accumulation in liver. {ECO:0000269|PubMed:20852621, CC ECO:0000269|PubMed:22170608, ECO:0000269|PubMed:23531614, CC ECO:0000269|PubMed:23616524}. CC -!- SIMILARITY: Belongs to the DNA photolyase class-1 family. CC {ECO:0000305}. CC -!- SIMILARITY: Contains 1 photolyase/cryptochrome alpha/beta domain. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF156987; AAD46561.1; -; mRNA. DR EMBL; AK041696; BAC31037.1; -; mRNA. DR EMBL; AK133781; BAE21836.1; -; mRNA. DR EMBL; BC054794; AAH54794.1; -; mRNA. DR EMBL; BC066799; AAH66799.1; -; mRNA. DR EMBL; AK172994; BAD32272.1; -; mRNA. DR EMBL; AB003433; BAA19864.1; -; mRNA. DR CCDS; CCDS16447.1; -. DR RefSeq; NP_034093.1; NM_009963.4. DR UniGene; Mm.254181; -. DR PDB; 4I6E; X-ray; 2.70 A; A=1-512. DR PDB; 4I6G; X-ray; 2.20 A; A/B=1-512. DR PDB; 4I6J; X-ray; 2.70 A; A=1-544. DR PDB; 4MLP; X-ray; 1.94 A; A/B/C/D=1-512. DR PDB; 4U8H; X-ray; 2.80 A; A/C=1-510. DR PDBsum; 4I6E; -. DR PDBsum; 4I6G; -. DR PDBsum; 4I6J; -. DR PDBsum; 4MLP; -. DR PDBsum; 4U8H; -. DR ProteinModelPortal; Q9R194; -. DR SMR; Q9R194; 21-512. DR BioGrid; 198907; 15. DR DIP; DIP-38517N; -. DR IntAct; Q9R194; 13. DR STRING; 10090.ENSMUSP00000088047; -. DR PhosphoSite; Q9R194; -. DR MaxQB; Q9R194; -. DR PaxDb; Q9R194; -. DR PRIDE; Q9R194; -. DR Ensembl; ENSMUST00000090559; ENSMUSP00000088047; ENSMUSG00000068742. DR Ensembl; ENSMUST00000111278; ENSMUSP00000106909; ENSMUSG00000068742. DR GeneID; 12953; -. DR KEGG; mmu:12953; -. DR UCSC; uc008kxy.2; mouse. DR CTD; 1408; -. DR MGI; MGI:1270859; Cry2. DR eggNOG; COG0415; -. DR GeneTree; ENSGT00500000044813; -. DR HOGENOM; HOG000245622; -. DR HOVERGEN; HBG053470; -. DR InParanoid; Q9R194; -. DR KO; K02295; -. DR OMA; IQENHDD; -. DR OrthoDB; EOG7QG43M; -. DR PhylomeDB; Q9R194; -. DR TreeFam; TF323191; -. DR Reactome; R-MMU-1368108; BMAL1:CLOCK,NPAS2 activates circadian gene expression. DR Reactome; R-MMU-1368110; Bmal1:Clock,Npas2 activates circadian gene expression. DR Reactome; R-MMU-400253; Circadian Clock. DR Reactome; R-MMU-508751; Circadian Clock. DR NextBio; 282666; -. DR PRO; PR:Q9R194; -. DR Proteomes; UP000000589; Chromosome 2. DR Bgee; Q9R194; -. DR CleanEx; MM_CRY2; -. DR Genevisible; Q9R194; MM. DR GO; GO:0005737; C:cytoplasm; ISO:MGI. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0003684; F:damaged DNA binding; ISO:MGI. DR GO; GO:0003677; F:DNA binding; ISO:MGI. DR GO; GO:0003913; F:DNA photolyase activity; IEA:InterPro. DR GO; GO:0071949; F:FAD binding; IDA:UniProtKB. DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB. DR GO; GO:0035257; F:nuclear hormone receptor binding; IPI:UniProtKB. DR GO; GO:0019902; F:phosphatase binding; ISO:MGI. DR GO; GO:0009881; F:photoreceptor activity; IEA:UniProtKB-KW. