Q49AN0 (CRY2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cryptochrome-2

Gene names

Name:	CRY2
Synonyms:	KIAA0658

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	593 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Blue light-dependent regulator of the circadian feedback loop. Inhibits CLOCK|NPAS2-ARNTL E box-mediated transcription. Acts, in conjunction with CRY2, in maintaining period length and circadian rhythmicity. Has no photolyase activity. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. May inhibit CLOCK|NPAS2-ARNTL transcriptional activity through stabilizing the unphosphorylated form of ARNTL. Ref.7
Cofactor	Binds 1 FAD per subunit By similarity. Binds 1 5,10-methenyltetrahydrofolate non-covalently per subunit By similarity.
Subunit structure	Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARNTL or ARNTL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts directly with PER1 and PER2 C-terminal domains. Interaction with PER2 inhibits its ubiquitination and vice versa. Interacts with NFIL3. Interacts with FBXL3 and FBXL21. Ref.8
Subcellular location	Cytoplasm. Nucleus. Note: Translocated to the nucleus through interaction with other Clock proteins such as PER2 or ARNTL. Ref.6
Tissue specificity	Expressed in all tissues examined including fetal brain, fibroblasts, heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocytes. Highest levels in heart and skeletal muscle. Ref.1 Ref.6
Post-translational modification	Phosphorylation on Ser-266 by MAPK is important for the inhibition of CLOCK-ARNTL-mediated transcriptional activity. Phosphorylation by CSKNE requires interaction with PER1 or PER2. Phosphorylated in a circadian manner at Ser-554 and Ser-558 in the suprachiasmatic nucleus (SCN) and liver. 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 By similarity. 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 CRY2. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY2 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. The SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser-554 and Ser-558 Probable.
Sequence similarities	Belongs to the DNA photolyase class-1 family. Contains 1 photolyase/cryptochrome alpha/beta domain.
Sequence caution	The sequence AAH35161.1 differs from that shown. Reason: Probable cloning artifact. Aberrant splice sites. The sequence BAG57993.1 differs from that shown. Reason: Erroneous termination at position 110. Translated as Trp. The sequence BAG57993.1 differs from that shown. Reason: Erroneous translation. Wrong choice of CDS.

Ontologies

Keywords
Biological process	Biological rhythms Sensory transduction Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Ligand	Chromophore FAD Flavoprotein Nucleotide-binding
Molecular function	Photoreceptor protein Receptor Repressor
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA repair Inferred from electronic annotation. Source: InterPro circadian rhythm Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of phosphoprotein phosphatase activity Inferred from direct assay PubMed 9383998. Source: UniProtKB negative regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 12397359PubMed 14672706PubMed 15147242. Source: BHF-UCL protein-chromophore linkage Inferred from electronic annotation. Source: UniProtKB-KW regulation of sodium-dependent phosphate transport Inferred from direct assay PubMed 9753616. Source: MGI transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytoplasm Inferred from direct assay. Source: HPA extracellular region Inferred from direct assay PubMed 9753616. Source: MGI nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	DNA photolyase activity Inferred from electronic annotation. Source: InterPro blue light photoreceptor activity Non-traceable author statement Ref.1. Source: UniProtKB damaged DNA binding Inferred from direct assay PubMed 12627958. Source: UniProtKB nucleotide binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding transcription factor activity Inferred from direct assay PubMed 15147242. Source: BHF-UCL single-stranded DNA binding Inferred from direct assay PubMed 12627958. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q49AN0-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q49AN0-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-72: MAATVATAAA...SSSVGINRWR → MPAPPGRTHTW

