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 27-MAR-2024, entry version 172. DE RecName: Full=Cryptochrome-2; GN Name=Cry2; Synonyms=Kiaa0658; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, INDUCTION, AND RP INTERACTION WITH PER1; PER2; PER3 AND TIMELESS. RC STRAIN=C57BL/6J; 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., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., 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., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., 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/6J, 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 project: RT 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: IV. RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs RT identified by screening of terminal sequences of cDNA clones randomly RT sampled from size-fractionated libraries."; RL DNA Res. 11:205-218(2004). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] OF 24-592, TISSUE SPECIFICITY, AND SUBCELLULAR RP 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., Yasui A.; RT "Characterization of photolyase/blue-light receptor homologs in mouse and RT 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 IDENTIFICATION IN A COMPLEX WITH CLOCK; PER1; PER2; CRY1; CRY2; CSNK1D AND RP CSNK1E, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=11779462; DOI=10.1016/s0092-8674(01)00610-9; RA Lee C., Etchegaray J.-P., Cagampang F.R.A., Loudon A.S.I., Reppert S.M.; RT "Posttranslational mechanisms regulate the mammalian circadian clock."; RL Cell 107:855-867(2001). RN [8] 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 protein RT kinase."; RL Genes Cells 9:697-708(2004). RN [9] RP INTERACTION WITH PER1 AND PER2, PHOSPHORYLATION, AND SUBCELLULAR 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 substrates RT of casein kinase Iepsilon."; RL J. Biol. Chem. 277:17248-17254(2002). RN [10] 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 for a RT functioning circadian clock."; RL Mol. Cell. Biol. 24:584-594(2004). RN [11] 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 phosphorylation RT by glycogen synthase kinase-3 beta."; RL J. Biol. Chem. 280:31714-31721(2005). RN [12] RP INTERACTION WITH CLOCK-BMAL1 COMPLEX, AND FUNCTION. RX PubMed=16628007; DOI=10.4161/cc.5.8.2684; RA Kondratov R.V., Kondratova A.A., Lee C., Gorbacheva V.Y., Chernov M.V., RA 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 [13] RP INTERACTION WITH CLOCK AND BMAL1. 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 clock RT function."; RL J. Biol. Chem. 281:21209-21215(2006). RN [14] 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 clock RT protein PERIOD2."; RL Biochem. Biophys. Res. Commun. 354:1010-1015(2007). RN [15] 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 [16] 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 [17] RP INTERACTION WITH BMAL1 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., Takahashi J.S., RA 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 [18] 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+ biosynthesis."; RL Science 324:651-654(2009). RN [19] RP INTERACTION WITH BMAL1 AND PER2, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP 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., Kavakli I.H.; RT "Identification of two amino acids in the C-terminal domain of mouse CRY2 RT essential for PER2 interaction."; RL BMC Mol. Biol. 11:69-69(2010). RN [20] 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 [21] 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., Montminy M., RA Kay S.A.; RT "Cryptochrome mediates circadian regulation of cAMP signaling and hepatic RT gluconeogenesis."; RL Nat. Med. 16:1152-1156(2010). RN [22] RP FUNCTION AS NR3C1 REPRESSOR, INTERACTION WITH AR AND NR3C1, AND DISRUPTION RP PHENOTYPE. RX PubMed=22170608; DOI=10.1038/nature10700; RA Lamia K.A., Papp S.J., Yu R.T., Barish G.D., Uhlenhaut N.H., Jonker J.W., RA Downes M., Evans R.M.; RT "Cryptochromes mediate rhythmic repression of the glucocorticoid RT receptor."; RL Nature 480:552-556(2011). RN [23] RP ACTIVITY REGULATION. RX PubMed=22798407; DOI=10.1126/science.1223710; RA Hirota T., Lee J.W., St John