ID CRY1_MOUSE Reviewed; 606 AA. AC P97784; DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1997, sequence version 1. DT 27-MAR-2024, entry version 184. DE RecName: Full=Cryptochrome-1; GN Name=Cry1; 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], SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RC TISSUE=Brain, Keratinocyte, and 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 [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC STRAIN=C57BL/6J; RA Kume K., Reppert S.M.; RT "Analysis of mouse cryptochromes."; RL Submitted (JUN-1999) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Embryo; 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J, and FVB/N; RC TISSUE=Brain, Embryonic brain, and Mammary tumor; 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 [5] RP TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=9600923; DOI=10.1073/pnas.95.11.6097; RA Miyamoto Y., Sancar A.; RT "Vitamin B2-based blue-light photoreceptors in the retinohypothalamic tract RT as the photoactive pigments for setting the circadian clock in mammals."; RL Proc. Natl. Acad. Sci. U.S.A. 95:6097-6102(1998). RN [6] RP FUNCTION, INTERACTION WITH PER1; PER2; PER3 AND TIMELESS, SUBCELLULAR RP LOCATION, TISSUE SPECIFICITY, AND INDUCTION. 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 [7] 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 [8] 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 [9] RP INTERACTION WITH PER2, SUBCELLULAR LOCATION, AND UBIQUITINATION. RX PubMed=11889036; DOI=10.1093/emboj/21.6.1301; RA Yagita K., Tamanini F., Yasuda M., Hoeijmakers J.H., van der Horst G.T., RA Okamura H.; RT "Nucleocytoplasmic shuttling and mCRY-dependent inhibition of RT ubiquitylation of the mPER2 clock protein."; RL EMBO J. 21:1301-1314(2002). RN [10] 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 [11] RP PHOSPHORYLATION AT SER-247, AND MUTAGENESIS OF SER-247. 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 [12] 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 [13] RP FUNCTION AS TRANSCRIPTION REPRESSOR, AND INTERACTION WITH HDAC1; HDAC2 AND RP SIN3B. RX PubMed=15226430; DOI=10.1128/mcb.24.14.6278-6287.2004; RA Naruse Y., Oh-hashi K., Iijima N., Naruse M., Yoshioka H., Tanaka M.; RT "Circadian and light-induced transcription of clock gene Per1 depends on RT histone acetylation and deacetylation."; RL Mol. Cell. Biol. 24:6278-6287(2004). RN [14] RP FUNCTION, AND SUBCELLULAR LOCATION. 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 [15] RP INTERACTION WITH EZH2; 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 [16] RP FUNCTION, INTERACTION WITH PER1 AND PER2, AND SUBCELLULAR LOCATION. RX PubMed=16478995; DOI=10.1128/mcb.26.5.1743-1753.2006; RA Chaves I., Yagita K., Barnhoorn S., Okamura H., van der Horst G.T.J., RA Tamanini F.; RT "Functional evolution of the photolyase/cryptochrome protein family: RT importance of the C terminus of mammalian CRY1 for circadian core RT oscillator performance."; RL Mol. Cell. Biol. 26:1743-1753(2006). RN [17] RP TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=16790549; DOI=10.1073/pnas.0604138103; RA Partch C.L., Shields K.F., Thompson C.L., Selby C.P., Sancar A.; RT "Posttranslational regulation of the mammalian circadian clock by RT cryptochrome and protein phosphatase 5."; RL Proc. Natl. Acad. Sci. U.S.A. 103:10467-10472(2006). RN [18] 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 [19] 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 [20] RP INTERACTION WITH FBXL21, AND UBIQUITINATION. RX PubMed=18953409; DOI=10.1371/journal.pone.0003530; RA Dardente H., Mendoza J., Fustin J.M., Challet E., Hazlerigg D.G.; RT "Implication of the F-Box Protein FBXL21 in circadian pacemaker function in RT mammals."; RL PLoS ONE 3:E3530-E3530(2008). RN [21] 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 [22] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH MYBBP1A; DOCK7; RP HNRNPU; RPL7A; RPL8 AND RPS3. RX PubMed=19129230; DOI=10.1093/nar/gkn1013; RA Hara Y., Onishi Y., Oishi K., Miyazaki K., Fukamizu A., Ishida N.; RT "Molecular characterization of Mybbp1a as a co-repressor on the Period2 RT promoter."; RL Nucleic Acids Res. 37:1115-1126(2009). RN [23] RP PHOSPHORYLATION AT SER-71 AND SER-280, AND MUTAGENESIS OF SER-71 AND RP SER-280. RX PubMed=19833968; DOI=10.1126/science.1172156; RA Lamia K.A., Sachdeva U.M., DiTacchio L., Williams E.C., Alvarez J.G., RA Egan D.F., Vasquez D.S., Juguilon H., Panda S., Shaw R.J., Thompson C.B., RA Evans R.M.; RT "AMPK regulates the circadian clock by cryptochrome phosphorylation and RT degradation."; RL Science 326:437-440(2009). RN [24] 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 [25] RP INTERACTION WITH PER2. RX PubMed=20159955; DOI=10.1101/gad.564110; RA Schmutz I., Ripperger J.A., Baeriswyl-Aebischer S., Albrecht U.; RT "The mammalian clock component PERIOD2 coordinates circadian output by RT interaction with nuclear receptors."; RL Genes Dev. 24:345-357(2010). RN [26] RP