Q16526 · CRY1_HUMAN
- ProteinCryptochrome-1
- GeneCRY1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids586 (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. More potent transcriptional repressor in cerebellum and liver than CRY2, though more effective in lengthening the period of the SCN oscillator. On its side, CRY2 seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY2, is dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. Interacts with CLOCK-BMAL1 independently of PER proteins and is found at CLOCK-BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK-BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1. Represses the CLOCK-BMAL1 induced transcription of ATF4, MTA1, KLF10 and NAMPT (By similarity).
May repress circadian target genes expression in collaboration with HDAC1 and HDAC2 through histone deacetylation. Mediates the clock-control activation of ATR and modulates ATR-mediated DNA damage checkpoint. In liver, mediates circadian regulation of cAMP signaling and gluconeogenesis by binding to membrane-coupled G proteins and blocking glucagon-mediated increases in intracellular cAMP concentrations and CREB1 phosphorylation. Inhibits hepatic gluconeogenesis by decreasing nuclear FOXO1 levels that down-regulates gluconeogenic gene expression (By similarity).
Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). 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 (By similarity).
Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (By similarity).
Plays an essential role in the generation of circadian rhythms in the retina (By similarity).
Represses the transcriptional activity of NR1I2 (By similarity).
May repress circadian target genes expression in collaboration with HDAC1 and HDAC2 through histone deacetylation. Mediates the clock-control activation of ATR and modulates ATR-mediated DNA damage checkpoint. In liver, mediates circadian regulation of cAMP signaling and gluconeogenesis by binding to membrane-coupled G proteins and blocking glucagon-mediated increases in intracellular cAMP concentrations and CREB1 phosphorylation. Inhibits hepatic gluconeogenesis by decreasing nuclear FOXO1 levels that down-regulates gluconeogenic gene expression (By similarity).
Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). 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 (By similarity).
Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (By similarity).
Plays an essential role in the generation of circadian rhythms in the retina (By similarity).
Represses the transcriptional activity of NR1I2 (By similarity).
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.
Features
Showing features for binding site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameCryptochrome-1
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ16526
Proteomes
Organism-specific databases
Disease & Variants
Involvement in disease
Delayed sleep phase syndrome (DSPS)
- Note
- DescriptionA circadian rhythm sleep disorder characterized by sleep-onset insomnia and difficulty in awakening at the desired time. Patients with DSPS have chronic difficulty in adjusting their sleep-onset and wake-up times to occupational, school, and social activities.
- See alsoMIM:614163
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 387 | Loss of binding to KL001. | ||||
Sequence: D → N | ||||||
Mutagenesis | 393 | Loss of binding to KL001. | ||||
Sequence: N → D |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 563 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, cross-link, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000261140 | 1-586 | UniProt | Cryptochrome-1 | |||
Sequence: MGVNAVHWFRKGLRLHDNPALKECIQGADTIRCVYILDPWFAGSSNVGINRWRFLLQCLEDLDANLRKLNSRLFVIRGQPADVFPRLFKEWNITKLSIEYDSEPFGKERDAAIKKLATEAGVEVIVRISHTLYDLDKIIELNGGQPPLTYKRFQTLISKMEPLEIPVETITSEVIEKCTTPLSDDHDEKYGVPSLEELGFDTDGLSSAVWPGGETEALTRLERHLERKAWVANFERPRMNANSLLASPTGLSPYLRFGCLSCRLFYFKLTDLYKKVKKNSSPPLSLYGQLLWREFFYTAATNNPRFDKMEGNPICVQIPWDKNPEALAKWAEGRTGFPWIDAIMTQLRQEGWIHHLARHAVACFLTRGDLWISWEEGMKVFEELLLDADWSINAGSWMWLSCSSFFQQFFHCYCPVGFGRRTDPNGDYIRRYLPVLRGFPAKYIYDPWNAPEGIQKVAKCLIGVNYPKPMVNHAEASRLNIERMKQIYQQLSRYRGLGLLASVPSNPNGNGGFMGYSAENIPGCSSSGSCSQGSGILHYAHGDSQQTHLLKQGRSSMGTGLSGGKRPSQEEDTQSIGPKVQRQSTN | |||||||
Cross-link | 11 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue | 71 | UniProt | Phosphoserine; by AMPK | ||||
Sequence: S | |||||||
Cross-link | 107 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Cross-link | 159 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue | 247 | UniProt | Phosphoserine; by MAPK | ||||
Sequence: S | |||||||
Modified residue | 280 | UniProt | Phosphoserine; by AMPK | ||||
Sequence: S | |||||||
Cross-link | 329 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Cross-link | 485 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Cross-link | 565 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue | 568 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 568 | PRIDE | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Phosphorylation on Ser-247 by MAPK is important for the inhibition of CLOCK-BMAL1-mediated transcriptional activity. Phosphorylation by CSNK1E requires interaction with PER1 or PER2. Phosphorylation at Ser-71 and Ser-280 by AMPK decreases protein stability. Phosphorylation at Ser-568 exhibits a robust circadian rhythm with a peak at CT8, increases protein stability, prevents SCF(FBXL3)-mediated degradation and is antagonized by interaction with PRKDC.
