Q9R194 · CRY2_MOUSE
- ProteinCryptochrome-2
- GeneCry2
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids592 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. Less potent transcriptional repressor in cerebellum and liver than CRY1, though less effective in lengthening the period of the SCN oscillator. Seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY1, dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. May mediate circadian regulation of cAMP signaling and gluconeogenesis by blocking glucagon-mediated increases in intracellular cAMP concentrations and in CREB1 phosphorylation. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1 and NAMPT. Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (PubMed:28683290).
Represses the transcriptional activity of NR1I2 (PubMed:28751364).
Represses the transcriptional activity of NR1I2 (PubMed:28751364).
Cofactor
Protein has several cofactor binding sites:
Note: Binds 1 FAD per subunit. Only a minority of the protein molecules contain bound FAD. Contrary to the situation in photolyases, the FAD is bound in a shallow, surface-exposed pocket.
Note: Binds 1 5,10-methenyltetrahydrofolate (MTHF) non-covalently per subunit.
Activity regulation
KL001 (N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-N-(2-furanylmethyl)-methanesulfonamide) binds to CRY1 and stabilizes it by inhibiting FBXL3- and ubiquitin-dependent degradation of CRY1 resulting in lengthening of the circadian periods. KL001-mediated CRY1 stabilization can inhibit glucagon-induced gluconeogenesis in primary hepatocytes.
Features
Showing features for binding site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Names & Taxonomy
Protein names
- Recommended nameCryptochrome-2
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ9R194
- Secondary accessions
Proteomes
Organism-specific databases
Phenotypes & Variants
Disruption phenotype
Animals show longer circadian periods. Double knockouts of CRY1 and CRY2 show slightly decrease body weight and lose the cycling rhythmicity of feeding behavior, energy expenditure and glucocorticorids expression. Glucose homeostasis is severely disrupted and animals exhibit elevated blood glucose in response to acute feeding after an overnight fast as well as severely impaired glucose clearance in a glucose tolerance test. When challenged with high-fat diet, animals rapidly gain weight and surpass that of wild-type mice, despite displaying hypophagia. They exhibit hyperinsulinemia and selective insulin resistance in the liver and muscle but show high insulin sensitivity in adipose tissue and consequent increased lipid uptake. Mice display enlarged gonadal, subcutaneous and perirenal fat deposits with adipocyte hypertrophy and increased lipied accumulation in liver. Mice show attentuated circadian rhythms in photopic ERG b-wave amplitudes (PubMed:29561690).
Both single CRY1 knockout and double CRY1 and CRY2 knockout mice show increased exercise performance and increased mitochondrial reserve capacity in primary myotubes (PubMed:28683290).
Both single CRY1 knockout and double CRY1 and CRY2 knockout mice show increased exercise performance and increased mitochondrial reserve capacity in primary myotubes (PubMed:28683290).
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 265 | Reduced in vitro MAPK-catalyzed phosphorylation. No effect on inhibition of CLOCK-BMAL1-mediated transcriptional activity. Very little in vitro MAPK-catalyzed phosphorylation; when associated with A-557. | ||||
Sequence: S → A | ||||||
Mutagenesis | 265 | Reduced inhibition of CLOCK-BMAL1-mediated transcriptional activity. No effect on nuclear localization nor on protein stability. | ||||
Sequence: S → D | ||||||
Mutagenesis | 310 | Decreases FBXL3 binding. Strongly decreases CRY2 degradation. | ||||
Sequence: W → A | ||||||
Mutagenesis | 339 | Strongly reduces PER1 binding. | ||||
Sequence: D → R | ||||||
Mutagenesis | 351 | Loss of ability to inhibit CLOCK-BMAL1-mediated transcriptional activity. No loss of ability to inhibit NR1I2 transcriptional activity. | ||||
Sequence: G → D | ||||||
Mutagenesis | 354 | Loss of ability to inhibit CLOCK-BMAL1-mediated transcriptional activity. No loss of ability to inhibit NR1I2 transcriptional activity. | ||||