FUNCTION, AND INDUCTION. RX PubMed=20385766; DOI=10.1128/mcb.01141-09; RA Guillaumond F., Grechez-Cassiau A., Subramaniam M., Brangolo S., RA Peteri-Brunback B., Staels B., Fievet C., Spelsberg T.C., Delaunay F., RA Teboul M.; RT "Kruppel-like factor KLF10 is a link between the circadian clock and RT metabolism in liver."; RL Mol. Cell. Biol. 30:3059-3070(2010). RN [27] 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 [28] RP FUNCTION IN CIRCADIAN RHYTHMS REGULATION, AND INDUCTION. RX PubMed=21236481; DOI=10.1016/j.cell.2010.12.019; RA Ukai-Tadenuma M., Yamada R.G., Xu H., Ripperger J.A., Liu A.C., Ueda H.R.; RT "Delay in feedback repression by cryptochrome 1 is required for circadian RT clock function."; RL Cell 144:268-281(2011). RN [29] RP INTERACTION WITH CLOCK-BMAL1 AND PER2. RX PubMed=21613214; DOI=10.1074/jbc.m111.254680; RA Ye R., Selby C.P., Ozturk N., Annayev Y., Sancar A.; RT "Biochemical analysis of the canonical model for the mammalian circadian RT clock."; RL J. Biol. Chem. 286:25891-25902(2011). RN [30] RP FUNCTION. RX PubMed=21768648; DOI=10.1074/jbc.m111.258970; RA Koyanagi S., Hamdan A.M., Horiguchi M., Kusunose N., Okamoto A., RA Matsunaga N., Ohdo S.; RT "cAMP-response element (CRE)-mediated transcription by activating RT transcription factor-4 (ATF4) is essential for circadian expression of the RT Period2 gene."; RL J. Biol. Chem. 286:32416-32423(2011). RN [31] RP FUNCTION AS NR3C1 REPRESSOR, INTERACTION WITH AR; NR1D1; NR3C1; RORA AND RP RORC, AND 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., 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 [32] RP FUNCTION, INDUCTION, AND INTERACTION WITH PRMT5. RX PubMed=23133559; DOI=10.1371/journal.pone.0048152; RA Na J., Lee K., Kim H.G., Shin J.Y., Na W., Jeong H., Lee J.W., Cho S., RA Kim W.S., Ju B.G.; RT "Role of type II protein arginine methyltransferase 5 in the regulation of RT Circadian Per1 gene."; RL PLoS ONE 7:E48152-E48152(2012). RN [33] 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 [34] 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 [35] RP UBIQUITINATION BY THE SCF(FBXL3) AND SCF(FBXL21) COMPLEXES, INTERACTION RP WITH FBXL3 AND FBXL21, AND UBIQUITINATION AT LYS-11. 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 [36] RP UBIQUITINATION BY THE SCF(FBXL3) AND SCF(FBXL21) COMPLEXES, UBIQUITINATION RP AT LYS-107; LYS-159; LYS-329 AND LYS-485, INTERACTION WITH FBXL3 AND RP FBXL21, AND MUTAGENESIS OF LYS-107. 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 [37] RP FUNCTION IN CIRCADIAN CLOCK, INTERACTION WITH PRKDC, PHOSPHORYLATION AT RP SER-588, AND MUTAGENESIS OF SER-551; SER-564 AND SER-588. 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 [38] 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 [39] RP FUNCTION IN CIRCADIAN CLOCK. 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 [40] RP FUNCTION. RX PubMed=24089055; DOI=10.1038/ncomms3545; RA Li D.Q., Pakala S.B., Reddy S.D., Peng S., Balasenthil S., Deng C.X., RA Lee C.C., Rea M.A., Kumar R.; RT "Metastasis-associated protein 1 is an integral component of the circadian RT molecular machinery."; RL Nat. Commun. 4:2545-2545(2013). RN [41] RP INTERACTION WITH TIMELESS AND PER2, AND SUBCELLULAR LOCATION. RX PubMed=23418588; DOI=10.1371/journal.pone.0056623; RA Engelen E., Janssens R.C., Yagita K., Smits V.A., van der Horst G.T., RA Tamanini F.; RT "Mammalian TIMELESS is involved in period determination and DNA damage- RT dependent phase advancing of the circadian clock."; RL PLoS ONE 8:E56623-E56623(2013). RN [42] 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 [43] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=24385426; DOI=10.1074/jbc.m113.534651; RA Annayev Y., Adar S., Chiou Y.Y., Lieb J., Sancar A., Ye R.; RT "Gene model 129 (Gm129) encodes a novel transcriptional repressor that RT modulates circadian gene expression."; RL J. Biol. Chem. 289:5013-5024(2014). RN [44] RP FUNCTION IN GR REPRESSION. RX PubMed=24378737; DOI=10.1016/j.mce.2013.12.013; RA Han D.H., Lee Y.J., Kim K., Kim C.J., Cho S.; RT "Modulation of glucocorticoid receptor induction properties by core RT circadian clock proteins."; RL Mol. Cell. Endocrinol. 383:170-180(2014). RN [45] RP FUNCTION IN DNA DAMAGE CHECKPOINT, INTERACTION WITH TIMELESS, AND RP SUBCELLULAR LOCATION. RX PubMed=24489120; DOI=10.1093/nar/gku094; RA Kang T.H., Leem S.H.; RT "Modulation of ATR-mediated DNA damage checkpoint response by cryptochrome RT 1."; RL Nucleic Acids Res. 42:4427-4434(2014). RN [46] 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 [47] RP FUNCTION, INTERACTION WITH DDB1-CUL4A COMPLEX, UBIQUITINATION AT LYS-585, RP AND MUTAGENESIS OF LYS-585. RX PubMed=26431207; DOI=10.1371/journal.pone.0139725; RA Tong X., Zhang D., Guha A., Arthurs B., Cazares V., Gupta N., Yin L.; RT "CUL4-DDB1-CDT2 E3 ligase regulates the molecular clock activity by RT promoting ubiquitination-dependent degradation of the mammalian CRY1."; RL PLoS ONE 10:E0139725-E0139725(2015). RN [48] RP UBIQUITINATION AND PROTEASOMAL DEGRADATION, AND INTERACTION WITH HDAC3 AND RP BMAL1. 