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0003697; F:single-stranded DNA binding; ISO:MGI. DR GO; GO:0000989; F:transcription factor activity, transcription factor binding; ISO:MGI. DR GO; GO:0000976; F:transcription regulatory region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0043130; F:ubiquitin binding; ISS:UniProtKB. DR GO; GO:0032922; P:circadian regulation of gene expression; IMP:UniProtKB. DR GO; GO:0007623; P:circadian rhythm; IMP:UniProtKB. DR GO; GO:0006281; P:DNA repair; IEA:InterPro. DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; IMP:UniProtKB. DR GO; GO:0042593; P:glucose homeostasis; IGI:UniProtKB. DR GO; GO:0019915; P:lipid storage; IGI:UniProtKB. DR GO; GO:0042754; P:negative regulation of circadian rhythm; IDA:UniProtKB. DR GO; GO:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; IGI:UniProtKB. DR GO; GO:2000850; P:negative regulation of glucocorticoid secretion; IGI:UniProtKB. DR GO; GO:0032515; P:negative regulation of phosphoprotein phosphatase activity; ISO:MGI. DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; ISO:MGI. DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB. DR GO; GO:0006606; P:protein import into nucleus; IPI:MGI. DR GO; GO:0018298; P:protein-chromophore linkage; IEA:UniProtKB-KW. DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB. DR GO; GO:0032868; P:response to insulin; IGI:UniProtKB. DR GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-KW. DR Gene3D; 3.40.50.620; -; 1. DR InterPro; IPR005101; Cryptochr/Photolyase_FAD-bd. DR InterPro; IPR006050; DNA_photolyase_N. DR InterPro; IPR014729; Rossmann-like_a/b/a_fold. DR Pfam; PF00875; DNA_photolyase; 1. DR Pfam; PF03441; FAD_binding_7; 1. DR SUPFAM; SSF48173; SSF48173; 1. DR SUPFAM; SSF52425; SSF52425; 1. DR PROSITE; PS51645; PHR_CRY_ALPHA_BETA; 1. PE 1: Evidence at protein level; KW 3D-structure; Biological rhythms; Chromophore; Complete proteome; KW Cytoplasm; FAD; Flavoprotein; Isopeptide bond; Nucleotide-binding; KW Nucleus; Phosphoprotein; Photoreceptor protein; Receptor; KW Reference proteome; Repressor; Sensory transduction; Transcription; KW Transcription regulation; Ubl conjugation. FT CHAIN 1 592 Cryptochrome-2. FT /FTId=PRO_0000261149. FT DOMAIN 21 150 Photolyase/cryptochrome alpha/beta. FT NP_BIND 405 407 FAD. FT REGION 389 488 Required for inhibition of CLOCK-ARNTL- FT mediated transcription. {ECO:0000250}. FT COMPBIAS 2 5 Poly-Ala. FT BINDING 270 270 FAD; via amide nitrogen. FT BINDING 307 307 FAD. {ECO:0000250}. FT BINDING 373 373 FAD. FT MOD_RES 89 89 Phosphoserine. FT {ECO:0000250|UniProtKB:P97784}. FT MOD_RES 265 265 Phosphoserine; by MAPK. FT {ECO:0000269|PubMed:11875063, FT ECO:0000269|PubMed:15298678}. FT MOD_RES 298 298 Phosphoserine. FT {ECO:0000250|UniProtKB:P97784}. FT MOD_RES 553 553 Phosphoserine; by GSK3-beta. FT {ECO:0000269|PubMed:11875063, FT ECO:0000269|PubMed:20123978}. FT MOD_RES 557 557 Phosphoserine; by DYRK1A and MAPK. FT {ECO:0000269|PubMed:11875063, FT ECO:0000269|PubMed:15298678, FT