Cryptochrome-2 (CRY2) is a flavoprotein member of the cryptochrome/photolyase family that functions as a light-independent transcriptional repressor in the mammalian circadian clock. CRY2 heterodimerizes with PER proteins (PER1, PER2, PER3) and translocates to the nucleus where the PER-CRY complex inhibits CLOCK:BMAL1-driven transcription, forming the negative limb of the transcription-translation feedback loop (TTFL). CRY2 retains a photolyase homology region with an FAD-binding pocket that serves as a regulatory hub for ubiquitin ligase recognition (FBXL3, FBXL21) and small-molecule stabilizers rather than for photoreception. CRY2 lacks DNA photolyase activity but can bind DNA weakly. CRY2 also inhibits protein phosphatase 5 (PP5) activity, interacts with nuclear receptors (glucocorticoid receptor, HNF4A) in a ligand-dependent manner, and contributes to glucose and glucocorticoid homeostasis. CRY2 stability is regulated by phosphorylation-dependent ubiquitination via SCF(FBXL3) and SCF(FBXL21) complexes, and by PER2-mediated protection from degradation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005634
nucleus
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: CRY2 localizes to the nucleus where it functions as a transcriptional repressor. UniProt curated location confirms nuclear localization (PMID:9801304, PMID:22798407). IBA annotation is phylogenetically well-supported across cryptochromes.
Reason: Nuclear localization is well-established for CRY2 and is essential for its transcriptional repressor function in the TTFL.
Supporting Evidence:
Q49AN0
Nucleus {ECO:0000269|PubMed:22798407, ECO:0000269|PubMed:9801304}
|
|
GO:0005737
cytoplasm
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: CRY2 localizes to the cytoplasm before nuclear translocation as part of the PER-CRY complex. UniProt curated location confirms cytoplasmic localization (PMID:9801304).
Reason: Cytoplasmic localization is well-established; CRY2 accumulates in the cytoplasm and translocates to the nucleus through interaction with PER2 or BMAL1.
Supporting Evidence:
Q49AN0
Cytoplasm {ECO:0000269|PubMed:9801304}
|
|
GO:0045892
negative regulation of DNA-templated transcription
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: CRY2 is a core transcriptional repressor in the mammalian circadian clock. It suppresses CLOCK:BMAL1-driven transcription of Per, Cry, Dec1, Dec2, and other E-box-containing genes (PMID:12397359, PMID:14672706, PMID:15147242).
Reason: Transcriptional repression is the primary molecular function of CRY2. Multiple independent studies demonstrate CRY2 suppresses CLOCK:BMAL1-induced transcription.
Supporting Evidence:
PMID:12397359
Cry proteins to inhibit Per transcription
PMID:14672706
PERs and CRYs suppressed the induced expression
|
|
GO:0003677
DNA binding
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Purified hCRY2 binds dsDNA weakly and ssDNA with higher affinity (PMID:12627958). However, CRY2 represses transcription primarily through protein-protein interactions with CLOCK:BMAL1 rather than direct DNA binding. DNA binding is a vestigial property from the photolyase ancestor.
Reason: DNA binding is experimentally demonstrated but is not the primary mechanism by which CRY2 functions in transcriptional repression. It is a retained ancestral property from the photolyase family.
Supporting Evidence:
PMID:12627958
binds to double-stranded DNA weakly and to single-stranded DNA with higher affinity
|
|
GO:0032922
circadian regulation of gene expression
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: CRY2 is a core component of the circadian TTFL that regulates rhythmic gene expression through repression of CLOCK:BMAL1 transcriptional activity (PMID:10531061, PMID:20840750).
Reason: Circadian regulation of gene expression is the primary biological process in which CRY2 functions. This is well-supported by multiple lines of evidence.
Supporting Evidence:
PMID:20840750
negatively regulate the transcription of Per and Cry core clock genes
Q49AN0
Transcriptional repressor which forms a core component of the circadian clock
|
|
GO:0043153
entrainment of circadian clock by photoperiod
|
IBA
GO_REF:0000033 |
REMOVE |
Summary: Mammalian CRY proteins function as light-independent transcriptional repressors, not as photoreceptors for entrainment. Unlike Drosophila and plant cryptochromes, mammalian CRYs do not serve as circadian photoreceptors (PMID:10531061). The IBA annotation may reflect ancestral function in non-mammalian family members.
