CRY1_SPAJD
ID CRY1_SPAJD Reviewed; 587 AA.
AC Q70AD6;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 79.
DE RecName: Full=Cryptochrome-1;
GN Name=CRY1;
OS Spalax judaei (Judean Mountains blind mole rat) (Nannospalax judaei).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Spalacidae; Spalacinae; Nannospalax.
OX NCBI_TaxID=134510;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND INDUCTION.
RC TISSUE=Brain;
RX PubMed=14964701; DOI=10.1177/0748730403260622;
RA Avivi A., Oster H., Joel A., Beiles A., Albrecht U., Nevo E.;
RT "Circadian genes in a blind subterranean mammal III: molecular cloning and
RT circadian regulation of cryptochrome genes in the blind subterranean mole
RT rat, Spalax ehrenbergi superspecies.";
RL J. Biol. Rhythms 19:22-34(2004).
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. More potent transcriptional repressor in
CC cerebellum and liver than CRY2, though more effective in lengthening
CC the period of the SCN oscillator. On its side, CRY2 seems to play a
CC critical role in tuning SCN circadian period by opposing the action of
CC CRY1. With CRY2, is dispensable for circadian rhythm generation but
CC necessary for the development of intercellular networks for rhythm
CC synchrony. Capable of translocating circadian clock core proteins such
CC as PER proteins to the nucleus. Interacts with CLOCK-ARNTL/BMAL1
CC independently of PER proteins and is found at CLOCK-ARNTL/BMAL1-bound
CC sites, suggesting that CRY may act as a molecular gatekeeper to
CC maintain CLOCK-ARNTL/BMAL1 in a poised and repressed state until the
CC proper time for transcriptional activation. Represses the CLOCK-
CC ARNTL/BMAL1 induced transcription of BHLHE40/DEC1, ATF4, MTA1, KLF10
CC and NAMPT. May repress circadian target genes expression in
CC collaboration with HDAC1 and HDAC2 through histone deacetylation.
CC Mediates the clock-control activation of ATR and modulates ATR-mediated
CC DNA damage checkpoint. In liver, mediates circadian regulation of cAMP
CC signaling and gluconeogenesis by binding to membrane-coupled G proteins
CC and blocking glucagon-mediated increases in intracellular cAMP
CC concentrations and CREB1 phosphorylation. Inhibits hepatic
CC gluconeogenesis by decreasing nuclear FOXO1 levels that down-regulates
CC gluconeogenic gene expression. Besides its role in the maintenance of
CC the circadian clock, is also involved in the regulation of other
CC processes. Represses glucocorticoid receptor NR3C1/GR-induced
CC transcriptional activity by binding to glucocorticoid response elements
CC (GREs). Plays a key role in glucose and lipid metabolism modulation, in
CC part, through the transcriptional regulation of genes involved in these
CC pathways, such as LEP or ACSL4 (By similarity). Represses PPARD and its
CC target genes in the skeletal muscle and limits exercise capacity (By
CC similarity). Plays an essential role in the generation of circadian
CC rhythms in the retina (By similarity). Represses the transcriptional
CC activity of NR1I2 (By similarity). {ECO:0000250|UniProtKB:P97784,
CC ECO:0000250|UniProtKB:Q16526}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:P97784};
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:P97784};
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 directly with TIMELESS (By similarity). Interacts directly
CC with PER1, PER2 and PER3; interaction with PER2 inhibits its
CC ubiquitination and vice versa (By similarity). Interacts with FBXL21
CC (By similarity). Interacts with FBXL3 (By similarity). Interacts with
CC CLOCK-ARNTL/BMAL1 independently of PER2 and DNA (By similarity).
CC Interacts with HDAC1, HDAC2 and SIN3B (By similarity). Interacts with
CC nuclear receptors AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction
CC with at least NR3C1/GR is ligand dependent (By similarity). Interacts
CC with PRKDC (By similarity). Interacts with the G protein subunit alpha
CC GNAS; the interaction may block GPCR-mediated regulation of cAMP
CC concentrations (By similarity). Interacts with PRMT5 (By similarity).
