| UniProt ID | CRY1_HUMAN | |
|---|---|---|
| UniProt AC | Q16526 | |
| Protein Name | Cryptochrome-1 | |
| Gene Name | CRY1 | |
| Organism | Homo sapiens (Human). | |
| Sequence Length | 586 | |
| Subcellular Localization | Cytoplasm. Nucleus . Translocated to the nucleus through interaction with other clock proteins such as PER2 or ARNTL/BMAL1.. | |
| Protein Description | 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, ARNTL/BMAL1, ARNTL2/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 ARNTL/BMAL1 or ARNTL2/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-ARNTL/BMAL1|ARNTL2/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 ARNTL/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-ARNTL/BMAL1 independently of PER proteins and is found at CLOCK-ARNTL/BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK-ARNTL/BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1. Represses the CLOCK-ARNTL/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. 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.. | |
| Protein Sequence | MGVNAVHWFRKGLRLHDNPALKECIQGADTIRCVYILDPWFAGSSNVGINRWRFLLQCLEDLDANLRKLNSRLFVIRGQPADVFPRLFKEWNITKLSIEYDSEPFGKERDAAIKKLATEAGVEVIVRISHTLYDLDKIIELNGGQPPLTYKRFQTLISKMEPLEIPVETITSEVIEKCTTPLSDDHDEKYGVPSLEELGFDTDGLSSAVWPGGETEALTRLERHLERKAWVANFERPRMNANSLLASPTGLSPYLRFGCLSCRLFYFKLTDLYKKVKKNSSPPLSLYGQLLWREFFYTAATNNPRFDKMEGNPICVQIPWDKNPEALAKWAEGRTGFPWIDAIMTQLRQEGWIHHLARHAVACFLTRGDLWISWEEGMKVFEELLLDADWSINAGSWMWLSCSSFFQQFFHCYCPVGFGRRTDPNGDYIRRYLPVLRGFPAKYIYDPWNAPEGIQKVAKCLIGVNYPKPMVNHAEASRLNIERMKQIYQQLSRYRGLGLLASVPSNPNGNGGFMGYSAENIPGCSSSGSCSQGSGILHYAHGDSQQTHLLKQGRSSMGTGLSGGKRPSQEEDTQSIGPKVQRQSTN | |
| Overview of Protein Modification Sites with Functional and Structural Information | ||
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* ASA = Accessible Surface Area
| Locations | Modification | Substrate Peptides & Secondary Structure |
ASA (%) | Reference | Orthologous Protein Cluster |
|---|---|---|---|---|---|
| 71 | Phosphorylation | ANLRKLNSRLFVIRG HHHHHHHCCEEEECC | 40.57 | - | |
| 89 | Ubiquitination | DVFPRLFKEWNITKL CHHHHHHHHCCCEEE | 67.42 | - | |
| 107 | Ubiquitination | YDSEPFGKERDAAIK ECCCCCCCHHHHHHH | 50.37 | - | |
| 151 | Acetylation | GQPPLTYKRFQTLIS CCCCCCHHHHHHHHH | 41.31 | 20167786 | |
| 151 | Ubiquitination | GQPPLTYKRFQTLIS CCCCCCHHHHHHHHH | 41.31 | - | |
| 159 | Ubiquitination | RFQTLISKMEPLEIP HHHHHHHHCCCCCCC | 40.04 | - | |
| 215 | Phosphorylation | AVWPGGETEALTRLE CCCCCCHHHHHHHHH | 29.81 | 29759185 | |
| 219 | Phosphorylation | GGETEALTRLERHLE CCHHHHHHHHHHHHH | 40.01 | 29759185 | |
| 228 | Ubiquitination | LERHLERKAWVANFE HHHHHHHHHHHHCCC | 36.91 | - | |
| 247 | Phosphorylation | NANSLLASPTGLSPY CHHHHCCCCCCCCHH | 23.98 | - | |
| 280 | Phosphorylation | YKKVKKNSSPPLSLY HHHHHHCCCCCCHHH | 53.77 | - | |
| 285 | Phosphorylation | KNSSPPLSLYGQLLW HCCCCCCHHHHHHHH | 25.89 | - | |