Reason: Griffin et al. 1999 (PMID:10531061) demonstrated a light-independent role of CRY1 and CRY2 in the mammalian circadian clock. Mammalian CRY2 is not involved in photic entrainment; this function is mediated by retinal photoreceptors signaling to the SCN.
Supporting Evidence:
Q49AN0
Transcriptional repressor which forms a core component of the circadian clock
|
|
GO:0071949
FAD binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: CRY2 binds FAD, confirmed by purification studies showing FAD and pterin cofactors (PMID:8909283). However, FAD binding is weak in mammalian CRYs and the FAD pocket primarily serves as a regulatory hub for FBXL3 recognition and small-molecule binding rather than for catalytic or photochemical function.
Reason: FAD binding is experimentally demonstrated and the FAD pocket is functionally important for CRY2 regulation, even though FAD occupancy is low.
Supporting Evidence:
PMID:8909283
were found to contain FAD and a pterin cofactor
|
|
GO:0000166
nucleotide binding
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: CRY2 binds FAD, which is a dinucleotide cofactor. The nucleotide binding annotation is a broader parent of the more informative FAD binding term.
Reason: This is a valid broader term that follows from the FAD binding annotation. As an IEA mapped from the UniProt nucleotide-binding keyword, it is appropriately general.
Supporting Evidence:
Q49AN0
Binds 1 FAD per subunit
|
|
GO:0005634
nucleus
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Duplicate IEA annotation for nucleus. Consistent with IBA and ISS annotations and UniProt curated localization.
Reason: Nuclear localization is well-established for CRY2.
Supporting Evidence:
Q49AN0
Nucleus {ECO:0000269|PubMed:22798407, ECO:0000269|PubMed:9801304}
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: Duplicate IEA annotation for cytoplasm. Consistent with IBA annotation and UniProt curated localization.
Reason: Cytoplasmic localization is well-established for CRY2.
Supporting Evidence:
Q49AN0
Cytoplasm {ECO:0000269|PubMed:9801304}
|
|
GO:0009881
photoreceptor activity
|
IEA
GO_REF:0000043 |
REMOVE |
Summary: Mammalian CRY2 does not function as a photoreceptor. This IEA annotation derives from the UniProt keyword "Photoreceptor protein" which is a legacy designation based on the photolyase family membership. Griffin et al. 1999 (PMID:10531061) established the light-independent function of mammalian CRYs.
Reason: Mammalian CRY2 functions as a light-independent transcriptional repressor. There is no evidence that human CRY2 has photoreceptor activity. The UniProt keyword is misleading for the mammalian protein.
Supporting Evidence:
PMID:8909283
may function as blue-light photoreceptors in humans
Q49AN0
Transcriptional repressor which forms a core component of the circadian clock
|
|
GO:0019902
phosphatase binding
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: hCRY2 specifically interacts with protein serine/threonine phosphatase 5 (PP5) via yeast two-hybrid and inhibits its phosphatase activity (PMID:9383998). This is a well-characterized direct interaction.
Reason: Direct phosphatase binding is experimentally demonstrated for CRY2 with PP5 (PMID:9383998). The IEA annotation is consistent with the experimental evidence.
Supporting Evidence:
PMID:9383998
protein serine/threonine phosphatase 5 (PP5) that contains the TPR motif specifically interacted with hCRY2
|
|
GO:0048511
rhythmic process
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: CRY2 is a core circadian clock component. The rhythmic process annotation is a valid broader term encompassing its role in circadian rhythms.
Reason: CRY2 is a core component of the circadian clock and participates in generating approximately 24-hour rhythms in gene expression and physiology.