P.C., Sawa M., Iwaisako K., Noguchi T., RA Pongsawakul P.Y., Sonntag T., Welsh D.K., Brenner D.A., Doyle F.J. III, RA Schultz P.G., Kay S.A.; RT "Identification of small molecule activators of cryptochrome."; RL Science 337:1094-1097(2012). RN [24] RP FUNCTION AS TRANSCRIPTIONAL REPRESSOR, INTERACTION WITH PER1, AND TISSUE RP 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 [25] 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., 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 [26] RP UBIQUITINATION BY THE SCF(FBXL3) AND SCF(FBXL21) COMPLEXES, AND INTERACTION RP 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 degradation RT of CRY in nucleus and cytoplasm."; RL Cell 152:1091-1105(2013). RN [27] RP UBIQUITINATION BY THE SCF(FBXL3) AND SCF(FBXL21) COMPLEXES, UBIQUITINATION RP AT LYS-125; LYS-241; LYS-347; LYS-474 AND LYS-503, AND INTERACTION WITH RP 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., Fukada Y.; RT "FBXL21 regulates oscillation of the circadian clock through ubiquitination RT and stabilization of cryptochromes."; RL Cell 152:1106-1118(2013). RN [28] 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 circadian RT period length."; RL J. Biol. Chem. 288:35277-35286(2013). RN [29] 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 revealed RT by the Fbxl3(Afh) mutation."; RL J. Neurosci. 33:7145-7153(2013). RN [30] 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 [31] 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 [32] 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., Abe T., RA Kiyonari H., Fujimoto K., Kato Y., Todo T., Matsubara A., Forger D., RA Takumi T.; RT "A novel protein, CHRONO, functions as a core component of the mammalian RT circadian clock."; RL PLoS Biol. 12:E1001839-E1001839(2014). RN [33] 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 [34] RP UBIQUITINATION AND PROTEASOMAL DEGRADATION. RX PubMed=26776516; DOI=10.1016/j.celrep.2015.12.076; RA Shi G., Xie P., Qu Z., Zhang Z., Dong Z., An Y., Xing L., Liu Z., Dong Y., RA Xu G., Yang L., Liu Y., Xu Y.; RT "Distinct roles of HDAC3 in the core circadian negative feedback loop are RT critical for clock function."; RL Cell Rep. 14:823-834(2016). RN [35] RP DEUBIQUITINATION BY USP7, AND INTERACTION WITH DDB1; USP7 AND TARDBP. RX PubMed=27123980; DOI=10.1371/journal.pone.0154263; RA Hirano A., Nakagawa T., Yoshitane H., Oyama M., Kozuka-Hata H., RA Lanjakornsiripan D., Fukada Y.; RT "USP7 and TDP-43: pleiotropic regulation of cryptochrome protein stability RT paces the oscillation of the mammalian circadian clock."; RL PLoS ONE 11:E0154263-E0154263(2016). RN [36] RP FUNCTION, DISRUPTION PHENOTYPE, AND INTERACTION WITH PPARA; PPARD AND RP PPARG. RX PubMed=28683290; DOI=10.1016/j.cmet.2017.06.002; RA Jordan S.D., Kriebs A., Vaughan M., Duglan D., Fan W., Henriksson E., RA Huber A.L., Papp S.J., Nguyen M., Afetian M., Downes M., Yu R.T., RA Kralli A., Evans R.M., Lamia K.A.; RT "CRY1/2 selectively repress PPARdelta and limit exercise capacity."; RL Cell Metab. 26:243-255(2017). RN [37] RP FUNCTION, INTERACTION WITH NR1I2; NR1I3; NR3C1; PPARD; VDR; AR AND HNF4A, RP AND MUTAGENESIS OF GLY-351; GLY-354; SER-394; VAL-396 AND ARG-397. RX PubMed=28751364; DOI=10.1073/pnas.1704955114; RA Kriebs A., Jordan S.D., Soto E., Henriksson E., Sandate C.R., Vaughan M.E., RA Chan A.B., Duglan D., Papp S.J., Huber A.L., Afetian M.E., Yu R.T., RA Zhao X., Downes M., Evans R.M., Lamia K.A.; RT "Circadian repressors CRY1 and CRY2 broadly interact with nuclear receptors RT and modulate transcriptional activity."; RL Proc. Natl. Acad. Sci. U.S.A. 114:8776-8781(2017). RN [38] RP DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY. RX PubMed=29561690; DOI=10.1096/fj.201701165rr; RA Wong J.C.Y., Smyllie N.J., Banks G.T., Pothecary C.A., Barnard A.R., RA Maywood E.S., Jagannath A., Hughes S., van der Horst G.T.J., MacLaren R.E., RA Hankins M.W., Hastings M.H., Nolan P.M., Foster R.G., Peirson S.N.; RT "Differential roles for cryptochromes in the mammalian retinal clock."; RL FASEB J. 32:4302-4314(2018). RN [39] RP X-RAY CRYSTALLOGRAPHY (1.94 ANGSTROMS) OF 1-512 IN COMPLEX WITH UBIQUITIN RP 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 [40] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-512 IN COMPLEXES WITH FAD; SKP1 RP AND FBXL3, IDENTIFICATION IN A COMPLEX WITH SKP1 AND FBXL3, COFACTOR, RP IDENTIFICATION BY MASS SPECTROMETRY, FAD-BINDING SITES, 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 of the CC circadian clock. The circadian clock, an internal time-keeping system, CC regulates various physiological processes through the generation of CC approximately 24 hour circadian rhythms in gene expression, which are CC translated into rhythms in metabolism and behavior. It is derived from CC the Latin roots 'circa' (about) and 'diem' (day) and acts as an CC important regulator of a wide array of physiological functions CC including metabolism, sleep, body temperature, blood pressure, CC endocrine, immune, cardiovascular, and renal function. Consists of two CC major components: the central clock, residing in the suprachiasmatic CC nucleus (SCN) of the brain, and the peripheral clocks that are present CC in nearly every tissue and organ system. Both the central and CC peripheral clocks can be reset by environmental cues, also known as CC Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the CC central clock is light, which is sensed by retina and signals directly CC to the SCN. The central clock entrains the peripheral clocks through CC neuronal and hormonal signals, body temperature and feeding-related CC cues, 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 to CC create a peak of protein expression once every 24 hours to control when CC a particular physiological process is most active with respect to the CC solar day. Transcription and translation of core clock components CC (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a CC critical role in rhythm generation, whereas delays imposed by post- CC translational modifications (PTMs) are important for determining the CC period (tau) of the rhythms (tau refers to the period of a rhythm and CC is 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 the CC pathology of cardiovascular diseases, cancer, metabolic syndromes and CC aging. A transcription/translation feedback loop (TTFL) forms the core CC of the molecular circadian clock mechanism. Transcription factors, CC CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the CC feedback loop, act in the form of a heterodimer and activate the CC transcription of core clock genes and clock-controlled genes (involved CC in key metabolic processes), harboring E-box elements (5'-CACGTG-3') CC within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which CC are transcriptional repressors form the negative limb of the feedback CC loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer CC inhibiting its activity and thereby negatively regulating their own CC expression. This heterodimer also activates nuclear receptors NR1D1/2 CC and RORA/B/G, which form a second feedback loop and which activate and CC repress BMAL1 transcription, respectively. CRY1 and CRY2 have redundant CC functions but also differential and selective contributions at least in CC defining the pace of the SCN circadian clock and its circadian CC transcriptional outputs. Less potent transcriptional repressor in CC cerebellum and liver than CRY1, though less effective in lengthening CC the period of the SCN oscillator. Seems to play a critical role in CC tuning SCN circadian period by opposing the action of CRY1. With CRY1, CC dispensable for circadian rhythm generation but necessary for the CC development of intercellular networks for rhythm synchrony. May mediate CC circadian regulation of cAMP signaling and gluconeogenesis by blocking CC glucagon-mediated increases in intracellular cAMP concentrations and in CC CREB1 phosphorylation. Besides its role in the maintenance of the CC circadian clock, is also involved in the regulation of other processes. CC Plays a key role in glucose and lipid metabolism modulation, in part, CC through the transcriptional regulation of genes involved in these CC pathways, such as LEP or ACSL4. Represses glucocorticoid receptor CC NR3C1/GR-induced transcriptional activity by binding to glucocorticoid CC response