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 CRY1. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY1 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by the SCF(FBXL21) complex but not by the SCF(FBXL3) complex. Ubiquitination may be inhibited by PER2 (PubMed:17463251, PubMed:22798407, PubMed:27565346).
Deubiquitinated by USP7 (By similarity).
Deubiquitinated by USP7 (By similarity).
Undergoes autophagy-mediated degradation in the liver in a time-dependent manner. Autophagic degradation of CRY1 (an inhibitor of gluconeogenesis) occurs during periods of reduced feeding allowing induction of gluconeogenesis and maintenance of blood glucose levels.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Induction
Expression is regulated by light and circadian rhythms and osicllates diurnally. Peak expression in the suprachiasma nucleus (SCN) and eye at the day/night transition (CT12). Levels decrease with BMAL1-CLOCK inhibition as part of the autoregulatory feedback loop.
Gene expression databases
Organism-specific 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 (By similarity).
Interacts directly with TIMELESS (By similarity).
Interacts directly with PER1 and PER3 (By similarity).
Interacts directly with PER2; interaction with PER2 inhibits its ubiquitination and vice versa (PubMed:21613214).
Interacts with FBXL21 (By similarity).
Interacts with FBXL3 (PubMed:17463251).
Interacts with PPP5C (via TPR repeats) (PubMed:16790549).
Interacts with CLOCK-BMAL1 independently of PER2 and DNA (PubMed:28388406).
Interacts with HDAC1, HDAC2 and SIN3B. Interacts with nuclear receptors AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction with at least NR3C1/GR is ligand dependent (PubMed:22170608).
Interacts with PRKDC (By similarity).
Interacts with the G protein subunit alpha GNAS; the interaction may block GPCR-mediated regulation of cAMP concentrations (PubMed:20852621).
Interacts with PRMT5 (PubMed:23133559).
Interacts with EZH2 (By similarity).
Interacts with MYBBP1A, DOCK7, HNRNPU, RPL7A, RPL8 and RPS3 (By similarity).
Interacts with MAP1LC3B (By similarity).
Interacts with CLOCK (By similarity).
Interacts with BMAL1 (By similarity).
Interacts weakly with HDAC3; this interaction is enhanced in the presence of FBXL3 (By similarity).
Interacts with TRIM28, KCTD5 and DDB1 (By similarity).
Interacts with FOXO1 (By similarity).
Interacts with DTL and DDB1-CUL4A complex (PubMed:26431207).
Interacts with HNF4A (PubMed:30530698).
Interacts with PSMD2 in a KDM8-dependent manner (By similarity).
Interacts with KDM8 in a FBXL3-dependent manner (By similarity).
Interacts with PPARG in a ligand-dependent manner (By similarity).
Interacts with PPARD (via domain NR LBD) and NR1I2 (via domain NR LBD) in a ligand-dependent manner (By similarity).
Interacts with PPARA, NR1I3 and VDR (By similarity).
Interacts directly with TIMELESS (By similarity).
Interacts directly with PER1 and PER3 (By similarity).
Interacts directly with PER2; interaction with PER2 inhibits its ubiquitination and vice versa (PubMed:21613214).
Interacts with FBXL21 (By similarity).
Interacts with FBXL3 (PubMed:17463251).
Interacts with PPP5C (via TPR repeats) (PubMed:16790549).
Interacts with CLOCK-BMAL1 independently of PER2 and DNA (PubMed:28388406).
Interacts with HDAC1, HDAC2 and SIN3B. Interacts with nuclear receptors AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction with at least NR3C1/GR is ligand dependent (PubMed:22170608).
Interacts with PRKDC (By similarity).
Interacts with the G protein subunit alpha GNAS; the interaction may block GPCR-mediated regulation of cAMP concentrations (PubMed:20852621).
