CRY1_MOUSE - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: CRY1_MOUSE
• UniProt AC: P97784
• Protein Name: Cryptochrome-1
• Gene Name: Cry1
• Organism: Mus musculus (Mouse).
• Sequence Length: 606
• Subcellular Localization: Cytoplasm. Nucleus . Transloctaed 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 atCLOCK-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, ATF4, MTA1, KLF10 and NAMPT. 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: MGVNAVHWFRKGLRLHDNPALKECIQGADTIRCVYILDPWFAGSSNVGINRWRFLLQCLEDLDANLRKLNSRLFVIRGQPADVFPRLFKEWNITKLSIEYDSEPFGKERDAAIKKLATEAGVEVIVRISHTLYDLDKIIELNGGQPPLTYKRFQTLVSKMEPLEMPADTITSDVIGKCMTPLSDDHDEKYGVPSLEELGFDTDGLSSAVWPGGETEALTRLERHLERKAWVANFERPRMNANSLLASPTGLSPYLRFGCLSCRLFYFKLTDLYKKVKKNSSPPLSLYGQLLWREFFYTAATNNPRFDKMEGNPICVQIPWDKNPEALAKWAEGRTGFPWIDAIMTQLRQEGWIHHLARHAVACFLTRGDLWISWEEGMKVFEELLLDADWSINAGSWMWLSCSSFFQQFFHCYCPVGFGRRTDPNGDYIRRYLPVLRGFPAKYIYDPWNAPEGIQKVAKCLIGVNYPKPMVNHAEASRLNIERMKQIYQQLSRYRGLGLLASVPSNSNGNGGLMGYAPGENVPSCSSSGNGGLMGYAPGENVPSCSGGNCSQGSGILHYAHGDSQQTHSLKQGRSSAGTGLSSGKRPSQEEDAQSVGPKVQRQSSN

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
11	Ubiquitination	NAVHWFRKGLRLHDN CHHHHHHHCCCCCCC	53.47	23452855
71	Phosphorylation	ANLRKLNSRLFVIRG HHHHHHHCCEEEECC	40.57	22817900
107	Ubiquitination	YDSEPFGKERDAAIK ECCCCCCCHHHHHHH	50.37	23452856
158	Phosphorylation	KRFQTLVSKMEPLEM HHHHHHHHHCCCCCC	29.42	22817900
159	Ubiquitination	RFQTLVSKMEPLEMP HHHHHHHHCCCCCCC	39.54	23452856
247	Phosphorylation	NANSLLASPTGLSPY CHHHHCCCCCCCCHH	23.98	15298678
249	Phosphorylation	NSLLASPTGLSPYLR HHHCCCCCCCCHHHH	48.54	22817900
280	Phosphorylation	YKKVKKNSSPPLSLY HHHHHHCCCCCCHHH	53.77	22817900
281	Phosphorylation	KKVKKNSSPPLSLYG HHHHHCCCCCCHHHH	39.67	22817900
326	Ubiquitination	PWDKNPEALAKWAEG CCCCCHHHHHHHHCC	17.68	27667366
329	Ubiquitination	KNPEALAKWAEGRTG CCHHHHHHHHCCCCC	48.03	23452856
447	Ubiquitination	PAKYIYDPWNAPEGI CHHHCCCCCCCCHHH	14.84	27667366
485	Ubiquitination	RLNIERMKQIYQQLS HCCHHHHHHHHHHHH	39.50	27667366
575	Phosphorylation	HSLKQGRSSAGTGLS CCCCCCCCCCCCCCC	31.22	25619855
576	Phosphorylation	SLKQGRSSAGTGLSS CCCCCCCCCCCCCCC	29.38	25619855
579	Phosphorylation	QGRSSAGTGLSSGKR CCCCCCCCCCCCCCC	34.37	25619855
582	Phosphorylation	SSAGTGLSSGKRPSQ CCCCCCCCCCCCCCH	38.09	25619855
583	Phosphorylation	SAGTGLSSGKRPSQE CCCCCCCCCCCCCHH	54.07	25619855
585	Acetylation	GTGLSSGKRPSQEED CCCCCCCCCCCHHHH	64.18	19847605
585	Ubiquitination	GTGLSSGKRPSQEED CCCCCCCCCCCHHHH	64.18	-
588	Phosphorylation	LSSGKRPSQEEDAQS CCCCCCCCHHHHHHH	55.01	26824392
595	Phosphorylation	SQEEDAQSVGPKVQR CHHHHHHHHCHHHHH	30.66	25619855
604	Phosphorylation	GPKVQRQSSN----- CHHHHHCCCC-----	33.75	19833968

