CRY2_HUMAN - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: CRY2_HUMAN
• UniProt AC: Q49AN0
• Protein Name: Cryptochrome-2
• Gene Name: CRY2
• Organism: Homo sapiens (Human).
• Sequence Length: 593
• 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. Represses the CLOCK-ARNTL/BMAL1 induced transcription of NAMPT (By similarity)..
• Protein Sequence: MAATVATAAAVAPAPAPGTDSASSVHWFRKGLRLHDNPALLAAVRGARCVRCVYILDPWFAASSSVGINRWRFLLQSLEDLDTSLRKLNSRLFVVRGQPADVFPRLFKEWGVTRLTFEYDSEPFGKERDAAIMKMAKEAGVEVVTENSHTLYDLDRIIELNGQKPPLTYKRFQAIISRMELPKKPVGLVTSQQMESCRAEIQENHDETYGVPSLEELGFPTEGLGPAVWQGGETEALARLDKHLERKAWVANYERPRMNANSLLASPTGLSPYLRFGCLSCRLFYYRLWDLYKKVKRNSTPPLSLFGQLLWREFFYTAATNNPRFDRMEGNPICIQIPWDRNPEALAKWAEGKTGFPWIDAIMTQLRQEGWIHHLARHAVACFLTRGDLWVSWESGVRVFDELLLDADFSVNAGSWMWLSCSAFFQQFFHCYCPVGFGRRTDPSGDYIRRYLPKLKAFPSRYIYEPWNAPESIQKAAKCIIGVDYPRPIVNHAETSRLNIERMKQIYQQLSRYRGLCLLASVPSCVEDLSHPVAEPSSSQAGSMSSAGPRPLPSGPASPKRKLEAAEEPPGEELSKRARVAELPTPELPSKDA

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
90	Phosphorylation	TSLRKLNSRLFVVRG HHHHHHHCCEEEECC	40.57	-
116	Phosphorylation	EWGVTRLTFEYDSEP HHCCEEEEEEECCCC	15.89	29083192
119	Phosphorylation	VTRLTFEYDSEPFGK CEEEEEEECCCCCCC	22.15	29083192
121	Phosphorylation	RLTFEYDSEPFGKER EEEEEECCCCCCCHH	46.39	29083192
126	Ubiquitination	YDSEPFGKERDAAIM ECCCCCCCHHHHHHH	50.37	-
147	Ubiquitination	GVEVVTENSHTLYDL CCEEECCCCCEEEEH	29.71	-
147	Ubiquitination	GVEVVTENSHTLYDL CCEEECCCCCEEEEH	29.71	-
170	Ubiquitination	QKPPLTYKRFQAIIS CCCCCCHHHHHHHHH	41.31	-
181	Ubiquitination	AIISRMELPKKPVGL HHHHHCCCCCCCCCE	5.72	21890473
184	Ubiquitination	SRMELPKKPVGLVTS HHCCCCCCCCCEECH	42.89	-
190	Phosphorylation	KKPVGLVTSQQMESC CCCCCEECHHHHHHH	26.34	-
191	Ubiquitination	KPVGLVTSQQMESCR CCCCEECHHHHHHHH	15.78	-
191	Ubiquitination	KPVGLVTSQQMESCR CCCCEECHHHHHHHH	15.78	-
191	Phosphorylation	KPVGLVTSQQMESCR CCCCEECHHHHHHHH	15.78	-
196	Phosphorylation	VTSQQMESCRAEIQE ECHHHHHHHHHHHHH	11.99	-
205	Ubiquitination	RAEIQENHDETYGVP HHHHHHCCCCCCCCC	33.27	-
205	Ubiquitination	RAEIQENHDETYGVP HHHHHHCCCCCCCCC	33.27	-
242	Ubiquitination	EALARLDKHLERKAW HHHHHHHHHHHHHHH	55.47	21890473
247	Ubiquitination	LDKHLERKAWVANYE HHHHHHHHHHHHCCC	36.91	-
263	Ubiquitination	PRMNANSLLASPTGL CCCCHHHHCCCCCCC	4.67	21890473
263	Ubiquitination	PRMNANSLLASPTGL CCCCHHHHCCCCCCC	4.67	-
266	Phosphorylation	NANSLLASPTGLSPY CHHHHCCCCCCCCHH	23.98	-
268	Ubiquitination	NSLLASPTGLSPYLR HHHCCCCCCCCHHHH	48.54	-
268	Ubiquitination	NSLLASPTGLSPYLR HHHCCCCCCCCHHHH	48.54	-
299	Phosphorylation	YKKVKRNSTPPLSLF HHHHHCCCCCCCHHH	46.45	-
300	Phosphorylation	KKVKRNSTPPLSLFG HHHHCCCCCCCHHHH	32.26	-
321	Phosphorylation	FFYTAATNNPRFDRM HHHHHHHCCCCCCCC	52.35	-
451	Phosphorylation	SGDYIRRYLPKLKAF CCHHHHHHHHHCCCC	19.94	-