Interacts with PRMT5 (PubMed:23133559).
Interacts with EZH2 (By similarity).
Interacts with MYBBP1A, DOCK7, HNRNPU, RPL7A, RPL8 and RPS3 (By similarity).
Interacts with MAP1LC3B (By similarity).
Interacts with CLOCK (By similarity).
Interacts with BMAL1 (By similarity).
Interacts weakly with HDAC3; this interaction is enhanced in the presence of FBXL3 (By similarity).
Interacts with TRIM28, KCTD5 and DDB1 (By similarity).
Interacts with FOXO1 (By similarity).
Interacts with DTL and DDB1-CUL4A complex (PubMed:26431207).
Interacts with HNF4A (PubMed:30530698).
Interacts with PSMD2 in a KDM8-dependent manner (By similarity).
Interacts with KDM8 in a FBXL3-dependent manner (By similarity).
Interacts with PPARG in a ligand-dependent manner (By similarity).
Interacts with PPARD (via domain NR LBD) and NR1I2 (via domain NR LBD) in a ligand-dependent manner (By similarity).
Interacts with PPARA, NR1I3 and VDR (By similarity).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q16526 | PER1 O15534 | 3 | EBI-741297, EBI-2557276 | |
BINARY | Q16526 | PRMT5 O14744 | 3 | EBI-741297, EBI-351098 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, motif, region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 3-132 | Photolyase/cryptochrome alpha/beta | ||||
Sequence: VNAVHWFRKGLRLHDNPALKECIQGADTIRCVYILDPWFAGSSNVGINRWRFLLQCLEDLDANLRKLNSRLFVIRGQPADVFPRLFKEWNITKLSIEYDSEPFGKERDAAIKKLATEAGVEVIVRISHTL | ||||||
Motif | 50-54 | LIR 1 | ||||
Sequence: NRWRF | ||||||
Motif | 82-87 | LIR 2 | ||||
Sequence: DVFPRL | ||||||
Motif | 151-156 | LIR 3 | ||||
Sequence: KRFQTL | ||||||
Motif | 255-260 | LIR 4 | ||||
Sequence: LRFGCL | ||||||
Motif | 271-276 | LIR 5 | ||||
Sequence: DLYKKV | ||||||
Motif | 285-290 | LIR 6 | ||||
Sequence: SLYGQL | ||||||
Motif | 335-339 | LIR 7 | ||||
Sequence: TGFPW | ||||||
Region | 371-470 | Required for inhibition of CLOCK-BMAL1-mediated transcription | ||||
Sequence: WISWEEGMKVFEELLLDADWSINAGSWMWLSCSSFFQQFFHCYCPVGFGRRTDPNGDYIRRYLPVLRGFPAKYIYDPWNAPEGIQKVAKCLIGVNYPKPM | ||||||
Motif | 379-384 | LIR 8 | ||||
Sequence: KVFEEL | ||||||
Motif | 395-400 | LIR 9 | ||||
Sequence: GSWMWL | ||||||
Motif | 411-416 | LIR 10 | ||||
Sequence: HCYCPV | ||||||
Motif | 430-435 | LIR 11 | ||||
Sequence: RRYLPV | ||||||
Region | 471-493 | Interaction with TIMELESS | ||||
Sequence: VNHAEASRLNIERMKQIYQQLSR | ||||||
Motif | 486-491 | LIR 12 | ||||
Sequence: QIYQQL | ||||||
Motif | 492-497 | LIR 13 | ||||
Sequence: SRYRGL | ||||||
Region | 552-586 | Disordered | ||||
Sequence: QGRSSMGTGLSGGKRPSQEEDTQSIGPKVQRQSTN |
Domain
The LIR motifs (LC3-interacting region) 3 and 5 are required for its interaction with MAP1LC3B and for its autophagy-mediated degradation.
Sequence similarities
Belongs to the DNA photolyase class-1 family.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length586
- Mass (Da)66,395
- Last updated1996-11-01 v1
- Checksum96A5B09A6364D3B9
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
H0YHT0 | H0YHT0_HUMAN | CRY1 | 106 |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
D84657 EMBL· GenBank· DDBJ | BAA12710.1 EMBL· GenBank· DDBJ | mRNA | ||
D83702 EMBL· GenBank· DDBJ | BAA12068.1 EMBL· GenBank· DDBJ | mRNA | ||
BC030519 EMBL· GenBank· DDBJ | AAH30519.1 EMBL· GenBank· DDBJ | mRNA |