CRY2_MOUSE - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: CRY2_MOUSE
• UniProt AC: Q9R194
• Protein Name: Cryptochrome-2
• Gene Name: Cry2
• Organism: Mus musculus (Mouse).
• Sequence Length: 592
• Subcellular Localization: Cytoplasm. Nucleus. Translocated to the nucleus through interaction with other Clock proteins such as PER2 or ARNTL.
• 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. 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-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1 and NAMPT..
• Protein Sequence: MAAAAVVAATVPAQSMGADGASSVHWFRKGLRLHDNPALLAAVRGARCVRCVYILDPWFAASSSVGINRWRFLLQSLEDLDTSLRKLNSRLFVVRGQPADVFPRLFKEWGVTRLTFEYDSEPFGKERDAAIMKMAKEAGVEVVTENSHTLYDLDRIIELNGQKPPLTYKRFQALISRMELPKKPAVAVSSQQMESCRAEIQENHDDTYGVPSLEELGFPTEGLGPAVWQGGETEALARLDKHLERKAWVANYERPRMNANSLLASPTGLSPYLRFGCLSCRLFYYRLWDLYKKVKRNSTPPLSLFGQLLWREFFYTAATNNPRFDRMEGNPICIQIPWDRNPEALAKWAEGKTGFPWIDAIMTQLRQEGWIHHLARHAVACFLTRGDLWVSWESGVRVFDELLLDADFSVNAGSWMWLSCSAFFQQFFHCYCPVGFGRRTDPSGDYIRRYLPKLKGFPSRYIYEPWNAPESVQKAAKCIIGVDYPRPIVNHAETSRLNIERMKQIYQQLSRYRGLCLLASVPSCVEDLSHPVAEPGSSQAGSISNTGPRALSSGPASPKRKLEAAEEPPGEELTKRARVTEMPTQEPASKDS

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
89	Phosphorylation	TSLRKLNSRLFVVRG HHHHHHHCCEEEEEC	40.57	-
125	Ubiquitination	YDSEPFGKERDAAIM ECCCCCCCHHHHHHH	50.37	23452856
241	Ubiquitination	EALARLDKHLERKAW HHHHHHHHHHHHHHH	55.47	23452856
265	Phosphorylation	NANSLLASPTGLSPY CHHHHCCCCCCCCHH	23.98	15298678
267	Phosphorylation	NSLLASPTGLSPYLR HHHCCCCCCCCHHHH	48.54	22817900
298	Phosphorylation	YKKVKRNSTPPLSLF HHHHHCCCCCCCHHH	46.45	-
347	Ubiquitination	RNPEALAKWAEGKTG CCHHHHHHHHCCCCC	48.03	23452856
440	Phosphorylation	PVGFGRRTDPSGDYI CCCCCCCCCCCCHHH	51.40	27180971
450	Phosphorylation	SGDYIRRYLPKLKGF CCHHHHHHHHHCCCC	19.94	24719451
459	Phosphorylation	PKLKGFPSRYIYEPW HHCCCCCCCCCCCCC	35.14	24719451
471	Phosphorylation	EPWNAPESVQKAAKC CCCCCCHHHHHHHHH	28.87	24719451
474	Ubiquitination	NAPESVQKAAKCIIG CCCHHHHHHHHHEEE	48.43	27667366
503	Ubiquitination	RLNIERMKQIYQQLS CCCHHHHHHHHHHHH	39.50	27667366
552	Phosphorylation	NTGPRALSSGPASPK CCCCCHHCCCCCCHH	32.06	28285833
553	Phosphorylation	TGPRALSSGPASPKR CCCCHHCCCCCCHHH	50.04	15980066
557	Phosphorylation	ALSSGPASPKRKLEA HHCCCCCCHHHHHHH	33.80	25521595
580	Phosphorylation	LTKRARVTEMPTQEP HHHHHCCCCCCCCCC	22.48	24719451
584	Phosphorylation	ARVTEMPTQEPASKD HCCCCCCCCCCCCCC	44.23	24719451

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
265	S	Phosphorylation	Kinase	MAPK1	P63085	GPS
265	S	Phosphorylation	Kinase	ERK2	Q8UWG6	PSP
265	S	Phosphorylation	Kinase	MAPK-FAMILY	-	GPS
265	S	Phosphorylation	Kinase	MAPK	-	Uniprot
553	S	Phosphorylation	Kinase	GSK3B	Q9WV60	PSP
557	S	Phosphorylation	Kinase	DYRK1A	Q61214	Uniprot
557	S	Phosphorylation	Kinase	GSK3B	Q9WV60	PSP
557	S	Phosphorylation	Kinase	MAPK-FAMILY	-	GPS
557	S	Phosphorylation	Kinase	MAPK	-	Uniprot

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
265	S	Phosphorylation	Phosphorylation on Ser-265 by MAPK is important for the inhibition of CLOCK-ARNTL-mediated transcriptional activity.	15298678
553	S	Phosphorylation	Phosphorylated in a circadian manner at Ser-553 and Ser-557 in the suprachiasmatic nucleus (SCN) and liver.	20123978
553	S	Phosphorylation	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.	20123978
553	S	Phosphorylation	The SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser-553 and Ser-557.	20123978
557	S	Phosphorylation	Phosphorylated in a circadian manner at Ser-553 and Ser-557 in the suprachiasmatic nucleus (SCN) and liver.	15298678
557	S	Phosphorylation	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.	15298678
557	S	Phosphorylation	The SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser-553 and Ser-557.	15298678

Disease-associated PTM Sites based on SAP

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

Oops, there are no SNP-PTM records of CRY2_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
CRY1_MOUSE	Cry1	physical	14701732
IMA1_MOUSE	Kpna2	physical	15689618
IMA3_MOUSE	Kpna4	physical	15689618
IMA7_MOUSE	Kpna6	physical	15689618
PER3_MOUSE	Per3	physical	15689618
FBXL3_HUMAN	FBXL3	physical	23503662
SKP1_HUMAN	SKP1	physical	23503662
PER1_HUMAN	PER1	physical	23503662
BMAL1_HUMAN	ARNTL	physical	23503662
PER2_MOUSE	Per2	physical	25127877
UBP2_MOUSE	Usp2	physical	23213472

Drug and Disease Associations

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

Related Literatures of Post-Translational Modification

Phosphorylation

"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-265 AND SER-557, ANDMUTAGENESIS OF SER-265 AND SER-557.
PubMed: 15298678