elements (GREs). Represses the CLOCK-BMAL1 induced CC transcription of BHLHE40/DEC1 and NAMPT. Represses PPARD and its target CC genes in the skeletal muscle and limits exercise capacity CC (PubMed:28683290). Represses the transcriptional activity of NR1I2 CC (PubMed:28751364). {ECO:0000269|PubMed:10428031, CC ECO:0000269|PubMed:16628007, ECO:0000269|PubMed:17310242, CC ECO:0000269|PubMed:19299583, ECO:0000269|PubMed:20852621, CC ECO:0000269|PubMed:22170608, ECO:0000269|PubMed:23531614, CC ECO:0000269|PubMed:23575670, ECO:0000269|PubMed:23616524, CC ECO:0000269|PubMed:24154698, ECO:0000269|PubMed:28683290, CC ECO:0000269|PubMed:28751364}. 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 molecules CC contain bound FAD. Contrary to the situation in photolyases, the FAD is CC bound in a shallow, surface-exposed pocket. CC {ECO:0000269|PubMed:23503662}; CC -!- COFACTOR: CC Name=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate; CC Xref=ChEBI:CHEBI:15636; Evidence={ECO:0000250}; CC Note=Binds 1 5,10-methenyltetrahydrofolate (MTHF) non-covalently per CC subunit. {ECO:0000250}; CC -!- ACTIVITY REGULATION: KL001 (N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-N- CC (2-furanylmethyl)-methanesulfonamide) binds to CRY1 and stabilizes it CC by inhibiting FBXL3- and ubiquitin-dependent degradation of CRY1 CC resulting in lengthening of the circadian periods. KL001-mediated CRY1 CC stabilization can inhibit glucagon-induced gluconeogenesis in primary CC hepatocytes. {ECO:0000269|PubMed:22798407}. CC -!- SUBUNIT: Component of the circadian core oscillator, which includes the CC CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, CC TIMELESS, and the PER proteins (PubMed:11779462). Interacts with CC TIMELESS (PubMed:10428031). Interacts directly with PER1, PER2 and CC PER3; interaction with PER2 inhibits its ubiquitination and vice versa CC (PubMed:10428031, PubMed:11875063, PubMed:14701732, PubMed:20840750, CC PubMed:24154698). Interacts with CLOCK-BMAL1 (PubMed:16628007). CC Interacts with BMAL1 (PubMed:16717091, PubMed:19917250, CC PubMed:20840750). Interacts with CLOCK (PubMed:16717091, CC PubMed:19917250). Interacts with NFIL3 (PubMed:17274955). Interacts CC with FBXL3 and FBXL21 (PubMed:17462724, PubMed:23452855, CC PubMed:23452856). FBXL3, PER2 and the cofactor FAD compete for CC overlapping binding sites (PubMed:24080726, PubMed:23503662). FBXL3 CC cannot bind CRY2 that interacts already with PER2 or that contains CC bound FAD (PubMed:23503662). Interacts with PPP5C (via TPR repeats); CC the interaction down-regulates the PPP5C phosphatase activity on CSNK1E CC (By similarity). Interacts with nuclear receptors AR and NR3C1/GR; the CC interaction is ligand dependent (PubMed:22170608, PubMed:28751364). CC Interacts with PRKDC (PubMed:24158435). Interacts with CIART CC (PubMed:24736997). Interacts with DDB1, USP7 and TARDBP CC (PubMed:27123980). Interacts with HNF4A (PubMed:28751364). Interacts CC with PPARA (PubMed:28683290). Interacts with PPARG in a ligand- CC dependent manner (PubMed:28683290). Interacts with PPARD (via domain NR CC LBD) in a ligand-dependent manner (PubMed:28683290, PubMed:28751364). CC Interacts with NR1I2 (via domain NR LBD) in a ligand-dependent manner CC (PubMed:28751364). Interacts with NR1I3 and VDR in a ligand-dependent CC manner (PubMed:28751364). {ECO:0000250|UniProtKB:Q49AN0, CC ECO:0000269|PubMed:10428031, ECO:0000269|PubMed:11779462, CC ECO:0000269|PubMed:11875063, ECO:0000269|PubMed:14701732, CC ECO:0000269|PubMed:16628007, ECO:0000269|PubMed:16717091, CC ECO:0000269|PubMed:17274955, ECO:0000269|PubMed:17462724, CC ECO:0000269|PubMed:19917250, ECO:0000269|PubMed:20840750, CC ECO:0000269|PubMed:22170608, ECO:0000269|PubMed:23452855, CC ECO:0000269|PubMed:23452856, ECO:0000269|PubMed:23503662, CC ECO:0000269|PubMed:24080726, ECO:0000269|PubMed:24154698, CC ECO:0000269|PubMed:24158435, ECO:0000269|PubMed:24736997, CC ECO:0000269|PubMed:27123980, ECO:0000269|PubMed:28683290, CC ECO:0000269|PubMed:28751364}. CC -!