CRY2_MOUSE
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 03-AUG-2022, entry version 163.
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-ARNTL 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 ARNTL.
RX PubMed=16717091; DOI=10.1074/jbc.m603722200;
RA Etchegaray J.P., Yang X., DeBruyne J.P., Peters A.H., Weaver D.R.,
RA Jenuwein T., Reppert S.M.;
RT "The polycomb group protein EZH2 is required for mammalian circadian 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 ARNTL AND CLOCK, AND INDUCTION.
RX PubMed=19917250; DOI=10.1016/j.molcel.2009.10.012;
RA Chen R., Schirmer A., Lee Y., Lee H., Kumar V., Yoo S.H., 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 ARNTL 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, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and
CC CRY2) plays a critical role in rhythm generation, whereas delays
CC imposed by post-translational modifications (PTMs) are important for
CC determining the period (tau) of the rhythms (tau refers to the period
CC of a rhythm and is the length, in time, of one complete cycle). A
CC diurnal rhythm is synchronized with the day/night cycle, while the
CC ultradian and infradian rhythms have a period shorter and longer than
CC 24 hours, respectively. Disruptions in the circadian rhythms contribute
CC to the pathology of cardiovascular diseases, cancer, metabolic
CC syndromes and aging. A transcription/translation feedback loop (TTFL)
CC forms the core of the molecular circadian clock mechanism.
CC Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2,
CC form the positive limb of the feedback loop, act in the form of a
CC heterodimer and activate the transcription of core clock genes and
CC clock-controlled genes (involved in key metabolic processes), harboring
CC E-box elements (5'-CACGTG-3') within their promoters. The core clock
CC genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form
CC the negative limb of the feedback loop and interact with the
CC CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its
CC activity and thereby negatively regulating their own expression. This
CC heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G,
CC which form a second feedback loop and which activate and repress
CC ARNTL/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-ARNTL/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, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D
CC and/or CSNK1E, TIMELESS, and the PER proteins (PubMed:11779462).
CC Interacts with TIMELESS (PubMed:10428031). Interacts directly with
CC PER1, PER2 and PER3; interaction with PER2 inhibits its ubiquitination
CC and vice versa (PubMed:10428031, PubMed:11875063, PubMed:14701732,
CC PubMed:20840750, PubMed:24154698). Interacts with CLOCK-ARNTL/BMAL1
CC (PubMed:16628007). Interacts with ARNTL/BMAL1 (PubMed:16717091,
CC PubMed:19917250, PubMed:20840750). Interacts with CLOCK
CC (PubMed:16717091, PubMed:19917250). Interacts with NFIL3
CC (PubMed:17274955). Interacts with FBXL3 and FBXL21 (PubMed:17462724,
CC PubMed:23452855, PubMed:23452856). FBXL3, PER2 and the cofactor FAD
CC compete for overlapping binding sites (PubMed:24080726,
CC PubMed:23503662). FBXL3 cannot bind CRY2 that interacts already with
CC PER2 or that contains bound FAD (PubMed:23503662). Interacts with PPP5C
CC (via TPR repeats); the interaction down-regulates the PPP5C phosphatase
CC activity on CSNK1E (By similarity). Interacts with nuclear receptors AR
CC and NR3C1/GR; the interaction is ligand dependent (PubMed:22170608,
CC PubMed:28751364). Interacts with PRKDC (PubMed:24158435). Interacts
CC with CIART (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: Arntl; 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 ARNTL.
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-ARNTL-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 PDBsum; 4I6E; -.
DR PDBsum; 4I6G; -.
DR PDBsum; 4I6J; -.
DR PDBsum; 4MLP; -.
DR PDBsum; 4U8H; -.
DR PDBsum; 6KX8; -.
DR PDBsum; 7D0N; -.
DR PDBsum; 7EJ9; -.
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 iPTMnet; Q9R194; -.
DR PhosphoSitePlus; Q9R194; -.
DR EPD; Q9R194; -.
DR jPOST; Q9R194; -.
DR MaxQB; Q9R194; -.
DR PaxDb; Q9R194; -.
DR PeptideAtlas; Q9R194; -.
DR PRIDE; Q9R194; -.
DR ProteomicsDB; 284176; -.
DR Antibodypedia; 26186; 258 antibodies from 34 providers.
DR Ensembl; ENSMUST00000090559; ENSMUSP00000088047; ENSMUSG00000068742.
DR Ensembl; ENSMUST00000111278; ENSMUSP00000106909; ENSMUSG00000068742.
DR GeneID; 12953; -.
DR KEGG; mmu:12953; -.
DR UCSC; uc008kxy.2; mouse.
DR CTD; 1408; -.
DR MGI; MGI:1270859; Cry2.
DR VEuPathDB; HostDB:ENSMUSG00000068742; -.
DR eggNOG; KOG0133; Eukaryota.
