ID CRY2_HUMAN Reviewed; 593 AA. AC Q49AN0; B4DH32; B4DZD6; O75148; Q8IV71; DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot. DT 28-NOV-2006, sequence version 2. DT 27-MAR-2024, entry version 162. DE RecName: Full=Cryptochrome-2; GN Name=CRY2; Synonyms=KIAA0658; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CHARACTERIZATION, AND TISSUE RP SPECIFICITY. RC TISSUE=Fetal brain; RX PubMed=8909283; DOI=10.1021/bi962209o; RA Hsu D.S., Zhao X., Zhao S., Kazantsev A., Wang R.-P., Todo T., Wei Y.-F., RA Sancar A.; RT "Putative human blue-light photoreceptors hCRY1 and hCRY2 are RT flavoproteins."; RL Biochemistry 35:13871-13877(1996). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain, and Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Testis; 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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 5-593 (ISOFORM 1). RC TISSUE=Brain; RX PubMed=9734811; DOI=10.1093/dnares/5.3.169; RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H., RA Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. X. The RT complete sequences of 100 new cDNA clones from brain which can code for RT large proteins in vitro."; RL DNA Res. 5:169-176(1998). RN [6] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. 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 [7] RP FUNCTION. RX PubMed=10531061; DOI=10.1126/science.286.5440.768; RA Griffin E.A. Jr., Staknis D., Weitz C.J.; RT "Light-independent role of CRY1 and CRY2 in the mammalian circadian RT clock."; RL Science 286:768-771(1999). RN [8] RP 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 [9] RP FUNCTION. RX PubMed=14672706; DOI=10.1016/j.bbrc.2003.11.099; RA Kawamoto T., Noshiro M., Sato F., Maemura K., Takeda N., Nagai R., RA Iwata T., Fujimoto K., Furukawa M., Miyazaki K., Honma S., Honma K.I., RA Kato Y.; RT "A novel autofeedback loop of Dec1 transcription involved in circadian RT rhythm regulation."; RL Biochem. Biophys. Res. Commun. 313:117-124(2004). RN [10] RP FUNCTION, AND INTERACTION WITH PPP5C. 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 [11] RP IDENTIFICATION BY MASS SPECTROMETRY, UBIQUITINATION BY FBXL3, AND RP INTERACTION WITH FBXL3. RX PubMed=17463251; DOI=10.1126/science.1141194; RA Busino L., Bassermann F., Maiolica A., Lee C., Nolan P.M., Godinho S.I., RA Draetta G.F., Pagano M.; RT "SCFFbxl3 controls the oscillation of the circadian clock by directing the RT degradation of cryptochrome proteins."; RL Science 316:900-904(2007). RN [12] RP ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND UBIQUITINATION. 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 [13] 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 [14] 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 [15] RP INTERACTION WITH ISCA1. RX PubMed=26569474; DOI=10.1038/nmat4484; RA Qin S., Yin H., Yang C., Dou Y., Liu Z., Zhang P., Yu H., Huang Y., RA Feng J., Hao J., Hao J., Deng L., Yan X., Dong X., Zhao Z., Jiang T., RA Wang H.W., Luo S.J., Xie C.; RT "A magnetic protein biocompass."; RL Nat. Mater. 15:217-226(2016). RN [16] RP INTERACTION WITH HNF4A. RX PubMed=30530698; DOI=10.1073/pnas.1816411115; RA Qu M., Duffy T., Hirota T., Kay S.A.; RT "Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue- RT specific circadian networks."; RL Proc. Natl. Acad. Sci. U.S.A. 115:E12305-E12312(2018). RN [17] RP INTERACTION WITH TIMELESS. RX PubMed=31138685; DOI=10.1073/pnas.1819110116; RA Kurien P., Hsu P.K., Leon J., Wu D., McMahon T., Shi G., Xu Y., Lipzen A., RA Pennacchio L.A., Jones C.R., Fu Y.H., Ptacek L.J.; RT "TIMELESS mutation alters phase responsiveness and causes advanced sleep RT phase."; RL Proc. Natl. Acad. Sci. U.S.A. 116:12045-12053(2019). CC -!