462	Phosphorylation	LKAFPSRYIYEPWNA CCCCCCCCCCCCCCC	16.52	-
464	Phosphorylation	AFPSRYIYEPWNAPE CCCCCCCCCCCCCCH	13.65	-
475	Ubiquitination	NAPESIQKAAKCIIG CCCHHHHHHHHHHHC	48.95	-
477	Ubiquitination	PESIQKAAKCIIGVD CHHHHHHHHHHHCCC	17.81	-
478	Ubiquitination	ESIQKAAKCIIGVDY HHHHHHHHHHHCCCC	30.72	-
496	Ubiquitination	IVNHAETSRLNIERM CCCHHHHHCCCHHHH	26.69	-
496	Ubiquitination	IVNHAETSRLNIERM CCCHHHHHCCCHHHH	26.69	-
499	Ubiquitination	HAETSRLNIERMKQI HHHHHCCCHHHHHHH	32.72	-
499	Ubiquitination	HAETSRLNIERMKQI HHHHHCCCHHHHHHH	32.72	-
504	Ubiquitination	RLNIERMKQIYQQLS CCCHHHHHHHHHHHH	39.50	-
507	Phosphorylation	IERMKQIYQQLSRYR HHHHHHHHHHHHHHH	6.42	27174698
511	Phosphorylation	KQIYQQLSRYRGLCL HHHHHHHHHHHCHHH	23.95	27174698
513	Phosphorylation	IYQQLSRYRGLCLLA HHHHHHHHHCHHHHH	12.98	27174698
525	Ubiquitination	LLASVPSCVEDLSHP HHHHCHHHHHHCCCC	2.96	-
525	Ubiquitination	LLASVPSCVEDLSHP HHHHCHHHHHHCCCC	2.96	-
537	Phosphorylation	SHPVAEPSSSQAGSM CCCCCCCCCCCCCCC	33.84	26074081
538	Phosphorylation	HPVAEPSSSQAGSMS CCCCCCCCCCCCCCC	36.87	26074081
539	Phosphorylation	PVAEPSSSQAGSMSS CCCCCCCCCCCCCCC	28.52	26074081
543	Phosphorylation	PSSSQAGSMSSAGPR CCCCCCCCCCCCCCC	20.64	26074081
545	Phosphorylation	SSQAGSMSSAGPRPL CCCCCCCCCCCCCCC	20.80	26074081
546	Phosphorylation	SQAGSMSSAGPRPLP CCCCCCCCCCCCCCC	28.71	26074081
554	Phosphorylation	AGPRPLPSGPASPKR CCCCCCCCCCCCHHH	66.16	26074081
558	Phosphorylation	PLPSGPASPKRKLEA CCCCCCCCHHHHHHH	33.80	25849741
575	Phosphorylation	EPPGEELSKRARVAE CCCCHHHHHHCHHHC	24.31	-
579	Phosphorylation	EELSKRARVAELPTP HHHHHHCHHHCCCCC	32.01	27251275
585	Phosphorylation	ARVAELPTPELPSKD CHHHCCCCCCCCCCC	41.86	30624053
590	Phosphorylation	LPTPELPSKDA---- CCCCCCCCCCC----	56.65	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
266	S	Phosphorylation	Kinase	MAPK	-	Uniprot
554	S	Phosphorylation	Kinase	GSK3-BETA	P49841	Uniprot
558	S	Phosphorylation	Kinase	DYRK1A	Q13627	Uniprot
558	S	Phosphorylation	Kinase	MAPK	-	Uniprot
-	K	Ubiquitination	E3 ubiquitin ligase	FBXL3	Q9UKT7	PMID:17463251
-	K	Ubiquitination	E3 ubiquitin ligase	FBXL21P	Q9UKT6	PMID:24658274
-	K	Ubiquitination	E3 ubiquitin ligase	FBXW7	Q969H0	PMID:25855785

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
266	S	Phosphorylation	Phosphorylation on Ser-266 by MAPK is important for the inhibition of CLOCK-ARNTL-mediated transcriptional activity.	-
554	S	Phosphorylation	Phosphorylated in a circadian manner at Ser-554 and Ser-558 in the suprachiasmatic nucleus (SCN) and liver.	-
554	S	Phosphorylation	Phosphorylation at Ser-558 by DYRK1A promotes subsequent phosphorylation at Ser-554 by GSK3-beta: the two-step phosphorylation at the neighboring Ser residues leads to its proteasomal degradation.	-
554	S	Phosphorylation	The SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser-554 and Ser-558.	17463251
