CRY2_RAT
ID CRY2_RAT Reviewed; 594 AA.
AC Q923I8;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 112.
DE RecName: Full=Cryptochrome-2;
GN Name=Cry2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=11804325;
RA Eun B.-K., Lee B.J., Kang H.M.;
RT "Cloning and expression of cryptochrome2 cDNA in the rat.";
RL Mol. Cells 12:286-291(2001).
RN [2]
RP 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).
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 (By similarity). Represses
CC PPARD and its target genes in the skeletal muscle and limits exercise
CC capacity (By similarity). Represses the transcriptional activity of
CC NR1I2 (By similarity). {ECO:0000250|UniProtKB:Q9R194}.
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 -!- 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 and FBXL21 (By similarity). FBXL3, PER2 and the
CC cofactor FAD compete for overlapping binding sites (By similarity).
CC FBXL3 cannot bind CRY2 that interacts already with PER2 or that
CC contains bound FAD (By similarity). Interacts with PPP5C (via TPR
CC repeats); the interaction down-regulates the PPP5C phosphatase activity
CC on CSNK1E (PubMed:16790549). Interacts with nuclear receptors AR and
CC NR3C1/GR; the interaction is ligand dependent (By similarity).
CC Interacts with PRKDC and CIART (By similarity). Interacts with DDB1,
CC USP7 and TARDBP (By similarity). Interacts with HNF4A and PPARA (By
CC similarity). Interacts with PPARD (via domain NR LBD) and NR1I2 (via
CC domain NR LBD) in a ligand-dependent manner (By similarity). Interacts
CC with PPARG, NR1I3 and VDR in a ligand-dependent manner (By similarity).
CC {ECO:0000250|UniProtKB:Q49AN0, ECO:0000250|UniProtKB:Q9R194,
CC ECO:0000269|PubMed:16790549}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9R194}. Nucleus
CC {ECO:0000250|UniProtKB:Q9R194}. Note=Translocated to the nucleus
CC through interaction with other Clock proteins such as PER2 or ARNTL.
CC {ECO:0000250|UniProtKB:Q9R194}.
CC -!- TISSUE SPECIFICITY: Expressed in all tissues examined including heart,
CC cerebellum, cerebral cortex, lung, liver, muscle, kidney and ovary.
CC Highest levels in heart, liver and ovary. Highly expressed in the
CC suprachiasmatic nucleus (SCN). {ECO:0000269|PubMed:11804325}.
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:0000250|UniProtKB:Q9R194}.
CC -!- PTM: Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes,
CC regulating the balance between degradation and stabilization (By
CC similarity). The SCF(FBXL3) complex is mainly nuclear and mediates
CC ubiquitination and subsequent degradation of CRY2 (By similarity). In
CC contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads
CC to stabilize CRY2 and counteract the activity of the SCF(FBXL3) complex
CC (By similarity). The SCF(FBXL3) and SCF(FBXL21) complexes probably
CC mediate ubiquitination at different Lys residues (By similarity). The
CC SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser-553
CC and Ser-557 (By similarity). Ubiquitination may be inhibited by PER2
CC (By similarity). Deubiquitinated by USP7 (By similarity).
CC {ECO:0000250|UniProtKB:Q9R194}.
CC -!- SIMILARITY: Belongs to the DNA photolyase class-1 family.
CC {ECO:0000305}.
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DR EMBL; AY033877; AAK61419.1; -; mRNA.
DR AlphaFoldDB; Q923I8; -.
DR SMR; Q923I8; -.
DR CORUM; Q923I8; -.
DR DIP; DIP-61214N; -.
DR IntAct; Q923I8; 1.
DR STRING; 10116.ENSRNOP00000010142; -.
DR PaxDb; Q923I8; -.
DR PRIDE; Q923I8; -.
DR UCSC; RGD:620935; rat.
DR RGD; 620935; Cry2.
DR eggNOG; KOG0133; Eukaryota.