- FUNCTION: Transcriptional repressor which forms a core component of the CC circadian clock. The circadian clock, an internal time-keeping system, CC regulates various physiological processes through the generation of CC approximately 24 hour circadian rhythms in gene expression, which are CC translated into rhythms in metabolism and behavior. It is derived from CC the Latin roots 'circa' (about) and 'diem' (day) and acts as an CC important regulator of a wide array of physiological functions CC including metabolism, sleep, body temperature, blood pressure, CC endocrine, immune, cardiovascular, and renal function. Consists of two CC major components: the central clock, residing in the suprachiasmatic CC nucleus (SCN) of the brain, and the peripheral clocks that are present CC in nearly every tissue and organ system. Both the central and CC peripheral clocks can be reset by environmental cues, also known as CC Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the CC central clock is light, which is sensed by retina and signals directly CC to the SCN. The central clock entrains the peripheral clocks through CC neuronal and hormonal signals, body temperature and feeding-related CC cues, aligning all clocks with the external light/dark cycle. Circadian CC rhythms allow an organism to achieve temporal homeostasis with its CC environment at the molecular level by regulating gene expression to CC create a peak of protein expression once every 24 hours to control when CC a particular physiological process is most active with respect to the CC solar day. Transcription and translation of core clock components CC (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a CC critical role in rhythm generation, whereas delays imposed by post- CC translational modifications (PTMs) are important for determining the CC period (tau) of the rhythms (tau refers to the period of a rhythm and CC is the length, in time, of one complete cycle). A diurnal rhythm is CC synchronized with the day/night cycle, while the ultradian and CC infradian rhythms have a period shorter and longer than 24 hours, CC respectively. Disruptions in the circadian rhythms contribute to the CC pathology of cardiovascular diseases, cancer, metabolic syndromes and CC aging. A transcription/translation feedback loop (TTFL) forms the core CC of the molecular circadian clock mechanism. Transcription factors, CC CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the CC feedback loop, act in the form of a heterodimer and activate the CC transcription of core clock genes and clock-controlled genes (involved CC in key metabolic processes), harboring E-box elements (5'-CACGTG-3') CC within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which CC are transcriptional repressors form the negative limb of the feedback CC loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer CC inhibiting its activity and thereby negatively regulating their own CC expression. This heterodimer also activates nuclear receptors NR1D1/2 CC and RORA/B/G, which form a second feedback loop and which activate and CC repress BMAL1 transcription, respectively. CRY1 and CRY2 have redundant CC functions but also differential and selective contributions at least in CC defining the pace of the SCN circadian clock and its circadian CC transcriptional outputs. Less potent transcriptional repressor in CC cerebellum and liver than CRY1, though less effective in lengthening CC the period of the SCN oscillator. Seems to play a critical role in CC tuning SCN circadian period by opposing the action of CRY1. With CRY1, CC dispensable for circadian rhythm generation but necessary for the CC development of intercellular networks for rhythm synchrony. May mediate CC circadian regulation of cAMP signaling and gluconeogenesis by blocking CC glucagon-mediated increases in intracellular cAMP concentrations