CC Interacts with EZH2 (By similarity). Interacts with MYBBP1A, DOCK7,
CC HNRNPU, RPL7A, RPL8 and RPS3 (By similarity). Interacts with PPP5C (via
CC TPR repeats) (By similarity). Interacts with MAP1LC3B (By similarity).
CC Interacts with CLOCK (By similarity). Interacts with ARNTL/BMAL1 (By
CC similarity). Interacts weakly with HDAC3; this interaction is enhanced
CC in the presence of FBXL3 (By similarity). Interacts with TRIM28, KCTD5
CC and DDB1 (By similarity) Interacts with HNF4A (By similarity).
CC Interacts with PSMD2 in a KDM8-dependent manner (By similarity).
CC Interacts with KDM8 in a FBXL3-dependent manner (By similarity).
CC Interacts with PPARG in a ligand-dependent manner (By similarity).
CC Interacts with PPARD (via domain NR LBD) and NR1I2 (via domain NR LBD)
CC in a ligand-dependent manner (By similarity). Interacts with PPARA,
CC NR1I3 and VDR (By similarity). {ECO:0000250|UniProtKB:P97784}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P97784}. Nucleus
CC {ECO:0000250|UniProtKB:P97784}. Note=Translocated to the nucleus
CC through interaction with other clock proteins such as PER2 or
CC ARNTL/BMAL1. {ECO:0000250|UniProtKB:P97784}.
CC -!- TISSUE SPECIFICITY: Expressed in all tissues tested including spleen,
CC liver, skeletal muscle, kidney, brain, intestine, eye, harderian gland,
CC liver and heart. Highest levels in the eye, brain, kidney and harderian
CC gland. In the brain, especially located to the suprachiasma nucleus
CC (SCN). {ECO:0000269|PubMed:14964701}.
CC -!- INDUCTION: Expression is regulated by light and circadian rhythms. In
CC the SCN and harderian gland, maximum expression at ZT 6, lowest
CC expression in the middle of the night at ZT 18. In the retina, peak
CC levels at ZT 12, lowest levels at ZT 18. {ECO:0000269|PubMed:14964701}.
CC -!- DOMAIN: The LIR motifs (LC3-interacting region) 3 and 5 are required
CC for its interaction with MAP1LC3B and for its autophagy-mediated
CC degradation. {ECO:0000250|UniProtKB:P97784}.
CC -!- PTM: Phosphorylation on Ser-247 by MAPK is important for the inhibition
CC of CLOCK-ARNTL/BMAL1-mediated transcriptional activity. Phosphorylation
CC by CSNK1E requires interaction with PER1 or PER2. Phosphorylation at
CC Ser-71 and Ser-280 by AMPK decreases protein stability. Phosphorylation
CC at Ser-569 exhibits a robust circadian rhythm with a peak at CT8,
CC increases protein stability, prevents SCF(FBXL3)-mediated degradation
CC and is antagonized by interaction with PRKDC.
CC {ECO:0000250|UniProtKB:P97784}.
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 CRY1 (By similarity). In
CC contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads
CC to stabilize CRY1 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).
CC Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by
CC the SCF(FBXL21) complex but not by the SCF(FBXL3) complex (By
CC similarity). Ubiquitination may be inhibited by PER2 (By similarity).
CC Deubiquitinated by USP7 (By similarity).
CC {ECO:0000250|UniProtKB:P97784}.
CC -!- PTM: Undergoes autophagy-mediated degradation in the liver in a time-
CC dependent manner. Autophagic degradation of CRY1 (an inhibitor of
CC gluconeogenesis) occurs during periods of reduced feeding allowing
CC induction of gluconeogenesis and maintenance of blood glucose levels.
CC {ECO:0000250|UniProtKB:P97784}.
CC -!- SIMILARITY: Belongs to the DNA photolyase class-1 family.
CC {ECO:0000305}.
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DR EMBL; AJ606298; CAE54425.1; -; mRNA.