| 329 | Ubiquitination | KNPEALAKWAEGRTG CCHHHHHHHHCCCCC | 48.03 | 21906983 | |
| 432 | Phosphorylation | NGDYIRRYLPVLRGF CCHHHHHHHHHHCCC | 12.90 | 22817900 | |
| 442 | Ubiquitination | VLRGFPAKYIYDPWN HHCCCCHHHCCCCCC | 32.21 | 21906983 | |
| 456 | Ubiquitination | NAPEGIQKVAKCLIG CCCHHHHHHHHHHHC | 42.09 | - | |
| 459 | Ubiquitination | EGIQKVAKCLIGVNY HHHHHHHHHHHCCCC | 32.34 | - | |
| 485 | Ubiquitination | RLNIERMKQIYQQLS HCCHHHHHHHHHHHH | 39.50 | - | |
| 488 | Phosphorylation | IERMKQIYQQLSRYR HHHHHHHHHHHHHHC | 6.42 | 27174698 | |
| 492 | Phosphorylation | KQIYQQLSRYRGLGL HHHHHHHHHHCCCCE | 23.95 | 27174698 | |
| 494 | Phosphorylation | IYQQLSRYRGLGLLA HHHHHHHHCCCCEEE | 12.98 | 27174698 | |
| 565 | Acetylation | GTGLSGGKRPSQEED CCCCCCCCCCCCCHH | 65.74 | 26051181 | |
| 568 | Phosphorylation | LSGGKRPSQEEDTQS CCCCCCCCCCHHHHC | 55.01 | 29255136 | |
| 573 | Phosphorylation | RPSQEEDTQSIGPKV CCCCCHHHHCCCHHH | 27.74 | 26657352 | |
| 575 | Phosphorylation | SQEEDTQSIGPKVQR CCCHHHHCCCHHHHH | 31.44 | 25056879 |
| Modified Location | Modified Residue | Modification | Type of Upstream Proteins | Gene Name of Upstream Proteins | UniProt AC of Upstream Proteins | Sources |
|---|---|---|---|---|---|---|
| 71 | S | Phosphorylation | Kinase | AMPK | Q9Y478 | Uniprot |
| 247 | S | Phosphorylation | Kinase | MAPK | - | Uniprot |
| 280 | S | Phosphorylation | Kinase | AMPK | Q9Y478 | Uniprot |
| - | K | Ubiquitination | E3 ubiquitin ligase | FBXL3 | Q9UKT7 | PMID:24658274 |
| - | K | Ubiquitination | E3 ubiquitin ligase | FBXL21P | Q9UKT6 | PMID:24658274 |
| - | K | Ubiquitination | E3 ubiquitin ligase | DTL | Q9NZJ0 | PMID:26431207 |
* Distance = the distance between SAP position and PTM sites.
| Modified Location | Modification | Variant Position (Distance <= 10) |
Residue Change | SAP | Related Disease | Reference |
|---|---|---|---|---|---|---|
Oops, there are no SNP-PTM records of CRY1_HUMAN !! | ||||||
| Kegg Disease | ||||||
|---|---|---|---|---|---|---|
| There are no disease associations of PTM sites. | ||||||
| OMIM Disease | ||||||
| There are no disease associations of PTM sites. | ||||||
| Kegg Drug | ||||||
| There are no disease associations of PTM sites. | ||||||
| DrugBank | ||||||
| There are no disease associations of PTM sites. | ||||||
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| Phosphorylation | |
| Reference | PubMed |
| "Global survey of phosphotyrosine signaling identifies oncogenickinases in lung cancer."; Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J.,Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L.,Mitchell J., Wetzel R., Macneill J., Ren J.M., Yuan J.,Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X.,Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J.; Cell 131:1190-1203(2007). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-432, AND MASSSPECTROMETRY. | |