and in CC CREB1 phosphorylation. Besides its role in the maintenance of the CC circadian clock, is also involved in the regulation of other processes. CC Plays a key role in glucose and lipid metabolism modulation, in part, CC through the transcriptional regulation of genes involved in these CC pathways, such as LEP or ACSL4. Represses glucocorticoid receptor CC NR3C1/GR-induced transcriptional activity by binding to glucocorticoid CC response elements (GREs). Represses the CLOCK-BMAL1 induced CC transcription of BHLHE40/DEC1. Represses the CLOCK-BMAL1 induced CC transcription of NAMPT (By similarity). Represses PPARD and its target CC genes in the skeletal muscle and limits exercise capacity (By CC similarity). Represses the transcriptional activity of NR1I2 (By CC similarity). {ECO:0000250|UniProtKB:Q9R194, CC ECO:0000269|PubMed:10531061, ECO:0000269|PubMed:14672706, CC ECO:0000269|PubMed:16790549}. CC -!- COFACTOR: CC Name=FAD; Xref=ChEBI:CHEBI:57692; CC Evidence={ECO:0000250|UniProtKB:Q9R194}; 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:0000250|UniProtKB:Q9R194}; 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. CC {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 (By similarity). Interacts with TIMELESS CC (PubMed:31138685). Interacts directly with PER1, PER2 and PER3; CC interaction with PER2 inhibits its ubiquitination and vice versa (By CC similarity). Interacts with CLOCK-BMAL1 (By similarity). Interacts with CC CLOCK (By similarity). Interacts with BMAL1 (By similarity). Interacts CC with NFIL3 (By similarity). Interacts with FBXL3 (PubMed:17463251). CC Interacts with FBXL21 (By similarity). FBXL3, PER2 and the cofactor FAD CC compete for overlapping binding sites (By similarity). FBXL3 cannot CC bind CRY2 that interacts already with PER2 or that contains bound FAD CC (By similarity). Interacts with PPP5C (via TPR repeats); the CC interaction down-regulates the PPP5C phosphatase activity on CSNK1E CC (PubMed:16790549). Interacts with nuclear receptors AR and NR3C1/GR; CC the interaction is ligand dependent (By similarity). Interacts with CC PRKDC and CIART (By similarity). Interacts with ISCA1 (in vitro) CC (PubMed:26569474). Interacts with DDB1, USP7 and TARDBP (By CC similarity). Interacts with HNF4A (PubMed:30530698). Interacts with CC PPARA (By similarity). Interacts with PPARD (via domain NR LBD) and CC NR1I2 (via domain NR LBD) in a ligand-dependent manner (By similarity). CC Interacts with PPARG, NR1I3 and VDR in a ligand-dependent manner (By CC similarity). {ECO:0000250|UniProtKB:Q9R194, CC ECO:0000269|PubMed:16790549, ECO:0000269|PubMed:17463251, CC ECO:0000269|PubMed:26569474, ECO:0000269|PubMed:30530698, CC ECO:0000269|PubMed:31138685}. CC -!- INTERACTION: CC Q49AN0; Q13363-2: CTBP1; NbExp=3; IntAct=EBI-2212355, EBI-10171858; CC Q49AN0; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-2212355, EBI-3867333; CC Q49AN0; P28799: GRN; NbExp=3; IntAct=EBI-2212355, EBI-747754; CC Q49AN0; Q8WZ60: KLHL6; NbExp=5; IntAct=EBI-2212355, EBI-6426464; CC Q49AN0; Q6A162: KRT40; NbExp=3; IntAct=EBI-2212355, EBI-10171697; CC Q49AN0; Q07627: KRTAP1-1; NbExp=3; IntAct=EBI-2212355, EBI-11959885; CC Q49AN0; Q8IUG1: KRTAP1-3; NbExp=3; IntAct=EBI-2212355, EBI-11749135; CC Q49AN0; P60409: KRTAP10-7; NbExp=3; IntAct=EBI-2212355, EBI-10172290; CC Q49AN0; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-2212355, EBI-10171774; CC Q49AN0; Q3LI70: KRTAP19-6; NbExp=3; IntAct=EBI-2212355, EBI-12805508; CC Q49AN0; Q9BYR5: KRTAP4-2; NbExp=3; IntAct=EBI-2212355, EBI-10172511; CC Q49AN0; Q6L8H4: KRTAP5-1; NbExp=3; IntAct=EBI-2212355, EBI-12074540; CC Q49AN0; Q701N4: KRTAP5-2; NbExp=3; IntAct=EBI-2212355, EBI-11958178; CC Q49AN0; Q6L8H1: KRTAP5-4; NbExp=3; IntAct=EBI-2212355, EBI-11963072; CC Q49AN0; Q6L8G8: KRTAP5-7; NbExp=3; IntAct=EBI-2212355, EBI-11987425; CC Q49AN0; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-2212355, EBI-3958099; CC Q49AN0; Q9BYQ0: KRTAP9-8; NbExp=3; IntAct=EBI-2212355, EBI-11958364; CC Q49AN0; O15344: MID1; NbExp=3; IntAct=EBI-2212355, EBI-2340316; CC Q49AN0; Q5JR59: MTUS2; NbExp=3; IntAct=EBI-2212355, EBI-742948; CC Q49AN0; Q5JR59-3: MTUS2; NbExp=5; IntAct=EBI-2212355, EBI-11522433; CC Q49AN0; O95544: NADK; NbExp=3; IntAct=EBI-2212355, EBI-743949; CC Q49AN0; P0DPK4: NOTCH2NLC; NbExp=3; IntAct=EBI-2212355, EBI-22310682; CC Q49AN0; O76083: PDE9A; NbExp=3; IntAct=EBI-2212355, EBI-742764; CC Q49AN0; O76083-2: PDE9A; NbExp=3; IntAct=EBI-2212355, EBI-11524542; CC Q49AN0; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-2212355, EBI-79165; CC Q49AN0; P53041: PPP5C; NbExp=3; IntAct=EBI-2212355, EBI-716663; CC Q49AN0; P0C264: SBK3; NbExp=3; IntAct=EBI-2212355, EBI-17181801; CC Q49AN0; Q9H190: SDCBP2; NbExp=3; IntAct=EBI-2212355, EBI-742426; CC Q49AN0; Q13077: TRAF1; NbExp=3; IntAct=EBI-2212355, EBI-359224; CC Q49AN0; Q12933: TRAF2; NbExp=3; IntAct=EBI-2212355, EBI-355744; CC Q49AN0; Q2TAL6: VWC2; NbExp=3; IntAct=EBI-2212355, EBI-11957238; CC Q49AN0; Q9H0D6: XRN2; NbExp=3; IntAct=EBI-2212355, EBI-372110; CC Q49AN0; B2RXF5: ZBTB42; NbExp=3; IntAct=EBI-2212355, EBI-12287587; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:9801304}. Nucleus CC {ECO:0000269|PubMed:22798407, ECO:0000269|PubMed:9801304}. CC Note=Translocated to the nucleus through interaction with other Clock CC proteins such as PER2 or BMAL1. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q49AN0-1; Sequence=Displayed; CC Name=2; CC IsoId=Q49AN0-2; Sequence=VSP_038970; CC -!- TISSUE SPECIFICITY: Expressed in all tissues examined including fetal CC brain, fibroblasts, heart, brain, placenta, lung, liver, skeletal CC muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, CC small intestine, colon and leukocytes. Highest levels in heart and CC skeletal muscle. {ECO:0000269|PubMed:8909283, CC ECO:0000269|PubMed:9801304}. CC -!- PTM: Phosphorylation on Ser-266 by MAPK is important for the inhibition CC of CLOCK-BMAL1-mediated transcriptional activity. Phosphorylation by CC CSKNE requires interaction with PER1 or PER2. Phosphorylated in a CC circadian manner at Ser-554 and Ser-558 in the suprachiasmatic nucleus CC (SCN) and liver. Phosphorylation at Ser-558 by DYRK1A promotes CC subsequent phosphorylation at Ser-554 by GSK3-beta: the two-step CC phosphorylation at the neighboring Ser residues leads to its CC proteasomal degradation. {ECO:0000250|UniProtKB:Q9R194}. 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 554 and Ser-558. Ubiquitination may be inhibited by PER2. CC Deubiquitinated by USP7 (By similarity). {ECO:0000250|UniProtKB:Q9R194, CC ECO:0000269|PubMed:11889036, ECO:0000269|PubMed:17463251, CC ECO:0000269|PubMed:22798407}. CC -!- SIMILARITY: Belongs to the DNA photolyase class-1 family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH35161.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact. Aberrant splice sites.; Evidence={ECO:0000305}; CC Sequence=BAG57993.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305}; CC Sequence=BAG57993.1; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305}; CC Sequence=BAG64048.