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 593	593	Cryptochrome-2		PRO_0000261148
Regions
	Domain	22 – 151	130	Photolyase/cryptochrome alpha/beta
	Region	230 – 507	278	FAD-binding
	Region	390 – 489	100	Required for inhibition of CLOCK-ARNTL-mediated transcription By similarity
Amino acid modifications
	Modified residue	266	1	Phosphoserine; by MAPK By similarity
	Modified residue	554	1	Phosphoserine; by GSK3-beta By similarity
	Modified residue	558	1	Phosphoserine; by DYRK1A and MAPK By similarity
	Cross-link	126		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
	Cross-link	242		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
	Cross-link	348		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
	Cross-link	475		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
	Cross-link	504		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Natural variations
	Alternative sequence	1 – 72	72	MAATV…INRWR → MPAPPGRTHTW in isoform 2.		VSP_038970
Experimental info
	Sequence conflict	422	1	S → G in AAH35161. Ref.4
Isoform 2:
	Sequence conflict	9	1	H → L in BAG57993. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 28, 2006. Version 2. Checksum: BF380424092BEBFB	FASTA	593	66,947
	10 20 30 40 50 60 MAATVATAAA VAPAPAPGTD SASSVHWFRK GLRLHDNPAL LAAVRGARCV RCVYILDPWF 70 80 90 100 110 120 AASSSVGINR WRFLLQSLED LDTSLRKLNS RLFVVRGQPA DVFPRLFKEW GVTRLTFEYD 130 140 150 160 170 180 SEPFGKERDA AIMKMAKEAG VEVVTENSHT LYDLDRIIEL NGQKPPLTYK RFQAIISRME 190 200 210 220 230 240 LPKKPVGLVT SQQMESCRAE IQENHDETYG VPSLEELGFP TEGLGPAVWQ GGETEALARL 250 260 270 280 290 300 DKHLERKAWV ANYERPRMNA NSLLASPTGL SPYLRFGCLS CRLFYYRLWD LYKKVKRNST 310 320 330 340 350 360 PPLSLFGQLL WREFFYTAAT NNPRFDRMEG NPICIQIPWD RNPEALAKWA EGKTGFPWID 370 380 390 400 410 420 AIMTQLRQEG WIHHLARHAV ACFLTRGDLW VSWESGVRVF DELLLDADFS VNAGSWMWLS 430 440 450 460 470 480 CSAFFQQFFH CYCPVGFGRR TDPSGDYIRR YLPKLKAFPS RYIYEPWNAP ESIQKAAKCI 490 500 510 520 530 540 IGVDYPRPIV NHAETSRLNI ERMKQIYQQL SRYRGLCLLA SVPSCVEDLS HPVAEPSSSQ 550 560 570 580 590 AGSMSSAGPR PLPSGPASPK RKLEAAEEPP GEELSKRARV AELPTPELPS KDA
	Isoform 2 [UniParc]. Checksum: 07E1FCDFAC27731A	FASTA	532	60,593
	10 20 30 40 50 60 MPAPPGRTHT WFLLQSLEDL DTSLRKLNSR LFVVRGQPAD VFPRLFKEWG VTRLTFEYDS 70 80 90 100 110 120 EPFGKERDAA IMKMAKEAGV EVVTENSHTL YDLDRIIELN GQKPPLTYKR FQAIISRMEL 130 140 150 160 170 180 PKKPVGLVTS QQMESCRAEI QENHDETYGV PSLEELGFPT EGLGPAVWQG GETEALARLD 190 200 210 220 230 240 KHLERKAWVA NYERPRMNAN SLLASPTGLS PYLRFGCLSC RLFYYRLWDL YKKVKRNSTP 250 260 270 280 290 300 PLSLFGQLLW REFFYTAATN NPRFDRMEGN PICIQIPWDR NPEALAKWAE GKTGFPWIDA 310 320 330 340 350 360 IMTQLRQEGW IHHLARHAVA CFLTRGDLWV SWESGVRVFD ELLLDADFSV NAGSWMWLSC 370 380 390 400 410 420 SAFFQQFFHC YCPVGFGRRT DPSGDYIRRY LPKLKAFPSR YIYEPWNAPE SIQKAAKCII 430 440 450 460 470 480 GVDYPRPIVN HAETSRLNIE RMKQIYQQLS RYRGLCLLAS VPSCVEDLSH PVAEPSSSQA 490 500 510 520 530 GSMSSAGPRP LPSGPASPKR KLEAAEEPPG EELSKRARVA ELPTPELPSK DA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Putative human blue-light photoreceptors hCRY1 and hCRY2 are flavoproteins." Hsu D.S., Zhao X., Zhao S., Kazantsev A., Wang R.-P., Todo T., Wei Y.-F., Sancar A. Biochemistry 35:13871-13877(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CHARACTERIZATION, TISSUE SPECIFICITY. Tissue: Fetal brain.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Brain.
[3]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Testis.
[5]	"Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro." Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O. DNA Res. 5:169-176(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 5-593 (ISOFORM 1). Tissue: Brain.
[6]	"Characterization of photolyase/blue-light receptor homologs in mouse and human cells." Kobayashi K., Kanno S., Smit B., van der Horst G.T.J., Takao M., Yasui A. Nucleic Acids Res. 26:5086-5092(1998) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[7]	"Light-independent role of CRY1 and CRY2 in the mammalian circadian clock." Griffin E.A. Jr., Staknis D., Weitz C.J. Science 286:768-771(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[8]	"SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins." Busino L., Bassermann F., Maiolica A., Lee C., Nolan P.M., Godinho S.I., Draetta G.F., Pagano M. Science 316:900-904(2007) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY, UBIQUITINATION BY FBXL3, INTERACTION WITH FBXL3.
+	Additional computationally mapped references.