- INTERACTION: CC Q9R194; Q9WTL8: Bmal1; NbExp=12; IntAct=EBI-1266619, EBI-644534; CC Q9R194; Q3TQ03: Ciart; NbExp=2; IntAct=EBI-1266619, EBI-16101489; CC Q9R194; P67871: Csnk2b; NbExp=3; IntAct=EBI-1266619, EBI-348179; CC Q9R194; Q8BFZ4: Fbxl21; NbExp=4; IntAct=EBI-1266619, EBI-6898235; CC Q9R194; Q8C4V4: Fbxl3; NbExp=6; IntAct=EBI-1266619, EBI-1266589; CC Q9R194; P06537-1: Nr3c1; NbExp=3; IntAct=EBI-1266619, EBI-15959147; CC Q9R194; O35973: Per1; NbExp=3; IntAct=EBI-1266619, EBI-1266764; CC Q9R194; O54943: Per2; NbExp=8; IntAct=EBI-1266619, EBI-1266779; CC Q9R194; Q9UKT7: FBXL3; Xeno; NbExp=13; IntAct=EBI-1266619, EBI-2557269; CC Q9R194; O15534: PER1; Xeno; NbExp=3; IntAct=EBI-1266619, EBI-2557276; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11779462}. Nucleus CC {ECO:0000269|PubMed:11779462}. Note=Translocated to the nucleus through CC interaction with other Clock proteins such as PER2 or BMAL1. CC {ECO:0000269|PubMed:11779462}. CC -!- TISSUE SPECIFICITY: Expression in the retina is restricted to the CC photoreceptor layer (at protein level) (PubMed:29561690). Expressed in CC all tissues examined including heart, brain, spleen, lung, liver, CC skeletal muscle, kidney and testis. Weak expression in spleen. CC {ECO:0000269|PubMed:10521578, ECO:0000269|PubMed:11779462, CC ECO:0000269|PubMed:24154698, ECO:0000269|PubMed:29561690, CC ECO:0000269|PubMed:9801304}. CC -!- INDUCTION: Shows no clear circadian oscillation pattern in testis, CC cerebellum nor liver. In skeletal muscle, under constant darkness and CC 12 hours light:12 hours dark conditions, levels peak between ZT6 and CC ZT9. {ECO:0000269|PubMed:10428031, ECO:0000269|PubMed:10521578, CC ECO:0000269|PubMed:19917250}. CC -!- PTM: Phosphorylation on Ser-265 by MAPK is important for the inhibition CC of CLOCK-BMAL1-mediated transcriptional activity. Phosphorylation by CC CSKNE requires interaction with PER1 or PER2. Phosphorylated in a CC circadian manner at Ser-553 and Ser-557 in the suprachiasmatic nucleus CC (SCN) and liver. Phosphorylation at Ser-557 by DYRK1A promotes CC subsequent phosphorylation at Ser-553 by GSK3-beta: the two-step CC phosphorylation at the neighboring Ser residues leads to its CC proteasomal degradation. {ECO:0000269|PubMed:11875063, CC ECO:0000269|PubMed:15298678, ECO:0000269|PubMed:15980066, CC 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 and CC subsequent degradation of CRY2. In contrast, cytoplasmic SCF(FBXL21) CC complex-mediated ubiquitination leads to stabilize CRY2 and counteract CC the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) CC complexes probably mediate ubiquitination at different Lys residues. CC The SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser- CC 553 and Ser-557. Ubiquitination may be inhibited by PER2. CC Deubiquitinated by USP7 (PubMed:27123980). 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 ECO:0000269|PubMed:26776516, ECO:0000269|PubMed:27123980}. CC -!- DISRUPTION PHENOTYPE: Animals show longer circadian periods. Double CC knockouts of CRY1 and CRY2 show slightly decrease body weight and lose CC the cycling rhythmicity of feeding behavior, energy expenditure and CC glucocorticorids expression. Glucose homeostasis is severely disrupted CC and animals exhibit elevated blood glucose in response to acute feeding CC after an overnight fast as well as severely impaired glucose clearance CC in a glucose tolerance test. When challenged with high-fat diet, CC animals 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 uptake. CC Mice display enlarged gonadal, subcutaneous and perirenal fat deposits CC with adipocyte hypertrophy and increased lipied accumulation in liver. CC Mice show attentuated circadian rhythms in photopic ERG b-wave CC amplitudes (PubMed:29561690). Both single CRY1 knockout and double CRY1 CC and CRY2 knockout mice show increased exercise performance and CC increased mitochondrial reserve capacity in primary myotubes CC (PubMed:28683290). {ECO:0000269|PubMed:20852621, CC ECO:0000269|PubMed:22170608, ECO:0000269|PubMed:23531614, CC ECO:0000269|PubMed:23616524, ECO:0000269|PubMed:28683290, CC ECO:0000269|PubMed:29561690}. CC -!- SIMILARITY: Belongs to the DNA photolyase class-1 family. 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 RefSeq; XP_017170770.1; XM_017315281.1. 