Sequence: G → D | ||||||
Mutagenesis | 376 | Impairs protein folding. Abolishes binding of BMAL1, PER1 and FBXL3. Strongly reduces SKP1 binding. | ||||
Sequence: R → A | ||||||
Mutagenesis | 394 | Reduced interaction with NR1I2 and NR1I3. Significant decrease in interaction with NR1I2 and NR1I3; when associated with M-396 and K-397. | ||||
Sequence: S → E | ||||||
Mutagenesis | 396 | Reduced interaction with NR1I2 and NR1I3. Significant decrease in interaction with NR1I2 and NR1I3; when associated with E-394 and K-397. | ||||
Sequence: V → M | ||||||
Mutagenesis | 397 | Reduced interaction with NR1I2 and NR1I3. Significant decrease in interaction with NR1I2 and NR1I3; when associated with E-394 and M-396. | ||||
Sequence: R → K | ||||||
Mutagenesis | 428 | Abolishes binding of FBXL3 and SKP1. Strongly decreases CRY2 degradation. | ||||
Sequence: F → D | ||||||
Mutagenesis | 499 | Abolishes binding of FBXL3 and SKP1. Strongly decreases CRY2 degradation. | ||||
Sequence: I → D | ||||||
Mutagenesis | 501 | Inhibits interaction with PER2. Does not suppress its nuclear localization. Inhibits its repression activity on CLOCK|NPAS2-BMAL1-driven transcription. | ||||
Sequence: R → Q | ||||||
Mutagenesis | 503 | Inhibits interaction with PER2. Does not suppress its nuclear localization. Inhibits its repression activity on CLOCK|NPAS2-BMAL1-driven transcription. | ||||
Sequence: K → R | ||||||
Mutagenesis | 517 | Decreases FBXL3 binding. Strongly decreases CRY2 degradation. | ||||
Sequence: L → D | ||||||
Mutagenesis | 553 | Shorter circadian rhythm; when associated with A-557. | ||||
Sequence: S → A | ||||||
Mutagenesis | 557 | Reduced in vitro MAPK-catalyzed phosphorylation. No effect on inhibition of CLOCK-BMAL1-mediated transcriptional activity. Very little in vitro MAPK-catalyzed phosphorylation; when associated with A-265. Shorter circadian rhythm; when associated with A-553. | ||||
Sequence: S → A | ||||||
Mutagenesis | 557 | Reduced inhibition of CLOCK-BMAL1-mediated transcriptional activity. No effect on nuclear localization nor on protein stability. | ||||
Sequence: S → D |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 19 variants from UniProt as well as other sources including ClinVar and dbSNP.
PTM/Processing
Features
Showing features for chain, cross-link, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000261149 | 1-592 | Cryptochrome-2 | |||
Sequence: MAAAAVVAATVPAQSMGADGASSVHWFRKGLRLHDNPALLAAVRGARCVRCVYILDPWFAASSSVGINRWRFLLQSLEDLDTSLRKLNSRLFVVRGQPADVFPRLFKEWGVTRLTFEYDSEPFGKERDAAIMKMAKEAGVEVVTENSHTLYDLDRIIELNGQKPPLTYKRFQALISRMELPKKPAVAVSSQQMESCRAEIQENHDDTYGVPSLEELGFPTEGLGPAVWQGGETEALARLDKHLERKAWVANYERPRMNANSLLASPTGLSPYLRFGCLSCRLFYYRLWDLYKKVKRNSTPPLSLFGQLLWREFFYTAATNNPRFDRMEGNPICIQIPWDRNPEALAKWAEGKTGFPWIDAIMTQLRQEGWIHHLARHAVACFLTRGDLWVSWESGVRVFDELLLDADFSVNAGSWMWLSCSAFFQQFFHCYCPVGFGRRTDPSGDYIRRYLPKLKGFPSRYIYEPWNAPESVQKAAKCIIGVDYPRPIVNHAETSRLNIERMKQIYQQLSRYRGLCLLASVPSCVEDLSHPVAEPGSSQAGSISNTGPRALSSGPASPKRKLEAAEEPPGEELTKRARVTEMPTQEPASKDS | ||||||
Cross-link | 29 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 89 | Phosphoserine | ||||
Sequence: S | ||||||
Cross-link | 125 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Cross-link | 241 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 265 | Phosphoserine; by MAPK | ||||
Sequence: S | ||||||
Modified residue | 298 | Phosphoserine | ||||
Sequence: S | ||||||
Cross-link | 347 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Cross-link | 474 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Cross-link | 503 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 553 | Phosphoserine; by GSK3-beta | ||||
Sequence: S | ||||||
Modified residue | 557 | Phosphoserine; by DYRK1A and MAPK | ||||
Sequence: S |
Post-translational modification
Phosphorylation on Ser-265 by MAPK is important for the inhibition of CLOCK-BMAL1-mediated transcriptional activity. Phosphorylation by CSKNE requires interaction with PER1 or PER2. Phosphorylated in a circadian manner at Ser-553 and Ser-557 in the suprachiasmatic nucleus (SCN) and liver. Phosphorylation at Ser-557 by DYRK1A promotes subsequent phosphorylation at Ser-553 by GSK3-beta: the two-step phosphorylation at the neighboring Ser residues leads to its proteasomal degradation.
Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes, regulating the balance between degradation and stabilization. The SCF(FBXL3) complex is mainly nuclear and mediates ubiquitination and subsequent degradation of CRY2. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY2 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. The SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser-553 and Ser-557. Ubiquitination may be inhibited by PER2. Deubiquitinated by USP7 (PubMed:27123980).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Expression in the retina is restricted to the photoreceptor layer (at protein level) (PubMed:29561690).
Expressed in all tissues examined including heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis. Weak expression in spleen
Expressed in all tissues examined including heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis. Weak expression in spleen
Induction
Shows no clear circadian oscillation pattern in testis, cerebellum nor liver. In skeletal muscle, under constant darkness and 12 hours light:12 hours dark conditions, levels peak between ZT6 and ZT9.
Gene expression databases
Interaction
Subunit
Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins (PubMed:11779462).
Interacts with TIMELESS (PubMed:10428031).
Interacts directly with PER1, PER2 and PER3; interaction with PER2 inhibits its ubiquitination and vice versa (PubMed:10428031, PubMed:11875063, PubMed:14701732, PubMed:20840750, PubMed:24154698).
Interacts with CLOCK-BMAL1 (PubMed:16628007).
Interacts with BMAL1 (PubMed:16717091, PubMed:19917250, PubMed:20840750).
Interacts with CLOCK (PubMed:16717091, PubMed:19917250).
Interacts with NFIL3 (PubMed:17274955).
Interacts with FBXL3 and FBXL21 (PubMed:17462724, PubMed:23452855, PubMed:23452856).
FBXL3, PER2 and the cofactor FAD compete for overlapping binding sites (PubMed:23503662, PubMed:24080726).
FBXL3 cannot bind CRY2 that interacts already with PER2 or that contains bound FAD (PubMed:23503662).
Interacts with PPP5C (via TPR repeats); the interaction down-regulates the PPP5C phosphatase activity on CSNK1E (By similarity).
Interacts with nuclear receptors AR and NR3C1/GR; the interaction is ligand dependent (PubMed:22170608, PubMed:28751364).
Interacts with PRKDC (PubMed:24158435).
Interacts with CIART (PubMed:24736997).
Interacts with DDB1, USP7 and TARDBP (PubMed:27123980).
Interacts with HNF4A (PubMed:28751364).
Interacts with PPARA (PubMed:28683290).
Interacts with PPARG in a ligand-dependent manner (PubMed:28683290).
Interacts with PPARD (via domain NR LBD) in a ligand-dependent manner (PubMed:28683290, PubMed:28751364).
Interacts with NR1I2 (via domain NR LBD) in a ligand-dependent manner (PubMed:28751364).
Interacts with NR1I3 and VDR in a ligand-dependent manner (PubMed:28751364).
Interacts with TIMELESS (PubMed:10428031).
Interacts directly with PER1, PER2 and PER3; interaction with PER2 inhibits its ubiquitination and vice versa (PubMed:10428031, PubMed:11875063, PubMed:14701732, PubMed:20840750, PubMed:24154698).
Interacts with CLOCK-BMAL1 (PubMed:16628007).
Interacts with BMAL1 (PubMed:16717091, PubMed:19917250, PubMed:20840750).
Interacts with CLOCK (PubMed:16717091, PubMed:19917250).
Interacts with NFIL3 (PubMed:17274955).
Interacts with FBXL3 and FBXL21 (PubMed:17462724, PubMed:23452855, PubMed:23452856).
FBXL3, PER2 and the cofactor FAD compete for overlapping binding sites (PubMed:23503662, PubMed:24080726).
FBXL3 cannot bind CRY2 that interacts already with PER2 or that contains bound FAD (PubMed:23503662).
Interacts with PPP5C (via TPR repeats); the interaction down-regulates the PPP5C phosphatase activity on CSNK1E (By similarity).
Interacts with nuclear receptors AR and NR3C1/GR; the interaction is ligand dependent (PubMed:22170608, PubMed:28751364).
Interacts with PRKDC (PubMed:24158435).
Interacts with CIART (PubMed:24736997).
Interacts with DDB1, USP7 and TARDBP (PubMed:27123980).
Interacts with HNF4A (PubMed:28751364).
Interacts with PPARA (PubMed:28683290).