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 [49] RP DEUBIQUITINATION BY USP7, AND INTERACTION WITH TRIM28; KCTD5 AND DDB1. 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 [50] 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 [51] RP FUNCTION, AND INTERACTION WITH FOXO1. RX PubMed=28790135; DOI=10.2337/db16-1600; RA Tong X., Zhang D., Charney N., Jin E., VanDommelen K., Stamper K., RA Gupta N., Saldate J., Yin L.; RT "DDB1-mediated CRY1 degradation promotes FOXO1-driven gluconeogenesis in RT liver."; RL Diabetes 66:2571-2582(2017). RN [52] RP FUNCTION, AND INTERACTION WITH NR1I2; NR1I3; NR3C1; PPARD; VDR; AR AND RP HNF4A. 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 [53] RP FUNCTION, 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 [54] RP INTERACTION WITH KDM8; FBXL3 AND PSMD2. RX PubMed=30500822; DOI=10.1371/journal.pbio.2006145; RA Saran A.R., Kalinowska D., Oh S., Janknecht R., DiTacchio L.; RT "JMJD5 links CRY1 function and proteasomal degradation."; RL PLoS Biol. 16:E2006145-E2006145(2018). RN [55] RP FUNCTION, INTERACTION WITH MAP1LC3B, LIR MOTIFS, DEGRADATION VIA AUTOPHAGY, RP AND MUTAGENESIS OF TYR-273; VAL-276; TYR-287; LEU-290; TYR-488; LEU-491; RP TYR-494 AND LEU-497. RX PubMed=29937374; DOI=10.1016/j.cmet.2018.05.023; RA Toledo M., Batista-Gonzalez A., Merheb E., Aoun M.L., Tarabra E., Feng D., RA Sarparanta J., Merlo P., Botre F., Schwartz G.J., Pessin J.E., Singh R.; RT "Autophagy regulates the liver clock and glucose metabolism by degrading RT CRY1."; RL Cell Metab. 28:268-281(2018). RN [56] RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF APOPROTEIN, INTERACTION WITH RP BMAL1; PER2 AND FBXL3, FUNCTION, FAD-BINDING SITES, AND MUTAGENESIS OF RP HIS-224; SER-247; 382-GLU-GLU-383; PHE-405 AND LYS-485. RX PubMed=23746849; DOI=10.1016/j.cell.2013.05.011; RA Czarna A., Berndt A., Singh H.R., Grudziecki A., Ladurner A.G., RA Timinszky G., Kramer A., Wolf E.; RT "Structures of Drosophila cryptochrome and mouse cryptochrome1 provide RT insight into circadian function."; RL Cell 153:1394-1405(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. More potent transcriptional repressor in CC cerebellum and liver than CRY2, though more effective in lengthening CC the period of the SCN oscillator. On its side, CRY2 seems to play a CC critical role in tuning SCN circadian period by opposing the action of CC CRY1. With CRY2, is dispensable for circadian rhythm generation but CC necessary for the development of intercellular networks for rhythm CC synchrony. Capable of translocating circadian clock core proteins such CC as PER proteins to the nucleus. Interacts with CLOCK-BMAL1 CC independently of PER proteins and is found at CLOCK-BMAL1-bound sites, CC suggesting that CRY may act as a molecular gatekeeper to maintain CC CLOCK-BMAL1 in a poised and repressed state until the proper time for CC transcriptional activation. Represses the CLOCK-BMAL1 induced CC transcription of BHLHE40/DEC1, ATF4, MTA1, KLF10 and NAMPT. May repress CC circadian target genes expression in collaboration with HDAC1 and HDAC2 CC through histone deacetylation. Mediates the clock-control activation of CC ATR and modulates ATR-mediated DNA damage checkpoint. In liver, CC mediates circadian regulation of cAMP signaling and gluconeogenesis by CC binding to membrane-coupled G proteins and blocking glucagon-mediated CC increases in intracellular cAMP concentrations and CREB1 CC phosphorylation. Inhibits hepatic gluconeogenesis by decreasing nuclear CC FOXO1 levels that down-regulates gluconeogenic gene expression. Besides CC its role in the maintenance of the circadian clock, is also involved in CC the regulation of other processes. Represses glucocorticoid receptor CC NR3C1/GR-induced transcriptional activity by binding to glucocorticoid CC response elements (GREs). Plays a key role in glucose and lipid CC metabolism modulation, in part, through the transcriptional regulation CC of genes involved in these pathways, such as LEP or ACSL4. Represses CC PPARD and its target genes in the skeletal muscle and limits exercise CC capacity (PubMed:28683290). Plays an essential role in the generation CC of circadian rhythms in the retina (PubMed:29561690). Represses the CC transcriptional activity of NR1I2 (PubMed:28751364). CC {ECO:0000269|PubMed:10428031, ECO:0000269|PubMed:15226430, CC ECO:0000269|PubMed:16478995, ECO:0000269|PubMed:16628007, CC ECO:0000269|PubMed:17310242, ECO:0000269|PubMed:19129230, CC ECO:0000269|PubMed:19299583, ECO:0000269|PubMed:20385766, CC ECO:0000269|PubMed:20852621, ECO:0000269|PubMed:21236481, CC ECO:0000269|PubMed:21768648, ECO:0000269|PubMed:22170608, CC ECO:0000269|PubMed:23133559, ECO:0000269|PubMed:23531614, CC ECO:0000269|PubMed:23575670, ECO:0000269|PubMed:23616524, CC ECO:0000269|PubMed:23746849, ECO:0000269|PubMed:24089055, CC ECO:0000269|PubMed:24158435, ECO:0000269|PubMed:24378737, CC ECO:0000269|PubMed:24385426, ECO:0000269|PubMed:24489120, CC ECO:0000269|PubMed:26431207, ECO:0000269|PubMed:28683290, CC ECO:0000269|PubMed:28751364, ECO:0000269|PubMed:28790135, CC ECO:0000269|PubMed:29561690, ECO:0000269|PubMed:29937374}. CC -!