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 PDB; 6KX8; X-ray; 2.25 A; A/B=1-512. DR PDB; 7D0N; X-ray; 2.80 A; A=1-512. DR PDB; 7EJ9; X-ray; 2.60 A; A/B=1-512. DR PDB; 7V8Y; X-ray; 1.90 A; A=1-512. DR PDB; 7V8Z; X-ray; 1.95 A; A=1-512. DR PDBsum; 4I6E; -. DR PDBsum; 4I6G; -. DR PDBsum; 4I6J; -. DR PDBsum; 4MLP; -. DR PDBsum; 4U8H; -. DR PDBsum; 6KX8; -. DR PDBsum; 7D0N; -. DR PDBsum; 7EJ9; -. DR PDBsum; 7V8Y; -. DR PDBsum; 7V8Z; -. DR AlphaFoldDB; Q9R194; -. DR SMR; Q9R194; -. DR BioGRID; 198907; 16. DR ComplexPortal; CPX-3210; Cry2-Per2 complex. DR ComplexPortal; CPX-3214; Cry2-Per1 complex. DR ComplexPortal; CPX-3218; Cry2-Per3 complex. DR CORUM; Q9R194; -. DR DIP; DIP-38517N; -. DR IntAct; Q9R194; 25. DR MINT; Q9R194; -. DR STRING; 10090.ENSMUSP00000088047; -. DR GlyGen; Q9R194; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q9R194; -. DR PhosphoSitePlus; Q9R194; -. DR EPD; Q9R194; -. DR jPOST; Q9R194; -. DR MaxQB; Q9R194; -. DR PaxDb; 10090-ENSMUSP00000088047; -. DR PeptideAtlas; Q9R194; -. DR ProteomicsDB; 284176; -. DR Pumba; Q9R194; -. DR Antibodypedia; 26186; 305 antibodies from 34 providers. DR Ensembl; ENSMUST00000090559.12; ENSMUSP00000088047.6; ENSMUSG00000068742.12. DR Ensembl; ENSMUST00000111278.2; ENSMUSP00000106909.2; ENSMUSG00000068742.12. DR GeneID; 12953; -. DR KEGG; mmu:12953; -. DR UCSC; uc008kxy.2; mouse. DR AGR; MGI:1270859; -. DR CTD; 1408; -. DR MGI; MGI:1270859; Cry2. DR VEuPathDB; HostDB:ENSMUSG00000068742; -. DR eggNOG; KOG0133; Eukaryota. DR GeneTree; ENSGT00940000159073; -. DR HOGENOM; CLU_010348_3_4_1; -. DR InParanoid; Q9R194; -. DR OMA; WHRTDLR; -. DR OrthoDB; 124765at2759; -. DR PhylomeDB; Q9R194; -. DR TreeFam; TF323191; -. DR BioGRID-ORCS; 12953; 2 hits in 79 CRISPR screens. DR PRO; PR:Q9R194; -. DR Proteomes; UP000000589; Chromosome 2. DR RNAct; Q9R194; Protein. DR Bgee; ENSMUSG00000068742; Expressed in olfactory tubercle and 248 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0005576; C:extracellular region; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0016607; C:nuclear speck; ISO:MGI. 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:0071949; F:FAD binding; IDA:UniProtKB. DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB. DR GO; GO:0016922; F:nuclear 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:0000976; F:transcription cis-regulatory region binding; IDA: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: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:0045892; P:negative regulation of DNA-templated transcription; 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:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:MGI. DR GO; GO:0006606; P:protein import into nucleus; IPI:MGI. DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB. DR GO; GO:2000118; P:regulation of sodium-dependent phosphate transport; IEA:Ensembl. DR GO; GO:0014823; P:response to activity; IMP:UniProtKB. DR GO; GO:0032868; P:response to insulin; IGI:UniProtKB. DR GO; GO:0009416; P:response to light stimulus; IMP:UniProtKB. DR Gene3D; 1.25.40.80; -; 1. DR Gene3D; 1.10.579.10; DNA Cyclobutane Dipyrimidine Photolyase, subunit A, domain 3; 1. DR Gene3D; 3.40.50.620; HUPs; 1. DR InterPro; IPR036134; Crypto/Photolyase_FAD-like_sf. DR InterPro; IPR036155; Crypto/Photolyase_N_sf. DR InterPro; IPR005101; Cryptochr/Photolyase_FAD-bd. DR InterPro; IPR002081; Cryptochrome/DNA_photolyase_1. DR InterPro; IPR006050; DNA_photolyase_N. DR InterPro; IPR014729; Rossmann-like_a/b/a_fold. DR PANTHER; PTHR11455; CRYPTOCHROME; 1. DR PANTHER; PTHR11455:SF15; CRYPTOCHROME-2; 1. DR Pfam; PF00875; DNA_photolyase; 1. DR Pfam; PF03441; FAD_binding_7; 1. DR SUPFAM; SSF48173; Cryptochrome/photolyase FAD-binding domain; 1. DR SUPFAM; SSF52425; Cryptochrome/photolyase, N-terminal domain; 1. DR PROSITE; PS51645; PHR_CRY_ALPHA_BETA; 1. DR Genevisible; Q9R194; MM. PE 1: Evidence at protein level; KW 3D-structure; Biological rhythms; Chromophore; Cytoplasm; FAD; KW Flavoprotein; Isopeptide bond; Nucleotide-binding; Nucleus; Phosphoprotein; KW Photoreceptor protein; Receptor; Reference proteome; Repressor; KW Sensory transduction; Transcription; Transcription regulation; KW Ubl conjugation. FT CHAIN 1..592 FT /note="Cryptochrome-2" FT /id="PRO_0000261149" FT DOMAIN 21..150 FT /note="Photolyase/cryptochrome alpha/beta" FT REGION 389..488 FT /note="Required for inhibition of CLOCK-BMAL1-mediated FT transcription" FT /evidence="ECO:0000250|UniProtKB:P97784" FT REGION 532..592 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 535..552 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 560..579 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 270 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:23503662" FT BINDING 307 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P97784" FT BINDING 373 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:23503662" FT BINDING 405..407 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:23503662" FT MOD_RES 89 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P97784" FT MOD_RES 265 FT /note="Phosphoserine; by MAPK" FT /evidence="ECO:0000269|PubMed:11875063, FT ECO:0000269|PubMed:15298678" FT MOD_RES 298 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P97784" FT MOD_RES 553 FT /note="Phosphoserine; by GSK3-beta" FT /evidence="ECO:0000269|PubMed:11875063, FT ECO:0000269|PubMed:20123978" FT MOD_RES 557 FT /note="Phosphoserine; by DYRK1A and MAPK" FT /evidence="ECO:0000269|PubMed:11875063, FT ECO:0000269|PubMed:15298678, ECO:0000269|PubMed:15980066, FT ECO:0000269|PubMed:20123978" FT CROSSLNK 29 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P97784" FT CROSSLNK 125 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23452856" FT CROSSLNK 241 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23452856" FT CROSSLNK 347 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23452856" FT CROSSLNK 474 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23452856" FT CROSSLNK 503 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23452856" FT MUTAGEN 265 FT /note="S->A: Reduced in vitro MAPK-catalyzed FT phosphorylation. No effect on inhibition of FT CLOCK-BMAL1-mediated transcriptional activity. Very little FT in vitro MAPK-catalyzed phosphorylation; when associated FT with A-557." FT /evidence="ECO:0000269|PubMed:15298678" FT MUTAGEN 265 FT /note="S->D: Reduced inhibition of CLOCK-BMAL1-mediated FT transcriptional activity. No effect on nuclear localization FT nor on protein stability." FT /evidence="ECO:0000269|PubMed:15298678" FT MUTAGEN 310 FT /note="W->A: Decreases FBXL3 binding. Strongly decreases FT CRY2 degradation." FT /evidence="ECO:0000269|PubMed:23503662" FT MUTAGEN 339 FT /note="D->R: Strongly reduces PER1 binding." FT /evidence="ECO:0000269|PubMed:23503662" FT MUTAGEN 351 FT /note="G->D: Loss of ability to inhibit FT CLOCK-BMAL1-mediated transcriptional activity. No loss of FT ability to inhibit NR1I2 transcriptional activity." FT /evidence="ECO:0000269|PubMed:28751364" FT MUTAGEN 354 FT /note="G->D: Loss of ability to inhibit FT CLOCK-BMAL1-mediated transcriptional activity. No loss of FT ability to inhibit NR1I2 transcriptional activity." FT /evidence="ECO:0000269|PubMed:28751364" FT MUTAGEN 376 FT /note="R->A: Impairs protein folding. Abolishes binding of FT BMAL1, PER1 and FBXL3. Strongly reduces SKP1 binding." FT /evidence="ECO:0000269|PubMed:23503662" FT MUTAGEN 394 FT /note="S->E: Reduced interaction with NR1I2 and NR1I3. FT Significant decrease in interaction with NR1I2 and NR1I3; FT when associated with M-396 and K-397." FT /evidence="ECO:0000269|PubMed:28751364" FT MUTAGEN 396 FT /note="V->M: Reduced interaction with NR1I2 and NR1I3. FT Significant decrease in interaction with NR1I2 and NR1I3; FT when associated with E-394 and K-397." FT /evidence="ECO:0000269|PubMed:28751364" FT MUTAGEN 397 FT /note="R->K: Reduced interaction with NR1I2 and NR1I3. FT Significant decrease in interaction with NR1I2 and NR1I3; FT when associated with E-394 and M-396." FT /evidence="ECO:0000269|PubMed:28751364" FT MUTAGEN 428 FT /note="F->D: Abolishes binding of FBXL3 and SKP1. Strongly FT decreases CRY2 degradation." FT /evidence="ECO:0000269|PubMed:23503662" FT MUTAGEN 499 FT /note="I->D: Abolishes binding of FBXL3 and SKP1. Strongly FT decreases CRY2 degradation." FT /evidence="ECO:0000269|PubMed:23503662" FT MUTAGEN 501 FT /note="R->Q: Inhibits interaction with PER2. Does not