ECO:0000269|PubMed:15980066, FT ECO:0000269|PubMed:20123978}. FT CROSSLNK 125 125 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT {ECO:0000269|PubMed:23452856}. FT CROSSLNK 241 241 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT {ECO:0000269|PubMed:23452856}. FT CROSSLNK 347 347 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT {ECO:0000269|PubMed:23452856}. FT CROSSLNK 474 474 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT {ECO:0000269|PubMed:23452856}. FT CROSSLNK 503 503 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT {ECO:0000269|PubMed:23452856}. FT MUTAGEN 265 265 S->A: Reduced in vitro MAPK-catalyzed FT phosphorylation. No effect on inhibition FT of CLOCK-ARNTL-mediated transcriptional FT activity. Very little in vitro MAPK- FT catalyzed phosphorylation; when FT associated with A-557. FT {ECO:0000269|PubMed:15298678}. FT MUTAGEN 265 265 S->D: Reduced inhibition of CLOCK-ARNTL- FT mediated transcriptional activity. No FT effect on nuclear localization nor on FT protein stability. FT {ECO:0000269|PubMed:15298678}. FT MUTAGEN 310 310 W->A: Decreases FBXL3 binding. Strongly FT decreases CRY2 degradation. FT {ECO:0000269|PubMed:23503662}. FT MUTAGEN 339 339 D->R: Strongly reduces PER1 binding. FT {ECO:0000269|PubMed:23503662}. FT MUTAGEN 376 376 R->A: Impairs protein folding. Abolishes FT binding of ARNTL, PER1 and FBXL3. FT Strongly reduces SKP1 binding. FT {ECO:0000269|PubMed:23503662}. FT MUTAGEN 428 428 F->D: Abolishes binding of FBXL3 and FT SKP1. Strongly decreases CRY2 FT degradation. FT {ECO:0000269|PubMed:23503662}. FT MUTAGEN 499 499 I->D: Abolishes binding of FBXL3 and FT SKP1. Strongly decreases CRY2 FT degradation. FT {ECO:0000269|PubMed:23503662}. FT MUTAGEN 501 501 R->Q: Inhibits interaction with PER2. FT Does not suppress its nuclear FT localization. Inhibits its repression FT activity on CLOCK|NPAS2-ARNTL-driven FT transcription. FT {ECO:0000269|PubMed:20840750}. FT MUTAGEN 503 503 K->R: Inhibits interaction with PER2. FT Does not suppress its nuclear FT localization. Inhibits its repression FT activity on CLOCK|NPAS2-ARNTL-driven FT transcription. FT {ECO:0000269|PubMed:20840750}. FT MUTAGEN 517 517 L->D: Decreases FBXL3 binding. Strongly FT decreases CRY2 degradation. FT {ECO:0000269|PubMed:23503662}. FT MUTAGEN 553 553 S->A: Shorter circadian rhythm; when FT associated with A-557. FT {ECO:0000269|PubMed:20123978}. FT MUTAGEN 557 557 S->A: Reduced in vitro MAPK-catalyzed FT phosphorylation. No effect on inhibition FT of CLOCK-ARNTL-mediated transcriptional FT activity. Very little in vitro MAPK- FT catalyzed phosphorylation; when FT associated with A-265. Shorter circadian FT rhythm; when associated with A-553. FT {ECO:0000269|PubMed:15298678, FT ECO:0000269|PubMed:20123978}. FT MUTAGEN 557 557 S->D: Reduced inhibition of CLOCK-ARNTL- FT mediated