- COFACTOR: CC Name=FAD; Xref=ChEBI:CHEBI:57692; CC Evidence={ECO:0000269|PubMed:23746849}; 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:23746849}; 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 directly CC with TIMELESS (PubMed:10428031, PubMed:24489120, PubMed:23418588). CC Interacts directly with PER1 and PER2; interaction with PER2 inhibits CC its ubiquitination and vice versa (PubMed:10428031, PubMed:11889036, CC PubMed:11875063, PubMed:14701732, PubMed:16478995, PubMed:23746849, CC PubMed:23418588, PubMed:21613214, PubMed:20159955). Interacts with PER3 CC (PubMed:10428031, PubMed:14701732). Interacts with FBXL21 CC (PubMed:18953409, PubMed:23452855, PubMed:23452856). Interacts with CC FBXL3 (PubMed:17462724, PubMed:23746849, PubMed:23452855, CC PubMed:23452856, PubMed:30500822). Interacts with PPP5C (via TPR CC repeats) (By similarity). Interacts with CLOCK-BMAL1 independently of CC PER2 and DNA (PubMed:21613214). Interacts with HDAC1, HDAC2 and SIN3B CC (PubMed:15226430). Interacts with nuclear receptors AR, NR1D1, CC NR3C1/GR, RORA and RORC; the interaction with at least NR3C1/GR is CC ligand dependent (PubMed:22170608, PubMed:28751364). Interacts with CC PRKDC (PubMed:24158435). Interacts with the G protein subunit alpha CC GNAS; the interaction may block GPCR-mediated regulation of cAMP CC concentrations (By similarity). Interacts with PRMT5 (PubMed:23133559). CC Interacts with EZH2 (PubMed:16717091). Interacts with MYBBP1A, DOCK7, CC HNRNPU, RPL7A, RPL8 and RPS3 (PubMed:19129230). Interacts with MAP1LC3B CC (PubMed:29937374). Interacts with CLOCK (PubMed:16717091, CC PubMed:19917250). Interacts with BMAL1 (PubMed:26776516, CC PubMed:16717091, PubMed:19917250, PubMed:23746849). Interacts weakly CC with HDAC3; this interaction is enhanced in the presence of FBXL3 CC (PubMed:26776516). Interacts with TRIM28, KCTD5 and DDB1 CC (PubMed:27123980). Interacts with DTL (By similarity). Interacts with CC DDB1-CUL4A complex (PubMed:26431207). Interacts with FOXO1 CC (PubMed:28790135). Interacts with PSMD2 in a KDM8-dependent manner CC (PubMed:30500822). Interacts with KDM8 in a FBXL3-dependent manner CC (PubMed:30500822). Interacts with PPARA (PubMed:28683290). Interacts CC with PPARG in a ligand-dependent manner (PubMed:28683290). Interacts CC with PPARD (via domain NR LBD) in a ligand-dependent manner CC (PubMed:28683290, PubMed:28751364). Interacts with NR1I2 (via domain NR CC LBD) in a ligand-dependent manner (PubMed:28751364). Interacts with CC NR1I3, VDR and HNF4A (PubMed:28751364). {ECO:0000250|UniProtKB:Q16526, CC ECO:0000269|PubMed:10428031, ECO:0000269|PubMed:11779462, CC ECO:0000269|PubMed:11875063, ECO:0000269|PubMed:11889036, CC ECO:0000269|PubMed:14701732, ECO:0000269|PubMed:15226430, CC ECO:0000269|PubMed:16478995, ECO:0000269|PubMed:16717091, CC ECO:0000269|PubMed:17462724, ECO:0000269|PubMed:18953409, CC ECO:0000269|PubMed:19129230, ECO:0000269|PubMed:19917250, CC ECO:0000269|PubMed:20159955, ECO:0000269|PubMed:21613214, CC ECO:0000269|PubMed:22170608, ECO:0000269|PubMed:23133559, CC ECO:0000269|PubMed:23418588, ECO:0000269|PubMed:23452855, CC ECO:0000269|PubMed:23452856, ECO:0000269|PubMed:23746849, CC ECO:0000269|PubMed:24158435, ECO:0000269|PubMed:24489120, CC ECO:0000269|PubMed:26431207, ECO:0000269|PubMed:26776516, CC ECO:0000269|PubMed:27123980, ECO:0000269|PubMed:28683290, CC ECO:0000269|PubMed:28751364, ECO:0000269|PubMed:28790135, CC ECO:0000269|PubMed:29937374, ECO:0000269|PubMed:30500822}. CC -!- INTERACTION: CC P97784; Q9WTL8: Bmal1; NbExp=23; IntAct=EBI-1266607, EBI-644534; CC P97784; Q9WTL8-2: Bmal1; NbExp=4; IntAct=EBI-1266607, EBI-644559; CC P97784; Q9WTL8-4: Bmal1; NbExp=4; IntAct=EBI-1266607, EBI-644568; CC P97784; Q2VPD4: Bmal2; NbExp=3; IntAct=EBI-1266607, EBI-9696862; CC P97784; O08785: Clock; NbExp=10; IntAct=EBI-1266607, EBI-79859; CC P97784; P67871: Csnk2b; NbExp=4; IntAct=EBI-1266607, EBI-348179; CC P97784; Q8BFZ4: Fbxl21; NbExp=10; IntAct=EBI-1266607, EBI-6898235; CC P97784; Q8C4V4: Fbxl3; NbExp=12; IntAct=EBI-1266607, EBI-1266589; CC P97784; P06537-1: Nr3c1; NbExp=3; IntAct=EBI-1266607, EBI-15959147; CC P97784; O35973: Per1; NbExp=3; IntAct=EBI-1266607, EBI-1266764; CC P97784; O54943: Per2; NbExp=22; IntAct=EBI-1266607, EBI-1266779; CC P97784; Q8CIG8: Prmt5; NbExp=2; IntAct=EBI-1266607, EBI-2527009; CC P97784; P67870: CSNK2B; Xeno; NbExp=2; IntAct=EBI-1266607, EBI-348169; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11779462}. Nucleus CC {ECO:0000269|PubMed:11779462, ECO:0000269|PubMed:19129230}. CC Note=Transloctaed to the nucleus through interaction with other clock CC proteins such as PER2 or BMAL1. CC -!