CRY2_HUMAN
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 03-AUG-2022, entry version 153.
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).
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. Represses the CLOCK-ARNTL/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, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D
CC and/or CSNK1E, TIMELESS, and the PER proteins (By similarity).
CC Interacts with TIMELESS (By similarity). Interacts directly with PER1,
CC PER2 and PER3; interaction with PER2 inhibits its ubiquitination and
CC vice versa (By similarity). Interacts with CLOCK-ARNTL/BMAL1 (By
CC similarity). Interacts with CLOCK (By similarity). Interacts with
CC ARNTL/BMAL1 (By similarity). Interacts with NFIL3 (By similarity).
CC Interacts with FBXL3 (PubMed:17463251). Interacts with FBXL21 (By
CC similarity). FBXL3, PER2 and the cofactor FAD compete for overlapping
CC binding sites (By similarity). FBXL3 cannot bind CRY2 that interacts
CC already with PER2 or that contains bound FAD (By similarity). Interacts
CC with PPP5C (via TPR repeats); the interaction down-regulates the PPP5C
CC phosphatase activity on CSNK1E (PubMed:16790549). Interacts with
CC nuclear receptors AR and NR3C1/GR; the interaction is ligand dependent
CC (By similarity). Interacts with PRKDC and CIART (By similarity).
CC Interacts with ISCA1 (in vitro) (PubMed:26569474). Interacts with DDB1,
CC USP7 and TARDBP (By similarity). Interacts with HNF4A
CC (PubMed:30530698). Interacts with PPARA (By similarity). Interacts with
CC PPARD (via domain NR LBD) and NR1I2 (via domain NR LBD) in a ligand-
CC dependent manner (By similarity). Interacts with PPARG, NR1I3 and VDR
CC in a ligand-dependent manner (By similarity).
CC {ECO:0000250|UniProtKB:Q9R194, ECO:0000269|PubMed:16790549,
CC ECO:0000269|PubMed:17463251, ECO:0000269|PubMed:26569474,
CC ECO:0000269|PubMed:30530698}.
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 ARNTL.
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-ARNTL-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";
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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; CCDS7915.2; -. [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; 193.
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; 50.
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; Q49AN0; -.
DR PeptideAtlas; Q49AN0; -.
DR PRIDE; Q49AN0; -.
DR ProteomicsDB; 62059; -. [Q49AN0-1]
DR ProteomicsDB; 62060; -. [Q49AN0-2]
DR Antibodypedia; 26186; 258 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 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; 378952at2759; -.
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 1085 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 186 other 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: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:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
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; 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 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-ARNTL-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