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
71	S	Phosphorylation	Kinase	PRKAA1	Q13131	GPS
71	S	Phosphorylation	Kinase	AMPK-FAMILY	-	GPS
71	S	Phosphorylation	Kinase	AMPK	-	Uniprot
247	S	Phosphorylation	Kinase	MAPK1	P63085	GPS
247	S	Phosphorylation	Kinase	ERK2	Q8UWG6	PSP
247	S	Phosphorylation	Kinase	MAPK-FAMILY	-	GPS
247	S	Phosphorylation	Kinase	MAPK	-	Uniprot
280	S	Phosphorylation	Kinase	AMPK-FAMILY	-	GPS
280	S	Phosphorylation	Kinase	AMPK	-	Uniprot
-	K	Ubiquitination	E3 ubiquitin ligase	Dtl	Q3TLR7	PMID:26431207

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
11	K	ubiquitylation	Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by the SCF(FBXL21) complex but not by the SCF(FBXL3) complex.	23452855
71	S	Phosphorylation	Phosphorylation at Ser-71 and Ser-280 by AMPK decreases protein stability.	19833968
107	K	ubiquitylation	Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by the SCF(FBXL21) complex but not by the SCF(FBXL3) complex.	23452856
247	S	Phosphorylation	Phosphorylation on Ser-247 by MAPK is important for the inhibition of CLOCK-ARNTL/BMAL1-mediated transcriptional activity.	15298678
280	S	Phosphorylation	Phosphorylation at Ser-71 and Ser-280 by AMPK decreases protein stability.	19833968
588	S	Phosphorylation	Phosphorylation at Ser-588 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.	24158435

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Oops, there are no SNP-PTM records of CRY1_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
CLOCK_MOUSE	Clock	physical	14701732
PER1_MOUSE	Per1	physical	14701732
PER2_MOUSE	Per2	physical	14701732
PER3_MOUSE	Per3	physical	14701732
CRY2_MOUSE	Cry2	physical	14701732
KC1E_HUMAN	CSNK1E	physical	11875063
TIM_MOUSE	Timeless	physical	20211142
BMAL1_MOUSE	Arntl	physical	15226430
SIN3B_MOUSE	Sin3b	physical	15226430
HDAC1_MOUSE	Hdac1	physical	15226430
HDAC2_MOUSE	Hdac2	physical	15226430
CRY1_HUMAN	CRY1	physical	20360068
PER1_HUMAN	PER1	physical	20360068
FBXL3_HUMAN	FBXL3	physical	20360068
BMAL1_MOUSE	Arntl	physical	21966515
UBP2_MOUSE	Usp2	physical	21966515
TIM_MOUSE	Timeless	physical	12875843
CLOCK_MOUSE	Clock	physical	25127877
BMAL1_MOUSE	Arntl	physical	25127877
PER1_MOUSE	Per1	physical	25127877
PER2_MOUSE	Per2	physical	25127877
UBP2_MOUSE	Usp2	physical	23213472
ANK3_HUMAN	ANK3	physical	26496610
BMAL1_HUMAN	ARNTL	physical	26496610
KC1D_HUMAN	CSNK1D	physical	26496610
KC1E_HUMAN	CSNK1E	physical	26496610
NFIB_HUMAN	NFIB	physical	26496610
NVL_HUMAN	NVL	physical	26496610
PER1_HUMAN	PER1	physical	26496610
TAGL2_HUMAN	TAGLN2	physical	26496610
CLOCK_HUMAN	CLOCK	physical	26496610
CNDG2_HUMAN	NCAPG2	physical	26496610
ELMO3_HUMAN	ELMO3	physical	26496610
RETR3_HUMAN	FAM134C	physical	26496610

Drug and Disease Associations

• Kegg Drug
• DrugBank
• There are no disease associations of PTM sites.

Related Literatures of Post-Translational Modification

Phosphorylation

"AMPK regulates the circadian clock by cryptochrome phosphorylationand degradation.";
Lamia K.A., Sachdeva U.M., DiTacchio L., Williams E.C., Alvarez J.G.,Egan D.F., Vasquez D.S., Juguilon H., Panda S., Shaw R.J.,Thompson C.B., Evans R.M.;
Science 326:437-440(2009).
Cited for: PHOSPHORYLATION AT SER-71 AND SER-280, AND MUTAGENESIS OF SER-71 ANDSER-280.
PubMed: 19833968

"Serine phosphorylation of mCRY1 and mCRY2 by mitogen-activatedprotein kinase.";
Sanada K., Harada Y., Sakai M., Todo T., Fukada Y.;
Genes Cells 9:697-708(2004).
Cited for: INTERACTION WITH MAPK, PHOSPHORYLATION AT SER-247, AND MUTAGENESIS OFSER-247.
PubMed: 15298678