FT suppress its nuclear localization. Inhibits its repression FT activity on CLOCK|NPAS2-BMAL1-driven transcription." FT /evidence="ECO:0000269|PubMed:20840750" FT MUTAGEN 503 FT /note="K->R: Inhibits interaction with PER2. Does not FT suppress its nuclear localization. Inhibits its repression FT activity on CLOCK|NPAS2-BMAL1-driven transcription." FT /evidence="ECO:0000269|PubMed:20840750" FT MUTAGEN 517 FT /note="L->D: Decreases FBXL3 binding. Strongly decreases FT CRY2 degradation." FT /evidence="ECO:0000269|PubMed:23503662" FT MUTAGEN 553 FT /note="S->A: Shorter circadian rhythm; when associated with FT A-557." FT /evidence="ECO:0000269|PubMed:20123978" FT MUTAGEN 557 FT /note="S->A: Reduced in vitro MAPK-catalyzed FT phosphorylation. No effect on inhibition of FT CLOCK-BMAL1-mediated transcriptional activity. Very little FT in vitro MAPK-catalyzed phosphorylation; when associated FT with A-265. Shorter circadian rhythm; when associated with FT A-553." FT /evidence="ECO:0000269|PubMed:15298678, FT ECO:0000269|PubMed:20123978" FT MUTAGEN 557 FT /note="S->D: Reduced inhibition of CLOCK-BMAL1-mediated FT transcriptional activity. No effect on nuclear localization FT nor on protein stability." FT /evidence="ECO:0000269|PubMed:15298678, FT ECO:0000269|PubMed:20123978" FT CONFLICT 191..192 FT /note="QQ -> SR (in Ref. 5; BAA19864)" FT /evidence="ECO:0000305" FT CONFLICT 202 FT /note="E -> K (in Ref. 5; BAA19864)" FT /evidence="ECO:0000305" FT CONFLICT 327 FT /note="M -> V (in Ref. 5; BAA19864)" FT /evidence="ECO:0000305" FT STRAND 21..29 FT /evidence="ECO:0007829|PDB:7V8Y" FT STRAND 32..35 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 37..43 FT /evidence="ECO:0007829|PDB:7V8Y" FT STRAND 46..55 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 59..61 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 67..85 FT /evidence="ECO:0007829|PDB:7V8Y" FT TURN 86..88 FT /evidence="ECO:0007829|PDB:7V8Y" FT STRAND 91..96 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 98..109 FT /evidence="ECO:0007829|PDB:7V8Y" FT STRAND 113..117 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 122..137 FT /evidence="ECO:0007829|PDB:7V8Y" FT STRAND 141..145 FT /evidence="ECO:0007829|PDB:7V8Y" FT STRAND 149..151 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 153..159 FT /evidence="ECO:0007829|PDB:7V8Y" FT TURN 160..162 FT /evidence="ECO:0007829|PDB:4I6E" FT HELIX 168..176 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 190..195 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 204..206 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 213..216 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 232..242 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 245..247 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 248..251 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 260..262 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 270..274 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 280..295 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 302..305 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 306..318 FT /evidence="ECO:0007829|PDB:7V8Y" FT TURN 322..325 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 342..350 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 356..368 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 373..383 FT /evidence="ECO:0007829|PDB:7V8Y" FT TURN 384..388 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 392..402 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 408..418 FT /evidence="ECO:0007829|PDB:7V8Y" FT STRAND 421..423 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 435..440 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 445..450 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 452..454 FT /evidence="ECO:0007829|PDB:7V8Y" FT TURN 459..463 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 465..467 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 470..475 FT /evidence="ECO:0007829|PDB:7V8Y" FT TURN 480..482 FT /evidence="ECO:0007829|PDB:7V8Y" FT HELIX 491..507 FT /evidence="ECO:0007829|PDB:7V8Y" FT STRAND 517..521 FT /evidence="ECO:0007829|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 //