Interacts with PPARG in a ligand-dependent manner (PubMed:28683290).
Interacts with PPARD (via domain NR LBD) in a ligand-dependent manner (PubMed:28683290, PubMed:28751364).
Interacts with NR1I2 (via domain NR LBD) in a ligand-dependent manner (PubMed:28751364).
Interacts with NR1I3 and VDR in a ligand-dependent manner (PubMed:28751364).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q9R194 | Bmal1 Q9WTL8 | 12 | EBI-1266619, EBI-644534 | |
BINARY | Q9R194 | Ciart Q3TQ03 | 2 | EBI-1266619, EBI-16101489 | |
BINARY | Q9R194 | Csnk2b P67871 | 3 | EBI-1266619, EBI-348179 | |
BINARY | Q9R194 | Fbxl21 Q8BFZ4 | 4 | EBI-1266619, EBI-6898235 | |
BINARY | Q9R194 | Fbxl3 Q8C4V4 | 6 | EBI-1266619, EBI-1266589 | |
XENO | Q9R194 | FBXL3 Q9UKT7 | 13 | EBI-1266619, EBI-2557269 | |
BINARY | Q9R194 | Nr3c1 P06537-1 | 3 | EBI-1266619, EBI-15959147 | |
BINARY | Q9R194 | Per1 O35973 | 3 | EBI-1266619, EBI-1266764 | |
XENO | Q9R194 | PER1 O15534 | 3 | EBI-1266619, EBI-2557276 | |
BINARY | Q9R194 | Per2 O54943 | 8 | EBI-1266619, EBI-1266779 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 21-150 | Photolyase/cryptochrome alpha/beta | ||||
Sequence: ASSVHWFRKGLRLHDNPALLAAVRGARCVRCVYILDPWFAASSSVGINRWRFLLQSLEDLDTSLRKLNSRLFVVRGQPADVFPRLFKEWGVTRLTFEYDSEPFGKERDAAIMKMAKEAGVEVVTENSHTL | ||||||
Region | 389-488 | Required for inhibition of CLOCK-BMAL1-mediated transcription | ||||
Sequence: WVSWESGVRVFDELLLDADFSVNAGSWMWLSCSAFFQQFFHCYCPVGFGRRTDPSGDYIRRYLPKLKGFPSRYIYEPWNAPESVQKAAKCIIGVDYPRPI | ||||||
Region | 532-592 | Disordered | ||||
Sequence: VAEPGSSQAGSISNTGPRALSSGPASPKRKLEAAEEPPGEELTKRARVTEMPTQEPASKDS | ||||||
Compositional bias | 535-552 | Polar residues | ||||
Sequence: PGSSQAGSISNTGPRALS | ||||||
Compositional bias | 560-579 | Basic and acidic residues | ||||
Sequence: RKLEAAEEPPGEELTKRARV |
Sequence similarities
Belongs to the DNA photolyase class-1 family.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length592
- Mass (Da)66,850
- Last updated2000-05-01 v1
- Checksum4D6E7B199C392CBB
Features
Showing features for sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 191-192 | in Ref. 5; BAA19864 | ||||
Sequence: QQ → SR | ||||||
Sequence conflict | 202 | in Ref. 5; BAA19864 | ||||
Sequence: E → K | ||||||
Sequence conflict | 327 | in Ref. 5; BAA19864 | ||||
Sequence: M → V | ||||||
Compositional bias | 535-552 | Polar residues | ||||
Sequence: PGSSQAGSISNTGPRALS | ||||||
Compositional bias | 560-579 | Basic and acidic residues | ||||
Sequence: RKLEAAEEPPGEELTKRARV |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF156987 EMBL· GenBank· DDBJ | AAD46561.1 EMBL· GenBank· DDBJ | mRNA | ||
AK041696 EMBL· GenBank· DDBJ | BAC31037.1 EMBL· GenBank· DDBJ | mRNA | ||
AK133781 EMBL· GenBank· DDBJ | BAE21836.1 EMBL· GenBank· DDBJ | mRNA | ||
BC054794 EMBL· GenBank· DDBJ | AAH54794.1 EMBL· GenBank· DDBJ | mRNA | ||
BC066799 EMBL· GenBank· DDBJ | AAH66799.1 EMBL· GenBank· DDBJ | mRNA | ||
AK172994 EMBL· GenBank· DDBJ | BAD32272.1 EMBL· GenBank· DDBJ | mRNA | ||
AB003433 EMBL· GenBank· DDBJ | BAA19864.1 EMBL· GenBank· DDBJ | mRNA |