- TISSUE SPECIFICITY: Expressed in cones, amacrine cells, and retinal CC ganglion cells of the retina (at protein level) (PubMed:29561690). CC Expressed in all tissues examined including heart, brain, spleen, lung, CC liver, skeletal muscle, kidney and testis. Higher levels in brain, CC liver and testis. In the retina, highly expressed in the ganglion cell CC layer (GCL) and in the inner nuclear layer (INL). Evenly distributed in CC central and peripheral retina. In the brain, highly expressed in the CC suprachiasmatic nucleus (SCN). High levels in cerebral cortical layers CC particularly in the pyramidial cell layer of the hippocampus, the CC granular cell layer of the dentate gyrus (DG) and the pyramidal cell CC layer of the piriform cortex (PFC). {ECO:0000269|PubMed:10428031, CC ECO:0000269|PubMed:10521578, ECO:0000269|PubMed:11779462, CC ECO:0000269|PubMed:16790549, ECO:0000269|PubMed:29561690, CC ECO:0000269|PubMed:9600923, ECO:0000269|PubMed:9801304}. CC -!- INDUCTION: Oscillates diurnally, rhythmic expression in the early night CC is critical for clock function (at protein level). In SCN, exhibits CC circadian rhythm expression with highest levels during the light phase CC at CT10. No detectable expression after 8 hours in the dark. Circadian CC oscillations also observed in liver, skeletal muscle and cerebellum, CC but not in testis. {ECO:0000269|PubMed:10428031, CC ECO:0000269|PubMed:10521578, ECO:0000269|PubMed:16790549, CC ECO:0000269|PubMed:19917250, ECO:0000269|PubMed:20385766, CC ECO:0000269|PubMed:21236481, ECO:0000269|PubMed:23133559, CC ECO:0000269|PubMed:9600923}. CC -!- DOMAIN: The LIR motifs (LC3-interacting region) 3 and 5 are required CC for its interaction with MAP1LC3B and for its autophagy-mediated CC degradation. {ECO:0000269|PubMed:29937374}. CC -!- PTM: Phosphorylation on Ser-247 by MAPK is important for the inhibition CC of CLOCK-BMAL1-mediated transcriptional activity. Phosphorylation by CC CSNK1E requires interaction with PER1 or PER2. Phosphorylation at Ser- CC 71 and Ser-280 by AMPK decreases protein stability. Phosphorylation at CC Ser-588 exhibits a robust circadian rhythm with a peak at CT8, CC increases protein stability, prevents SCF(FBXL3)-mediated degradation CC and is antagonized by interaction with PRKDC. CC {ECO:0000269|PubMed:11875063, ECO:0000269|PubMed:15298678, CC ECO:0000269|PubMed:19833968, ECO:0000269|PubMed:24158435}. 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 CRY1. In contrast, cytoplasmic SCF(FBXL21) CC complex-mediated ubiquitination leads to stabilize CRY1 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 Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by CC the SCF(FBXL21) complex but not by the SCF(FBXL3) complex. CC Ubiquitination may be inhibited by PER2. Deubiquitinated by USP7 CC (PubMed:27123980). {ECO:0000269|PubMed:11889036, CC ECO:0000269|PubMed:17462724, ECO:0000269|PubMed:18953409, CC ECO:0000269|PubMed:23452855, ECO:0000269|PubMed:23452856, CC ECO:0000269|PubMed:26776516, ECO:0000269|PubMed:27123980}. CC -!- PTM: Undergoes autophagy-mediated degradation in the liver in a time- CC dependent manner. Autophagic degradation of CRY1 (an inhibitor of CC gluconeogenesis) occurs during periods of reduced feeding allowing CC induction of gluconeogenesis and maintenance of blood glucose levels. CC {ECO:0000269|PubMed:29937374}. CC -!- DISRUPTION PHENOTYPE: Mice show an advanced phase shift (around 4 CC hours) in the expression of DBP, NR1D1 and PER1 genes in the liver. CC Double knockouts of CRY1 and CRY2 show slightly decrease body weight CC and lose the cycling rhythmicity of feeding behavior, energy CC expenditure and glucocorticoids expression. Glucose homeostasis is CC severely disrupted and animals exhibit elevated blood glucose in CC response to acute feeding after an overnight fast as well as severely CC impaired glucose clearance in a glucose tolerance test. When challenged CC with high-fat diet, animals rapidly gain weight and surpass that of CC wild-type mice, despite displaying hypophagia. They exhibit CC hyperinsulinemia and selective insulin resistance in the liver and CC muscle but show high insulin sensitivity in adipose tissue and CC consequent increased lipid uptake. Mice display enlarged gonadal, CC subcutaneous and perirenal fat deposits with adipocyte hypertrophy and CC increased lipied accumulation in liver. Mice show loss of circadian CC rhythms in photopic ERG b-wave amplitudes, visual contrast sensitivity CC and pupillary light responses, with reduced robustness and stability of CC bioluminescent rhythms (PubMed:29561690). Both single CRY1 knockout and CC double CRY1 and CRY2 knockout mice show increased exercise performance CC and 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:24385426, CC ECO:0000269|PubMed:28683290, 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; AB000777; BAA19175.1; -; mRNA. DR EMBL; AF156986; AAD39548.1; -; mRNA. DR EMBL; AK162460; BAE36931.1; -; mRNA. DR EMBL; BC022174; AAH22174.1; -; mRNA. DR EMBL; BC085499; AAH85499.1; -; mRNA. DR CCDS; CCDS24089.1; -. DR RefSeq; NP_031797.1; NM_007771.3. DR PDB; 