transcriptional activity. No FT effect on nuclear localization nor on FT protein stability. FT {ECO:0000269|PubMed:15298678, FT ECO:0000269|PubMed:20123978}. FT CONFLICT 191 192 QQ -> SR (in Ref. 5; BAA19864). FT {ECO:0000305}. FT CONFLICT 202 202 E -> K (in Ref. 5; BAA19864). FT {ECO:0000305}. FT CONFLICT 327 327 M -> V (in Ref. 5; BAA19864). FT {ECO:0000305}. FT STRAND 22 26 {ECO:0000244|PDB:4MLP}. FT STRAND 32 35 {ECO:0000244|PDB:4MLP}. FT HELIX 37 43 {ECO:0000244|PDB:4MLP}. FT STRAND 47 55 {ECO:0000244|PDB:4MLP}. FT HELIX 59 61 {ECO:0000244|PDB:4MLP}. FT HELIX 67 85 {ECO:0000244|PDB:4MLP}. FT TURN 86 88 {ECO:0000244|PDB:4MLP}. FT STRAND 91 96 {ECO:0000244|PDB:4MLP}. FT HELIX 98 109 {ECO:0000244|PDB:4MLP}. FT STRAND 113 117 {ECO:0000244|PDB:4MLP}. FT HELIX 122 137 {ECO:0000244|PDB:4MLP}. FT STRAND 141 145 {ECO:0000244|PDB:4MLP}. FT STRAND 148 151 {ECO:0000244|PDB:4MLP}. FT HELIX 153 159 {ECO:0000244|PDB:4MLP}. FT TURN 160 162 {ECO:0000244|PDB:4I6E}. FT HELIX 168 176 {ECO:0000244|PDB:4MLP}. FT HELIX 190 194 {ECO:0000244|PDB:4MLP}. FT HELIX 204 208 {ECO:0000244|PDB:4MLP}. FT TURN 213 217 {ECO:0000244|PDB:4MLP}. FT HELIX 232 242 {ECO:0000244|PDB:4MLP}. FT HELIX 245 251 {ECO:0000244|PDB:4MLP}. FT HELIX 259 262 {ECO:0000244|PDB:4MLP}. FT HELIX 270 274 {ECO:0000244|PDB:4MLP}. FT HELIX 280 294 {ECO:0000244|PDB:4MLP}. FT STRAND 295 297 {ECO:0000244|PDB:4I6G}. FT HELIX 302 305 {ECO:0000244|PDB:4MLP}. FT HELIX 306 318 {ECO:0000244|PDB:4MLP}. FT TURN 322 325 {ECO:0000244|PDB:4MLP}. FT HELIX 342 350 {ECO:0000244|PDB:4MLP}. FT HELIX 356 368 {ECO:0000244|PDB:4MLP}. FT HELIX 373 383 {ECO:0000244|PDB:4MLP}. FT TURN 384 388 {ECO:0000244|PDB:4MLP}. FT HELIX 392 402 {ECO:0000244|PDB:4MLP}. FT HELIX 408 418 {ECO:0000244|PDB:4MLP}. FT STRAND 421 423 {ECO:0000244|PDB:4MLP}. FT HELIX 435 440 {ECO:0000244|PDB:4MLP}. FT HELIX 445 450 {ECO:0000244|PDB:4MLP}. FT HELIX 452 454 {ECO:0000244|PDB:4MLP}. FT HELIX 459 462 {ECO:0000244|PDB:4MLP}. FT HELIX 465 467 {ECO:0000244|PDB:4MLP}. FT HELIX 470 475 {ECO:0000244|PDB:4MLP}. FT TURN 480 482 {ECO:0000244|PDB:4MLP}. FT HELIX 491 507 {ECO:0000244|PDB:4MLP}. FT STRAND 517 521 {ECO:0000244|PDB:4I6J}. SQ SEQUENCE 592 AA; 66850 MW; 4D6E7B199C392CBB CRC64; MAAAAVVAAT VPAQSMGADG ASSVHWFRKG LRLHDNPALL AAVRGARCVR CVYILDPWFA ASSSVGINRW RFLLQSLEDL DTSLRKLNSR LFVVRGQPAD VFPRLFKEWG VTRLTFEYDS EPFGKERDAA IMKMAKEAGV EVVTENSHTL YDLDRIIELN GQKPPLTYKR FQALISRMEL PKKPAVAVSS QQMESCRAEI QENHDDTYGV PSLEELGFPT EGLGPAVWQG GETEALARLD KHLERKAWVA NYERPRMNAN SLLASPTGLS PYLRFGCLSC RLFYYRLWDL YKKVKRNSTP PLSLFGQLLW REFFYTAATN NPRFDRMEGN PICIQIPWDR NPEALAKWAE GKTGFPWIDA IMTQLRQEGW IHHLARHAVA CFLTRGDLWV SWESGVRVFD ELLLDADFSV NAGSWMWLSC SAFFQQFFHC YCPVGFGRRT DPSGDYIRRY LPKLKGFPSR YIYEPWNAPE SVQKAAKCII GVDYPRPIVN HAETSRLNIE RMKQIYQQLS RYRGLCLLAS VPSCVEDLSH PVAEPGSSQA GSISNTGPRA LSSGPASPKR KLEAAEEPPG EELTKRARVT EMPTQEPASK DS //