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Cryptochrome entry; CC URL="https://en.wikipedia.org/wiki/Cryptochrome"; 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; AK294904; BAG57993.1; ALT_SEQ; mRNA. DR EMBL; AK302865; BAG64048.1; ALT_INIT; mRNA. DR EMBL; AC068385; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; KF455380; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC035161; AAH35161.1; ALT_SEQ; mRNA. DR EMBL; BC041814; AAH41814.1; -; mRNA. DR EMBL; AB014558; BAA31633.1; -; mRNA. DR CCDS; CCDS44576.1; -. [Q49AN0-2] DR CCDS; CCDS7915.3; -. [Q49AN0-1] DR RefSeq; NP_001120929.1; NM_001127457.2. [Q49AN0-2] DR RefSeq; NP_066940.2; NM_021117.3. [Q49AN0-1] DR AlphaFoldDB; Q49AN0; -. DR SMR; Q49AN0; -. DR BioGRID; 107798; 198. DR ComplexPortal; CPX-3220; Cry2-Per2 complex. DR ComplexPortal; CPX-3221; Cry2-Per1 complex. DR ComplexPortal; CPX-3224; Cry2-Per3 complex. DR CORUM; Q49AN0; -. DR DIP; DIP-47396N; -. DR IntAct; Q49AN0; 49. DR MINT; Q49AN0; -. DR STRING; 9606.ENSP00000478187; -. DR BindingDB; Q49AN0; -. DR ChEMBL; CHEMBL4296116; -. DR iPTMnet; Q49AN0; -. DR PhosphoSitePlus; Q49AN0; -. DR BioMuta; CRY2; -. DR DMDM; 118572252; -. DR EPD; Q49AN0; -. DR jPOST; Q49AN0; -. DR MassIVE; Q49AN0; -. DR MaxQB; Q49AN0; -. DR PaxDb; 9606-ENSP00000478187; -. DR PeptideAtlas; Q49AN0; -. DR ProteomicsDB; 62059; -. [Q49AN0-1] DR ProteomicsDB; 62060; -. [Q49AN0-2] DR Pumba; Q49AN0; -. DR Antibodypedia; 26186; 305 antibodies from 34 providers. DR DNASU; 1408; -. DR Ensembl; ENST00000417225.6; ENSP00000397419.2; ENSG00000121671.12. [Q49AN0-2] DR Ensembl; ENST00000616080.2; ENSP00000484684.1; ENSG00000121671.12. [Q49AN0-1] DR GeneID; 1408; -. DR KEGG; hsa:1408; -. DR MANE-Select; ENST00000616080.2; ENSP00000484684.1; NM_021117.5; NP_066940.3. DR UCSC; uc009ykw.4; human. [Q49AN0-1] DR AGR; HGNC:2385; -. DR CTD; 1408; -. DR DisGeNET; 1408; -. DR GeneCards; CRY2; -. DR HGNC; HGNC:2385; CRY2. DR HPA; ENSG00000121671; Low tissue specificity. DR MIM; 603732; gene. DR neXtProt; NX_Q49AN0; -. DR OpenTargets; ENSG00000121671; -. DR PharmGKB; PA26905; -. DR VEuPathDB; HostDB:ENSG00000121671; -. DR eggNOG; KOG0133; Eukaryota. DR GeneTree; ENSGT00940000159073; -. DR HOGENOM; CLU_010348_3_4_1; -. DR InParanoid; Q49AN0; -. DR OrthoDB; 124765at2759; -. DR PhylomeDB; Q49AN0; -. DR TreeFam; TF323191; -. DR PathwayCommons; Q49AN0; -. DR Reactome; R-HSA-400253; Circadian Clock. DR SABIO-RK; Q49AN0; -. DR SignaLink; Q49AN0; -. DR SIGNOR; Q49AN0; -. DR BioGRID-ORCS; 1408; 15 hits in 1163 CRISPR screens. DR ChiTaRS; CRY2; human. DR GenomeRNAi; 1408; -. DR Pharos; Q49AN0; Tbio. DR PRO; PR:Q49AN0; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q49AN0; Protein. DR Bgee; ENSG00000121671; Expressed in hindlimb stylopod muscle and 188 other cell types or tissues. DR ExpressionAtlas; Q49AN0; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005576; C:extracellular region; IDA:MGI. DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0009882; F:blue light photoreceptor activity; NAS:UniProtKB. DR GO; GO:0003684; F:damaged DNA binding; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0071949; F:FAD binding; ISS:UniProtKB. DR GO; GO:0016922; F:nuclear receptor binding; IEA:Ensembl. DR GO; GO:0019902; F:phosphatase binding; IPI:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IEA:Ensembl. DR GO; GO:0003697; F:single-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISS:UniProtKB. DR GO; GO:0009785; P:blue light signaling pathway; NAS:UniProtKB. DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB. DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB. DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; ISS:UniProtKB. DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB. DR GO; GO:0019915; P:lipid storage; IEA:Ensembl. DR GO; GO:0042754; P:negative regulation of circadian rhythm; ISS:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; ISS:UniProtKB. DR GO; GO:2000850; P:negative regulation of glucocorticoid secretion; IEA:Ensembl. DR GO; GO:0032515; P:negative regulation of phosphoprotein phosphatase activity; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl. DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB. DR GO; GO:2000118; P:regulation of sodium-dependent phosphate transport; IDA:MGI. DR GO; GO:0014823; P:response to