DR GeneTree; ENSGT00940000159073; -.
DR HOGENOM; CLU_010348_3_4_1; -.
DR InParanoid; Q9R194; -.
DR OMA; NWNYTAG; -.
DR OrthoDB; 378952at2759; -.
DR PhylomeDB; Q9R194; -.
DR TreeFam; TF323191; -.
DR BioGRID-ORCS; 12953; 2 hits in 74 CRISPR screens.
DR PRO; PR:Q9R194; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q9R194; protein.
DR Bgee; ENSMUSG00000068742; Expressed in olfactory tubercle and 245 other tissues.
DR Genevisible; Q9R194; MM.
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:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; IGI:UniProtKB.
DR GO; GO:2000850; P:negative regulation of glucocorticoid secretion; IGI:UniProtKB.
DR GO; GO:0032515; P:negative regulation of phosphoprotein phosphatase activity; ISO:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:MGI.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0006606; P:protein import into nucleus; IPI:MGI.
DR GO; GO: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; 3.40.50.620; -; 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; PTHR11455; 1.
DR Pfam; PF00875; DNA_photolyase; 1.
DR Pfam; PF03441; FAD_binding_7; 1.
DR SUPFAM; SSF48173; SSF48173; 1.
DR SUPFAM; SSF52425; SSF52425; 1.
DR PROSITE; PS51645; PHR_CRY_ALPHA_BETA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Biological rhythms; Chromophore; 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-ARNTL-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 CLOCK-ARNTL-
FT mediated transcriptional activity. Very little in vitro
FT MAPK-catalyzed phosphorylation; when associated with A-
FT 557."
FT /evidence="ECO:0000269|PubMed:15298678"
FT MUTAGEN 265
FT /note="S->D: Reduced inhibition of CLOCK-ARNTL-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 CLOCK-ARNTL-
FT mediated transcriptional activity. No loss of ability to
FT inhibit NR1I2 transcriptional activity."
FT /evidence="ECO:0000269|PubMed:28751364"
FT MUTAGEN 354
FT /note="G->D: Loss of ability to inhibit CLOCK-ARNTL-
FT mediated transcriptional activity. No loss of ability to
FT inhibit NR1I2 transcriptional activity."
FT /evidence="ECO:0000269|PubMed:28751364"
FT MUTAGEN 376
FT /note="R->A: Impairs protein folding. Abolishes binding of
FT ARNTL, 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-ARNTL-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-ARNTL-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 CLOCK-ARNTL-
FT mediated transcriptional activity. Very little in vitro
FT MAPK-catalyzed phosphorylation; when associated with A-265.
FT Shorter circadian rhythm; when associated with A-553."
FT /evidence="ECO:0000269|PubMed:15298678,
FT ECO:0000269|PubMed:20123978"
FT MUTAGEN 557
FT /note="S->D: Reduced inhibition of CLOCK-ARNTL-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 22..26
FT /evidence="ECO:0007829|PDB:4MLP"
FT STRAND 32..35
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 37..43
FT /evidence="ECO:0007829|PDB:4MLP"
FT STRAND 47..55
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 59..61
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 67..85
FT /evidence="ECO:0007829|PDB:4MLP"
FT TURN 86..88
FT /evidence="ECO:0007829|PDB:4MLP"
FT STRAND 91..96
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 98..109
FT /evidence="ECO:0007829|PDB:4MLP"
FT STRAND 113..117
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 122..137
FT /evidence="ECO:0007829|PDB:4MLP"
FT STRAND 141..145
FT /evidence="ECO:0007829|PDB:4MLP"
FT STRAND 148..151
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 153..159
FT /evidence="ECO:0007829|PDB:4MLP"
FT TURN 160..162
FT /evidence="ECO:0007829|PDB:4I6E"
FT HELIX 168..176
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 190..194
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 204..208
FT /evidence="ECO:0007829|PDB:4MLP"
FT TURN 213..217
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 232..242
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 245..251
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 259..262
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 270..274
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 280..294
FT /evidence="ECO:0007829|PDB:4MLP"
FT STRAND 295..297
FT /evidence="ECO:0007829|PDB:4I6G"
FT HELIX 302..305
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 306..318
FT /evidence="ECO:0007829|PDB:4MLP"
FT TURN 322..325
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 342..350
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 356..368
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 373..383
FT /evidence="ECO:0007829|PDB:4MLP"
FT TURN 384..388
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 392..402
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 408..418
FT /evidence="ECO:0007829|PDB:4MLP"
FT STRAND 421..423
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 435..440
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 445..450
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 452..454
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 459..462
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 465..467
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 470..475
FT /evidence="ECO:0007829|PDB:4MLP"
FT TURN 480..482
FT /evidence="ECO:0007829|PDB:4MLP"
FT HELIX 491..507
FT /evidence="ECO:0007829|PDB:4MLP"
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