DR AlphaFoldDB; Q70AD6; -.
DR SMR; Q70AD6; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR GO; GO:0009881; F:photoreceptor activity; IEA:UniProtKB-KW.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB.
DR GO; GO:0006975; P:DNA damage induced protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; ISS:UniProtKB.
DR GO; GO:0006094; P:gluconeogenesis; ISS:UniProtKB.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0042754; P:negative regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0045744; P:negative regulation of G protein-coupled receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0045721; P:negative regulation of gluconeogenesis; ISS:UniProtKB.
DR GO; GO:0031397; P:negative regulation of protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:2000001; P:regulation of DNA damage checkpoint; ISS:UniProtKB.
DR GO; GO:0014823; P:response to activity; ISS:UniProtKB.
DR GO; GO:0033762; P:response to glucagon; ISS:UniProtKB.
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 2: Evidence at transcript level;
KW Biological rhythms; Chromophore; Cytoplasm; FAD; Flavoprotein;
KW Isopeptide bond; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Photoreceptor protein; Receptor; Repressor; Sensory transduction;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..587
FT /note="Cryptochrome-1"
FT /id="PRO_0000261144"
FT DOMAIN 3..132
FT /note="Photolyase/cryptochrome alpha/beta"
FT REGION 371..470
FT /note="Required for inhibition of CLOCK-ARNTL/BMAL1-
FT mediated transcription"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT REGION 471..493
FT /note="Interaction with TIMELESS"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT REGION 554..587
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 50..54
FT /note="LIR 1"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 82..87
FT /note="LIR 2"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 151..156
FT /note="LIR 3"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 255..260
FT /note="LIR 4"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 271..276
FT /note="LIR 5"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 285..290
FT /note="LIR 6"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 335..339
FT /note="LIR 7"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 379..384
FT /note="LIR 8"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 395..400
FT /note="LIR 9"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 411..416
FT /note="LIR 10"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 430..435
FT /note="LIR 11"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 486..491
FT /note="LIR 12"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOTIF 492..497
FT /note="LIR 13"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT BINDING 252
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT BINDING 289
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT BINDING 355
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT BINDING 387..389
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOD_RES 71
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOD_RES 247
FT /note="Phosphoserine; by MAPK"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOD_RES 280
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT MOD_RES 569
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT CROSSLNK 11
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT CROSSLNK 107
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT CROSSLNK 159
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT CROSSLNK 329
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P97784"
FT CROSSLNK 485
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P97784"
SQ SEQUENCE 587 AA; 66434 MW; FB315F841E692A57 CRC64;
MGVNAVHWFR KGLRLHDNPA LKECIQGADT IRCVYILDPW FAGSSNVGIN RWRFLLQCLE
DLDANLRKLN SRLLVIRGQP ADVFPRLFKE WNITKLSIEY DSEPFGKERD AAIKKLATEA
GVEVIVRISH TLYDLDKIIE LNGGQPPLTY KRFQTLISKM EPLEIPVETI TSEVIEKCTT
PLSDDHDEKY GVPSLEELGF DTDGLSSAVW PGGETEALTR LERHLERRAW VANFERPRMN
ANSLLASPTG LSPYLRFGCL SCRLFYFKLT DLYKKVKKNS SPPLSLYGQL LWREFFYTAA
TNNPRFDKME GNPICVQIPW DKNPEALAKW AEGRTGFPWI DAIMTQLRQE GWIHHLARHA
VACFLTGSDL WISWEEGMKV FEELLLDADW SINAGSWMWL SCSSFFQQFF HCYCPVGFGR
RTDPNGDYIR RYLPVLRGFP AKYIYDPWNA PEGIQKVAKC LIGVNYPKPM VNHAEASRLN
IERMKQIYQQ LSRYRGLGLL ASVPSNPNGN GGLMGYTPGE NIPNCSSSGS CSQGSGILHY
AHGDSQQAHL LKQGSSSMGH GLSNGKRPSQ EEDTQSIGPK VQRQSTN