Supporting Evidence:
Q49AN0
Transcriptional repressor which forms a core component of the circadian clock
|
|
GO:0005515
protein binding
|
IPI
PMID:16790549 Posttranslational regulation of the mammalian circadian cloc... |
MARK AS OVER ANNOTATED |
Summary: PMID:16790549 demonstrates CRY2 interacts with PP5 (PPP5C) to modulate CKIepsilon phosphorylation. The specific interaction is better captured by the phosphatase binding (GO:0019902) and protein phosphatase inhibitor activity (GO:0004864) annotations already present.
Reason: Generic protein binding does not convey the specific functional interaction between CRY2 and PP5. More informative terms (phosphatase binding, protein phosphatase inhibitor activity) are already annotated.
Supporting Evidence:
PMID:16790549
cryptochrome regulates clock protein phosphorylation by modulating the effect of PP5 on CKIepsilon
|
|
GO:0005515
protein binding
|
IPI
PMID:25416956 A proteome-scale map of the human interactome network. |
MARK AS OVER ANNOTATED |
Summary: Large-scale proteome interactome mapping study. Generic protein binding from high-throughput screens is uninformative.
Reason: High-throughput interactome mapping does not provide functional insight beyond generic protein binding. More specific interaction terms should be used where validated.
Supporting Evidence:
PMID:25416956
A proteome-scale map of the human interactome network
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: Binary interactome reference map study. This is a high-throughput screen reporting many interaction partners. Generic protein binding from such studies is uninformative.
Reason: High-throughput binary interactome mapping provides no functional specificity for CRY2 interactions. Many of the reported partners (keratin associated proteins, etc.) may represent false positives or indirect interactions.
Supporting Evidence:
PMID:32296183
A reference map of the human binary protein interactome
|
|
GO:0005515
protein binding
|
IPI
PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... |
MARK AS OVER ANNOTATED |
Summary: Neurodegenerative disease interactome mapping study. Generic protein binding annotation from a high-throughput screen.
Reason: High-throughput interactome mapping does not provide functional specificity for CRY2 interactions.
Supporting Evidence:
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
|
|
GO:0000976
transcription cis-regulatory region binding
|
IEA
GO_REF:0000107 |
MODIFY |
Summary: This annotation is transferred from mouse CRY2 (Q9R194). CRY2 does not bind cis-regulatory regions specifically; its DNA binding is non-specific and weak (PMID:12627958). CRY2 represses transcription through protein-protein interactions with CLOCK:BMAL1 rather than through direct cis-regulatory element binding.
Reason: CRY2 binds DNA non-specifically and weakly. The term "transcription cis-regulatory region binding" implies sequence-specific DNA binding which is not demonstrated for CRY2. A general DNA binding term is more appropriate.
Proposed replacements:
DNA binding
Supporting Evidence:
PMID:12627958
binds to double-stranded DNA weakly and to single-stranded DNA with higher affinity
|
|
GO:0005739
mitochondrion
|
IEA
GO_REF:0000107 |
REMOVE |
Summary: CRY2 is well-characterized as a cytoplasmic/nuclear protein. Mitochondrial localization is not supported by any direct evidence for CRY2. UniProt curated localization reports only cytoplasm and nucleus.
Reason: No evidence supports mitochondrial localization of CRY2. UniProt curated location indicates only cytoplasm and nucleus.
Supporting Evidence:
Q49AN0
Cytoplasm {ECO:0000269|PubMed:9801304}. Nucleus {ECO:0000269|PubMed:22798407, ECO:0000269|PubMed:9801304}
|
|
GO:0009416
response to light stimulus
|
IEA
GO_REF:0000107 |
REMOVE |
Summary: Transferred from mouse CRY2. Mammalian CRY2 functions as a light-independent transcriptional repressor (PMID:10531061). While CRY2 retains a photolyase-like fold with FAD binding, it does not function as a light sensor in mammals.
Reason: Mammalian CRY2 has a well-established light-independent role in the circadian clock. The response to light stimulus annotation is based on ancestral function from the photolyase family that is not retained in mammalian cryptochromes.
Supporting Evidence:
Q49AN0
Transcriptional repressor which forms a core component of the circadian clock
|
|
GO:0014823
response to activity
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Transferred from mouse CRY2. UniProt mentions CRY2 represses PPARD and limits exercise capacity (by similarity). This would be a downstream pleiotropic effect of circadian clock function rather than a core function of CRY2.