4CT0; X-ray; 2.45 A; A=1-496. DR PDB; 4K0R; X-ray; 2.65 A; A=1-606. DR PDB; 5T5X; X-ray; 1.84 A; A=1-491. DR PDB; 6KX4; X-ray; 2.00 A; A=1-496. DR PDB; 6KX5; X-ray; 2.00 A; A=1-496. DR PDB; 6KX6; X-ray; 2.00 A; A/B=1-496. DR PDB; 6KX7; X-ray; 2.10 A; A=1-496. DR PDB; 6LUE; X-ray; 2.10 A; A/B=1-496. DR PDB; 6OF7; X-ray; 3.11 A; A=1-491. DR PDB; 7D0M; X-ray; 1.95 A; A=1-496. DR PDB; 7D19; X-ray; 2.35 A; A/B=1-496. DR PDB; 7D1C; X-ray; 1.91 A; A=1-496. DR PDB; 7DLI; X-ray; 2.20 A; A/B/C=1-496. DR PDB; 7WVA; X-ray; 2.05 A; A=1-496. DR PDBsum; 4CT0; -. DR PDBsum; 4K0R; -. DR PDBsum; 5T5X; -. DR PDBsum; 6KX4; -. DR PDBsum; 6KX5; -. DR PDBsum; 6KX6; -. DR PDBsum; 6KX7; -. DR PDBsum; 6LUE; -. DR PDBsum; 6OF7; -. DR PDBsum; 7D0M; -. DR PDBsum; 7D19; -. DR PDBsum; 7D1C; -. DR PDBsum; 7DLI; -. DR PDBsum; 7WVA; -. DR AlphaFoldDB; P97784; -. DR SMR; P97784; -. DR BioGRID; 198906; 35. DR ComplexPortal; CPX-3209; Cry1-Per2 complex. DR ComplexPortal; CPX-3216; Cry1-Per1 complex. DR ComplexPortal; CPX-3217; Cry1-Per3 complex. DR CORUM; P97784; -. DR DIP; DIP-38515N; -. DR IntAct; P97784; 49. DR MINT; P97784; -. DR STRING; 10090.ENSMUSP00000020227; -. DR iPTMnet; P97784; -. DR PhosphoSitePlus; P97784; -. DR EPD; P97784; -. DR MaxQB; P97784; -. DR PaxDb; 10090-ENSMUSP00000020227; -. DR PeptideAtlas; P97784; -. DR ProteomicsDB; 284026; -. DR Pumba; P97784; -. DR Antibodypedia; 3122; 347 antibodies from 35 providers. DR DNASU; 12952; -. DR Ensembl; ENSMUST00000020227.11; ENSMUSP00000020227.10; ENSMUSG00000020038.11. DR GeneID; 12952; -. DR KEGG; mmu:12952; -. DR UCSC; uc007gle.1; mouse. DR AGR; MGI:1270841; -. DR CTD; 1407; -. DR MGI; MGI:1270841; Cry1. DR VEuPathDB; HostDB:ENSMUSG00000020038; -. DR eggNOG; KOG0133; Eukaryota. DR GeneTree; ENSGT00940000155455; -. DR HOGENOM; CLU_010348_3_4_1; -. DR InParanoid; P97784; -. DR OMA; TPYKNAW; -. DR OrthoDB; 124765at2759; -. DR PhylomeDB; P97784; -. DR TreeFam; TF323191; -. DR BioGRID-ORCS; 12952; 2 hits in 78 CRISPR screens. DR ChiTaRS; Cry1; mouse. DR PRO; PR:P97784; -. DR Proteomes; UP000000589; Chromosome 10. DR RNAct; P97784; Protein. DR Bgee; ENSMUSG00000020038; Expressed in secondary oocyte and 270 other cell types or tissues. DR ExpressionAtlas; P97784; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. 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:0003677; F:DNA binding; IBA:GO_Central. DR GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0003690; F:double-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0070888; F:E-box binding; IDA:UniProtKB. DR GO; GO:0071949; F:FAD binding; IBA:GO_Central. DR GO; GO:0042826; F:histone deacetylase binding; IPI: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:0032922; P:circadian regulation of gene expression; IMP:UniProtKB. DR GO; GO:0007623; P:circadian rhythm; IDA:MGI. DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; IMP:UniProtKB. DR GO; GO:0006094; P:gluconeogenesis; 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:0045744; P:negative regulation of G protein-coupled receptor signaling pathway; IMP:UniProtKB. DR GO; GO:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; IDA:UniProtKB. DR GO; GO:2000850; P:negative regulation of glucocorticoid secretion; IGI:UniProtKB. DR GO; GO:0045721; P:negative regulation of gluconeogenesis; IMP:UniProtKB. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:UniProtKB. DR GO; GO:0045722; P:positive regulation of gluconeogenesis; IDA:DisProt. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IMP:UniProtKB. DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB. DR GO; GO:2000001; P:regulation of DNA damage checkpoint; IDA:UniProtKB. DR GO; GO:0006111; P:regulation of gluconeogenesis; IMP:DisProt. DR GO; GO:0014823; P:response to activity; IMP:UniProtKB. DR GO; GO:0033762; P:response to glucagon; IMP:UniProtKB. DR GO; GO:0032868; P:response to insulin; IGI:UniProtKB. DR GO; GO:0009416; P:response to light stimulus; IMP:UniProtKB. DR GO; GO:0042770; P:signal transduction in response to DNA damage; IDA:UniProtKB. DR DisProt; DP03007; -. DR Gene3D; 1.25.40.80; -; 2. DR Gene3D; 1.10.579.10; DNA Cyclobutane Dipyrimidine Photolyase, subunit A, domain 3; 1. DR Gene3D; 3.40.50.620; HUPs; 1. DR IDEAL; IID50287; -. 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:SF16; CRYPTOCHROME-1; 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; P97784; 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..606 FT /note="Cryptochrome-1" FT /id="PRO_0000261142" FT DOMAIN 3..132 FT /note="Photolyase/cryptochrome alpha/beta" FT REGION 371..470 FT /note="Required for inhibition of CLOCK-BMAL1-mediated FT transcription" FT /evidence="ECO:0000269|PubMed:16478995" FT REGION 471..493 FT /note="Interaction with TIMELESS" FT /evidence="ECO:0000269|PubMed:23418588" FT REGION 559..606 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 50..54 FT /note="LIR 1" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 82..87 FT /note="LIR 2" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 151..156 