558	S	Phosphorylation	Phosphorylated in a circadian manner at Ser-554 and Ser-558 in the suprachiasmatic nucleus (SCN) and liver.	-
558	S	Phosphorylation	Phosphorylation at Ser-558 by DYRK1A promotes subsequent phosphorylation at Ser-554 by GSK3-beta: the two-step phosphorylation at the neighboring Ser residues leads to its proteasomal degradation.	-
558	S	Phosphorylation	The SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser-554 and Ser-558.	17463251

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_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
CRY2_HUMAN	CRY2	physical	17073458
TTC1_HUMAN	TTC1	physical	9383998
PPP5_HUMAN	PPP5C	physical	9383998
FBXL3_HUMAN	FBXL3	physical	17463251
FBW1A_HUMAN	BTRC	physical	17463251
SKP1_HUMAN	SKP1	physical	17463251
CUL1_HUMAN	CUL1	physical	17463251
CTBP1_HUMAN	CTBP1	physical	25416956
PDE9A_HUMAN	PDE9A	physical	25416956
MTUS2_HUMAN	MTUS2	physical	25416956
BRCA1_HUMAN	BRCA1	physical	25184681
DEC1_HUMAN	DEC1	physical	23555304
BHE41_HUMAN	BHLHE41	physical	23555304
PER1_HUMAN	PER1	physical	23555304
PER2_HUMAN	PER2	physical	23555304
2A5D_HUMAN	PPP2R5D	physical	23555304
2AAB_HUMAN	PPP2R1B	physical	23555304
2A5E_HUMAN	PPP2R5E	physical	23555304
EZH2_HUMAN	EZH2	physical	23555304
NPAS2_HUMAN	NPAS2	physical	23555304
FBXW7_HUMAN	FBXW7	physical	25855785
CRY1_ARATH	CRY1	physical	15751956
FBXL3_HUMAN	FBXL3	physical	25756610
PRKDC_HUMAN	PRKDC	physical	25756610
PER1_HUMAN	PER1	physical	25756610
HUWE1_HUMAN	HUWE1	physical	25756610
TCPB_HUMAN	CCT2	physical	25756610
HAT1_HUMAN	HAT1	physical	25756610
EF2_HUMAN	EEF2	physical	25756610
DDX3X_HUMAN	DDX3X	physical	25756610
IF4A1_HUMAN	EIF4A1	physical	25756610
UBP7_HUMAN	USP7	physical	25756610
LAP2A_HUMAN	TMPO	physical	25756610
LAP2B_HUMAN	TMPO	physical	25756610
HNRPK_HUMAN	HNRNPK	physical	25756610
RPN1_HUMAN	RPN1	physical	25756610
FLNA_HUMAN	FLNA	physical	25756610
1433E_HUMAN	YWHAE	physical	25756610
ACLY_HUMAN	ACLY	physical	25756610
SYEP_HUMAN	EPRS	physical	25756610
SYIC_HUMAN	IARS	physical	25756610
EF1A1_HUMAN	EEF1A1	physical	25756610
LPPRC_HUMAN	LRPPRC	physical	25756610
RS3_HUMAN	RPS3	physical	25756610
SC16A_HUMAN	SEC16A	physical	25756610
PSMD3_HUMAN	PSMD3	physical	25756610
FUBP2_HUMAN	KHSRP	physical	25756610
DDX3Y_HUMAN	DDX3Y	physical	25756610
TERA_HUMAN	VCP	physical	25756610
RUVB2_HUMAN	RUVBL2	physical	25756610
DCTP1_HUMAN	DCTPP1	physical	25756610
IF4A2_HUMAN	EIF4A2	physical	25756610
BAG2_HUMAN	BAG2	physical	25756610
DDB1_HUMAN	DDB1	physical	25756610
2ABA_HUMAN	PPP2R2A	physical	25756610
KHDR1_HUMAN	KHDRBS1	physical	25756610
EFTU_HUMAN	TUFM	physical	25756610
NUCL_HUMAN	NCL	physical	25756610
EF1A2_HUMAN	EEF1A2	physical	25756610
PUR6_HUMAN	PAICS	physical	25756610
PRS7_HUMAN	PSMC2	physical	25756610