Web resources

Wikipedia

Cryptochrome entry

Cross-references

Sequence databases
EMBL GenBank DDBJ	AK294904 mRNA. Translation: BAG57993.1. Sequence problems. AC068385 Genomic DNA. No translation available. BC035161 mRNA. Translation: AAH35161.1. Sequence problems. BC041814 mRNA. Translation: AAH41814.1. AB014558 mRNA. Translation: BAA31633.1.
IPI	IPI00216898. IPI00895886.
RefSeq	NP_001120929.1. NM_001127457.1. NP_066940.2. NM_021117.3.
UniGene	Hs.532491.
3D structure databases
ProteinModelPortal	Q49AN0.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q49AN0. 3 interactions.
STRING	9606.ENSP00000406751.
Polymorphism databases
DMDM	118572252.
Proteomic databases
PaxDb	Q49AN0.
PRIDE	Q49AN0.
Protocols and materials databases
DNASU	1408.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000417225; ENSP00000397419; ENSG00000121671.
GeneID	1408.
KEGG	hsa:1408.
UCSC	uc009ykw.3. human. uc010rgo.2. human.
Organism-specific databases
CTD	1408.
GeneCards	GC11P045868.
H-InvDB	HIX0201587.
HGNC	HGNC:2385. CRY2.
HPA	HPA037577.
MIM	603732. gene.
neXtProt	NX_Q49AN0.
PharmGKB	PA26905.
HUGE	Search...
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0415.
HOGENOM	HOG000245622.
HOVERGEN	HBG053470.
InParanoid	Q49AN0.
KO	K02295.
OrthoDB	EOG4VT5WZ.
PhylomeDB	Q49AN0.
Enzyme and pathway databases
Reactome	REACT_24941. Circadian Clock.
Gene expression databases
ArrayExpress	Q49AN0.
Bgee	Q49AN0.
CleanEx	HS_CRY2.
Genevestigator	Q49AN0.
GermOnline	ENSG00000121671. Homo sapiens.
Family and domain databases
Gene3D	3.40.50.620. 1 hit.
InterPro	IPR006050. DNA_photolyase_N. IPR005101. Photolyase_FAD-bd/Cryptochr_C. IPR014729. Rossmann-like_a/b/a_fold. [Graphical view]
Pfam	PF00875. DNA_photolyase. 1 hit. PF03441. FAD_binding_7. 1 hit. [Graphical view]
SUPFAM	SSF52425. DNA_photolyase_N. 1 hit. SSF48173. Photolyase_FAD-bd/Cryptochr_C. 1 hit.
PROSITE	PS00394. DNA_PHOTOLYASES_1_1. False negative. PS51645. PHR_CRY_ALPHA_BETA. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	1408.
NextBio	5757.
SOURCE	Search...

Entry information

Entry name

CRY2_HUMAN

Accession

Primary (citable) accession number: Q49AN0
Secondary accession number(s): B4DH32, O75148, Q8IV71

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 28, 2006
Last sequence update:	November 28, 2006
Last modified:	May 1, 2013
This is version 76 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.