FT /note="LIR 3" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 255..260 FT /note="LIR 4" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 271..276 FT /note="LIR 5" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 285..290 FT /note="LIR 6" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 335..339 FT /note="LIR 7" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 379..384 FT /note="LIR 8" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 395..400 FT /note="LIR 9" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 411..416 FT /note="LIR 10" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 430..435 FT /note="LIR 11" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 486..491 FT /note="LIR 12" FT /evidence="ECO:0000305|PubMed:29937374" FT MOTIF 492..497 FT /note="LIR 13" FT /evidence="ECO:0000305|PubMed:29937374" FT BINDING 252 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:23746849" FT BINDING 289 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:23746849" FT BINDING 355 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:23746849" FT BINDING 387..389 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000269|PubMed:23746849" FT MOD_RES 71 FT /note="Phosphoserine; by AMPK" FT /evidence="ECO:0000269|PubMed:19833968" FT MOD_RES 247 FT /note="Phosphoserine; by MAPK" FT /evidence="ECO:0000269|PubMed:15298678" FT MOD_RES 280 FT /note="Phosphoserine; by AMPK" FT /evidence="ECO:0000269|PubMed:19833968" FT MOD_RES 588 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:24158435" FT CROSSLNK 11 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000305|PubMed:23452855" FT CROSSLNK 107 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23452856" FT CROSSLNK 159 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23452856" FT CROSSLNK 329 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23452856" FT CROSSLNK 485 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23452856" FT CROSSLNK 585 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:26431207" FT MUTAGEN 71 FT /note="S->A: Phosphomimetic mutant that leads to FT stabilization of the protein; when associated with A-280." FT /evidence="ECO:0000269|PubMed:19833968" FT MUTAGEN 71 FT /note="S->D: Phosphomimetic mutant that leads to FT destabilization of the protein and abolishes ability to FT bind PER2; when associated with D-280." FT /evidence="ECO:0000269|PubMed:19833968" FT MUTAGEN 107 FT /note="K->R: Sensitive to FBXL3-ediated degradation but noz FT affected by expression of FBXL21." FT /evidence="ECO:0000269|PubMed:23452856" FT MUTAGEN 224 FT /note="H->E: Reduces affinity for FBXL3." FT /evidence="ECO:0000269|PubMed:23746849" FT MUTAGEN 247 FT /note="S->A: Reduced MAPK-catalyzed in vitro FT phosphorylation. No effect on inhibition of FT CLOCK-BMAL1-mediated transcriptional activity." FT /evidence="ECO:0000269|PubMed:15298678, FT ECO:0000269|PubMed:23746849" FT MUTAGEN 247 FT /note="S->D: Reduced inhibition of CLOCK-BMAL1-mediated FT transcriptional activity." FT /evidence="ECO:0000269|PubMed:15298678, FT ECO:0000269|PubMed:23746849" FT MUTAGEN 273 FT /note="Y->A: Reduced interaction with MAP1LC3B and FT significant decrease in its autophagy-mediated degradation; FT when associated with A-276." FT /evidence="ECO:0000269|PubMed:29937374" FT MUTAGEN 276 FT /note="V->A: Reduced interaction with MAP1LC3B and FT significant decrease in its autophagy-mediated degradation; FT when associated with A-273." FT /evidence="ECO:0000269|PubMed:29937374" FT MUTAGEN 280 FT /note="S->A: Phosphomimetic mutant that leads to FT stabilization of the protein; when associated with A-71." FT /evidence="ECO:0000269|PubMed:19833968" FT MUTAGEN 280 FT /note="S->D: Phosphomimetic mutant that leads to FT destabilization of the protein and abolishes ability to FT bind PER2; when associated with D-71." FT /evidence="ECO:0000269|PubMed:19833968" FT MUTAGEN 287 FT /note="Y->A: No effect on its interaction with MAP1LC3B and FT moderate decrease in its autophagy-mediated degradation; FT when associated with A-290." FT /evidence="ECO:0000269|PubMed:29937374" FT MUTAGEN 290 FT /note="L->A: No effect on its interaction with MAP1LC3B and FT moderate decrease in its autophagy-mediated degradation; FT when associated with A-287." FT /evidence="ECO:0000269|PubMed:29937374" FT MUTAGEN 336 FT /note="G->D: Abolishes transcriptional repression of target FT genes. Abolishes interaction with PER2." FT MUTAGEN 382..383 FT /note="EE->RR: Decreases transcriptional repression of FT target genes. Decreases FBXL3 binding. Increases PER2 FT binding." FT /evidence="ECO:0000269|PubMed:23746849" FT MUTAGEN 405 FT /note="F->A: Decreases affinity for FBXL3. Slightly FT increases affinity for PER2." FT /evidence="ECO:0000269|PubMed:23746849" FT MUTAGEN 485 FT /note="K->D,E: Strongly reduces FBXL3 binding. Reduces PER2 FT binding." FT /evidence="ECO:0000269|PubMed:23746849" FT MUTAGEN 488 FT /note="Y->A: No effect on its interaction with MAP1LC3B and FT moderate decrease in its