PRS8_HUMAN	PSMC5	physical	25756610
RS2_HUMAN	RPS2	physical	25756610
MCM7_HUMAN	MCM7	physical	25756610
FAS_HUMAN	FASN	physical	25756610
DHX15_HUMAN	DHX15	physical	25756610
MATR3_HUMAN	MATR3	physical	25756610
NONO_HUMAN	NONO	physical	25756610
UBR5_HUMAN	UBR5	physical	25756610
TCPE_HUMAN	CCT5	physical	25756610
HSP7C_HUMAN	HSPA8	physical	25756610
APC7_HUMAN	ANAPC7	physical	25756610
DDX17_HUMAN	DDX17	physical	25756610
SDHA_HUMAN	SDHA	physical	25756610
TCPD_HUMAN	CCT4	physical	25756610
CH60_HUMAN	HSPD1	physical	25756610
PSD11_HUMAN	PSMD11	physical	25756610
DNJC7_HUMAN	DNAJC7	physical	25756610
SYDC_HUMAN	DARS	physical	25756610
DICER_HUMAN	DICER1	physical	25756610
XPO1_HUMAN	XPO1	physical	25756610
HS90B_HUMAN	HSP90AB1	physical	25756610
AT1A1_HUMAN	ATP1A1	physical	25756610
DSRAD_HUMAN	ADAR	physical	25756610
GARS_HUMAN	GARS	physical	25756610
C1TC_HUMAN	MTHFD1	physical	25756610
PRS6B_HUMAN	PSMC4	physical	25756610
U5S1_HUMAN	EFTUD2	physical	25756610
PSMD1_HUMAN	PSMD1	physical	25756610
NXN_HUMAN	NXN	physical	25756610
U520_HUMAN	SNRNP200	physical	25756610
PSMD2_HUMAN	PSMD2	physical	25756610
COPA_HUMAN	COPA	physical	25756610
RS14_HUMAN	RPS14	physical	25756610
TCPQ_HUMAN	CCT8	physical	25756610
MYCB2_HUMAN	MYCBP2	physical	25756610
MAP4_HUMAN	MAP4	physical	25756610
SMC2_HUMAN	SMC2	physical	25756610
RS17_HUMAN	RPS17	physical	25756610
IMA5_HUMAN	KPNA1	physical	25756610
SERA_HUMAN	PHGDH	physical	25756610
HS90A_HUMAN	HSP90AA1	physical	25756610
USP9X_HUMAN	USP9X	physical	25756610
PP2AB_HUMAN	PPP2CB	physical	25756610
1433T_HUMAN	YWHAQ	physical	25756610
2ABD_HUMAN	PPP2R2D	physical	25756610
XPO2_HUMAN	CSE1L	physical	25756610
RL10_HUMAN	RPL10	physical	25756610
HNRPM_HUMAN	HNRNPM	physical	25756610
RAN_HUMAN	RAN	physical	25756610
SMC4_HUMAN	SMC4	physical	25756610
DYHC1_HUMAN	DYNC1H1	physical	25756610
AKAP8_HUMAN	AKAP8	physical	25756610
PCBP1_HUMAN	PCBP1	physical	25756610
PRS6A_HUMAN	PSMC3	physical	25756610
XRCC6_HUMAN	XRCC6	physical	25756610
HNRDL_HUMAN	HNRNPDL	physical	25756610
AT1A3_HUMAN	ATP1A3	physical	25756610
XRN2_HUMAN	XRN2	physical	25756610
GCN1_HUMAN	GCN1L1	physical	25756610
RS6_HUMAN	RPS6	physical	25756610
SYMC_HUMAN	MARS	physical	25756610
DDX20_HUMAN	DDX20	physical	25756610
UBP11_HUMAN	USP11	physical	25756610
ANM1_HUMAN	PRMT1	physical	25756610
CKAP4_HUMAN	CKAP4	physical	25756610
CRKL_HUMAN	CRKL	physical	25756610
MCM5_HUMAN	MCM5	physical	25756610
MCM4_HUMAN	MCM4	physical	25756610
RBP2_HUMAN	RANBP2	physical	25756610
SPEE_HUMAN	SRM	physical	25756610
GEMI5_HUMAN	GEMIN5	physical	25756610
RN219_HUMAN	RNF219	physical	25756610
CAND1_HUMAN	CAND1	physical	25756610
TCPZ_HUMAN	CCT6A	physical	25756610
CN37_HUMAN	CNP	physical	25756610

Drug and Disease Associations

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