activity; ISS:UniProtKB. DR GO; GO:0032868; P:response to insulin; IEA:Ensembl. DR GO; GO:0009416; P:response to light stimulus; IMP:CAFA. DR DisProt; DP00473; -. DR Gene3D; 1.25.40.80; -; 1. DR Gene3D; 1.10.579.10; DNA Cyclobutane Dipyrimidine Photolyase, subunit A, domain 3; 1. DR Gene3D; 3.40.50.620; HUPs; 1. DR InterPro; IPR036134; Crypto/Photolyase_FAD-like_sf. DR InterPro; IPR036155; Crypto/Photolyase_N_sf. DR InterPro; IPR005101; Cryptochr/Photolyase_FAD-bd. DR InterPro; IPR002081; Cryptochrome/DNA_photolyase_1. DR InterPro; IPR006050; DNA_photolyase_N. DR InterPro; IPR014729; Rossmann-like_a/b/a_fold. DR PANTHER; PTHR11455; CRYPTOCHROME; 1. DR PANTHER; PTHR11455:SF15; CRYPTOCHROME-2; 1. DR Pfam; PF00875; DNA_photolyase; 1. DR Pfam; PF03441; FAD_binding_7; 1. DR SUPFAM; SSF48173; Cryptochrome/photolyase FAD-binding domain; 1. DR SUPFAM; SSF52425; Cryptochrome/photolyase, N-terminal domain; 1. DR PROSITE; PS51645; PHR_CRY_ALPHA_BETA; 1. PE 1: Evidence at protein level; KW Alternative splicing; 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..593 FT /note="Cryptochrome-2" FT /id="PRO_0000261148" FT DOMAIN 22..151 FT /note="Photolyase/cryptochrome alpha/beta" FT REGION 390..489 FT /note="Required for inhibition of CLOCK-BMAL1-mediated FT transcription" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT REGION 532..593 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 533..547 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 561..580 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 271 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT BINDING 308 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:P97784" FT BINDING 374 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT BINDING 406..408 FT /ligand="FAD" FT /ligand_id="ChEBI:CHEBI:57692" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT MOD_RES 90 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P97784" FT MOD_RES 266 FT /note="Phosphoserine; by MAPK" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT MOD_RES 299 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P97784" FT MOD_RES 554 FT /note="Phosphoserine; by GSK3-beta" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT MOD_RES 558 FT /note="Phosphoserine; by DYRK1A and MAPK" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT CROSSLNK 30 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P97784" FT CROSSLNK 126 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT CROSSLNK 242 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT CROSSLNK 348 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT CROSSLNK 475 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT CROSSLNK 504 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q9R194" FT VAR_SEQ 1..72 FT /note="MAATVATAAAVAPAPAPGTDSASSVHWFRKGLRLHDNPALLAAVRGARCVRC FT VYILDPWFAASSSVGINRWR -> MPAPPGRTHTW (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_038970" FT CONFLICT 422 FT /note="S -> G (in Ref. 4; AAH35161)" FT /evidence="ECO:0000305" FT CONFLICT Q49AN0-2:9 FT /note="H -> L (in Ref. 2; BAG57993)" FT /evidence="ECO:0000305" SQ SEQUENCE 593 AA; 66947 MW; BF380424092BEBFB CRC64; MAATVATAAA VAPAPAPGTD SASSVHWFRK GLRLHDNPAL LAAVRGARCV RCVYILDPWF AASSSVGINR WRFLLQSLED LDTSLRKLNS RLFVVRGQPA DVFPRLFKEW GVTRLTFEYD SEPFGKERDA AIMKMAKEAG VEVVTENSHT LYDLDRIIEL NGQKPPLTYK RFQAIISRME LPKKPVGLVT SQQMESCRAE IQENHDETYG VPSLEELGFP TEGLGPAVWQ GGETEALARL DKHLERKAWV ANYERPRMNA NSLLASPTGL SPYLRFGCLS CRLFYYRLWD LYKKVKRNST PPLSLFGQLL WREFFYTAAT NNPRFDRMEG NPICIQIPWD RNPEALAKWA EGKTGFPWID AIMTQLRQEG WIHHLARHAV ACFLTRGDLW VSWESGVRVF DELLLDADFS VNAGSWMWLS CSAFFQQFFH CYCPVGFGRR TDPSGDYIRR YLPKLKAFPS RYIYEPWNAP ESIQKAAKCI IGVDYPRPIV NHAETSRLNI ERMKQIYQQL SRYRGLCLLA SVPSCVEDLS HPVAEPSSSQ AGSMSSAGPR PLPSGPASPK RKLEAAEEPP GEELSKRARV AELPTPELPS KDA //