autophagy-mediated degradation; FT when associated with A-491." FT /evidence="ECO:0000269|PubMed:29937374" FT MUTAGEN 491 FT /note="L->A: No effect on its interaction with MAP1LC3B and FT moderate decrease in its autophagy-mediated degradation; FT when associated with A-488." FT /evidence="ECO:0000269|PubMed:29937374" FT MUTAGEN 494 FT /note="Y->A: Loss of interaction with MAP1LC3B and FT significant decrease in its autophagy-mediated degradation; FT when associated with A-497." FT /evidence="ECO:0000269|PubMed:29937374" FT MUTAGEN 497 FT /note="L->A: Loss of interaction with MAP1LC3B and FT significant decrease in its autophagy-mediated degradation; FT when associated with A-494." FT /evidence="ECO:0000269|PubMed:29937374" FT MUTAGEN 551 FT /note="S->A: No effect on circadian period length and FT protein stability." FT /evidence="ECO:0000269|PubMed:24158435" FT MUTAGEN 551 FT /note="S->D: No effect on circadian period length and FT protein stability." FT /evidence="ECO:0000269|PubMed:24158435" FT MUTAGEN 564 FT /note="S->A: No effect on circadian period length and FT protein stability." FT /evidence="ECO:0000269|PubMed:24158435" FT MUTAGEN 564 FT /note="S->D: No effect on circadian period length and FT protein stability." FT /evidence="ECO:0000269|PubMed:24158435" FT MUTAGEN 585 FT /note="K->A: Loss of ubiquitination. No loss of interaction FT with DDB1-CUL4A complex." FT /evidence="ECO:0000269|PubMed:26431207" FT MUTAGEN 588 FT /note="S->A: No effect on circadian period length and FT protein stability." FT /evidence="ECO:0000269|PubMed:24158435" FT MUTAGEN 588 FT /note="S->D: Lengthen circadian period. No effect on FT repressive activity. Increases protein stability." FT /evidence="ECO:0000269|PubMed:24158435" FT STRAND 4..11 FT /evidence="ECO:0007829|PDB:5T5X" FT STRAND 14..17 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 19..25 FT /evidence="ECO:0007829|PDB:5T5X" FT STRAND 29..37 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 39..41 FT /evidence="ECO:0007829|PDB:6KX7" FT HELIX 42..44 FT /evidence="ECO:0007829|PDB:7D1C" FT HELIX 46..48 FT /evidence="ECO:0007829|PDB:7D19" FT HELIX 49..67 FT /evidence="ECO:0007829|PDB:5T5X" FT TURN 68..70 FT /evidence="ECO:0007829|PDB:5T5X" FT STRAND 73..78 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 80..91 FT /evidence="ECO:0007829|PDB:5T5X" FT STRAND 93..99 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 104..119 FT /evidence="ECO:0007829|PDB:5T5X" FT STRAND 123..127 FT /evidence="ECO:0007829|PDB:5T5X" FT STRAND 130..133 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 135..141 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 150..158 FT /evidence="ECO:0007829|PDB:5T5X" FT TURN 174..177 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 186..190 FT /evidence="ECO:0007829|PDB:5T5X" FT TURN 195..199 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 214..229 FT /evidence="ECO:0007829|PDB:5T5X" FT TURN 231..234 FT /evidence="ECO:0007829|PDB:7DLI" FT HELIX 241..244 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 252..256 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 262..277 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 284..287 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 288..300 FT /evidence="ECO:0007829|PDB:5T5X" FT TURN 304..307 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 324..332 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 338..350 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 355..365 FT /evidence="ECO:0007829|PDB:5T5X" FT TURN 366..370 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 374..384 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 390..400 FT /evidence="ECO:0007829|PDB:5T5X" FT STRAND 403..405 FT /evidence="ECO:0007829|PDB:6KX7" FT HELIX 417..422 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 427..432 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 434..436 FT /evidence="ECO:0007829|PDB:5T5X" FT TURN 441..445 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 447..449 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 452..457 FT /evidence="ECO:0007829|PDB:5T5X" FT TURN 462..464 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 473..487 FT /evidence="ECO:0007829|PDB:5T5X" FT HELIX 490..494 FT /evidence="ECO:0007829|PDB:7D1C" SQ SEQUENCE 606 AA; 68001 MW; 2F2B8DD53F0A9AF9 CRC64; MGVNAVHWFR KGLRLHDNPA LKECIQGADT IRCVYILDPW FAGSSNVGIN RWRFLLQCLE DLDANLRKLN SRLFVIRGQP ADVFPRLFKE WNITKLSIEY DSEPFGKERD AAIKKLATEA GVEVIVRISH TLYDLDKIIE LNGGQPPLTY KRFQTLVSKM EPLEMPADTI TSDVIGKCMT PLSDDHDEKY GVPSLEELGF DTDGLSSAVW PGGETEALTR LERHLERKAW VANFERPRMN ANSLLASPTG LSPYLRFGCL SCRLFYFKLT DLYKKVKKNS SPPLSLYGQL LWREFFYTAA TNNPRFDKME GNPICVQIPW DKNPEALAKW AEGRTGFPWI DAIMTQLRQE GWIHHLARHA VACFLTRGDL WISWEEGMKV FEELLLDADW SINAGSWMWL SCSSFFQQFF HCYCPVGFGR RTDPNGDYIR RYLPVLRGFP AKYIYDPWNA PEGIQKVAKC LIGVNYPKPM VNHAEASRLN IERMKQIYQQ LSRYRGLGLL ASVPSNSNGN GGLMGYAPGE NVPSCSSSGN GGLMGYAPGE NVPSCSGGNC SQGSGILHYA HGDSQQTHSL KQGRSSAGTG LSSGKRPSQE EDAQSVGPKV QRQSSN //