DR InParanoid; Q923I8; -.
DR PhylomeDB; Q923I8; -.
DR PRO; PR:Q923I8; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005576; C:extracellular region; ISO:RGD.
DR GO; GO:0005739; C:mitochondrion; ISO:RGD.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003684; F:damaged DNA binding; ISO:RGD.
DR GO; GO:0003677; F:DNA binding; ISO:RGD.
DR GO; GO:0071949; F:FAD binding; ISS:UniProtKB.
DR GO; GO:0019900; F:kinase binding; ISO:RGD.
DR GO; GO:0016922; F:nuclear receptor binding; ISO:RGD.
DR GO; GO:0019902; F:phosphatase binding; ISO:RGD.
DR GO; GO:0009881; F:photoreceptor activity; IEA:UniProtKB-KW.
DR GO; GO:0019901; F:protein kinase binding; ISO:RGD.
DR GO; GO:0003697; F:single-stranded DNA binding; ISO:RGD.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISS:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; IEP:RGD.
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; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0032515; P:negative regulation of phosphoprotein phosphatase activity; ISO:RGD.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0006606; P:protein import into nucleus; ISO:RGD.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:2000118; P:regulation of sodium-dependent phosphate transport; ISO:RGD.
DR GO; GO:0014823; P:response to activity; ISS:UniProtKB.
DR GO; GO:0032868; P:response to insulin; ISO:RGD.
DR GO; GO:0009416; P:response to light stimulus; ISS: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 Biological rhythms; Chromophore; Cytoplasm; FAD; Flavoprotein;
KW 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..594
FT /note="Cryptochrome-2"
FT /id="PRO_0000261150"
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:Q9R194"
FT REGION 532..594
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..574
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 580..594
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 270
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q9R194"
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:0000250|UniProtKB:Q9R194"
FT BINDING 405..407
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q9R194"
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:0000250|UniProtKB:Q9R194"
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:0000250|UniProtKB:Q9R194"
FT MOD_RES 557
FT /note="Phosphoserine; by DYRK1A and MAPK"
FT /evidence="ECO:0000250|UniProtKB:Q9R194"
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:0000250|UniProtKB:Q9R194"
FT CROSSLNK 241
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9R194"
FT CROSSLNK 347
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9R194"
FT CROSSLNK 474
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9R194"
FT CROSSLNK 503
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9R194"
SQ SEQUENCE 594 AA; 67223 MW; 9B99F650E3845E11 CRC64;
MAAAAVVAAT VPVQSMGADG ASSVHWFRKG LRLHDNPALL AAVRGARCVR CVYILDPWFA
ASSSVGINRW RFLLQSLEDL DTSLRKLNSR LFVVRGQPAD VFPRLFKEWG VTRLTFEYDS
EPFGKERDAA IMKMAKEAGV EVVTENSHTL YDLDRIIELN GQKPPLTYKR FQALISRMEL
PKKPVGAVSS QHMENCRAEI QENHDDTYGV PSLEELGFPT EGLGPAVWQG GETEALVRLD
KHLERKAWVA NYERPRMNAN SLLASPTGLS PYLRFGCLSC RLFYYRLWDL YRKVKRNSTP
PLSLFGQLLW REFFYTAATN NPRFDRMEGN PICIQIPWDR NPEALAKWAE GKTGFPWIDA
IMTQLRQEGW IHHLARHAVA CFLTRGDLWV SWESGVRVFD ELLLDADFSV NAGSWMWLSC
SAFFQQFFHC YCPVGFGRRT DPSGDYIRRY LPKLKGFPSR YIYEPWNAPE SVQKAANCII
GVDYPRPIVN HAETSRLNIE RMKQIYQQLS RYRGLCLWAS VPSCVEDLSH PVAEPGSSQA
GSISNTGPRP LSSGPASPKR KLEAAEEPPG EELSKRARVT VTQMPAQEPP SKDS