Reason: CRY2 may indirectly affect exercise-related physiology through transcriptional repression of PPARD in skeletal muscle. This is a secondary downstream effect of circadian regulation, not a core function.
Supporting Evidence:
Q49AN0
Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (By similarity)
|
|
GO:0016922
nuclear receptor binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: CRY2 interacts with the glucocorticoid receptor (NR3C1/GR) in a ligand-dependent manner (PMID:22170608) and with HNF4A (PMID:30530698). UniProt also reports interactions with AR, PPARA, PPARD, PPARG, NR1I2, NR1I3, and VDR.
Reason: Nuclear receptor binding is well-supported by multiple studies demonstrating direct ligand-dependent interactions between CRY2 and various nuclear receptors including GR, HNF4A, and others.
Supporting Evidence:
PMID:22170608
cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent fashion
PMID:30530698
HNF4A strongly transrepresses the transcriptional activity of the CLOCK:BMAL1 heterodimer
|
|
GO:0019900
kinase binding
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: CRY2 modulates CKIepsilon (CSNK1E) activity through PP5 interaction (PMID:16790549). UniProt reports phosphorylation by CSNK1E requires interaction with PER1 or PER2, suggesting indirect rather than direct kinase binding. However, the circadian core oscillator complex includes CSNK1D/CSNK1E as components.
Reason: CRY2 interacts with kinases as part of the circadian repressor complex but direct kinase binding has not been definitively demonstrated independent of complex partners. The interaction may be mediated through PER proteins.
Supporting Evidence:
PMID:16790549
cryptochrome regulates clock protein phosphorylation by modulating the effect of PP5 on CKIepsilon
Q49AN0
Phosphorylation by CSKNE requires interaction with PER1 or PER2
|
|
GO:0019901
protein kinase binding
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Similar to kinase binding above. CRY2 is part of a complex with CSNK1D/CSNK1E but direct protein kinase binding independent of PER proteins is not well-demonstrated.
Reason: CRY2 functions in a complex containing protein kinases (CSNK1D/CSNK1E) but direct binding may be mediated through PER protein intermediaries.
Supporting Evidence:
Q49AN0
Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E
|
|
GO:0019915
lipid storage
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: UniProt notes CRY2 plays a key role in lipid metabolism modulation through transcriptional regulation of genes like ACSL4. CRY2 repression via PER2 promotes adipogenesis through circadian control of Wnt signaling. However, lipid storage per se is a downstream pleiotropic consequence of circadian regulation.
Reason: CRY2 contributes to lipid metabolism modulation through transcriptional regulation, which is a downstream effect of its circadian clock function rather than a direct role in lipid storage.
Supporting Evidence:
Q49AN0
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
|
|
GO:0032868
response to insulin
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Loss of cryptochromes causes glucose intolerance (PMID:22170608), which relates to insulin responsiveness. However, this is a downstream metabolic consequence of cryptochrome deficiency affecting glucocorticoid signaling and glucose homeostasis rather than a direct insulin response function.
Reason: CRY2 affects insulin sensitivity indirectly through its role in circadian regulation of glucocorticoid signaling and glucose metabolism. This is a pleiotropic downstream effect rather than a core function.
Supporting Evidence:
PMID:22170608
genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone
|
|
GO:0032922
circadian regulation of gene expression
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate IEA annotation for circadian regulation of gene expression. Consistent with IBA and other annotations.
Reason: Circadian regulation of gene expression is a core function of CRY2, well-supported across multiple evidence types.
Supporting Evidence:
PMID:20840750
negatively regulate the transcription of Per and Cry core clock genes
|
|
GO:0042593
glucose homeostasis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Cryptochrome deficiency causes glucose intolerance and elevated corticosterone (PMID:22170608). CRY2 may mediate circadian regulation of cAMP signaling and gluconeogenesis. This is a downstream metabolic effect of circadian clock function.
Reason: Glucose homeostasis is affected by CRY2 through its circadian regulation of glucocorticoid signaling and gluconeogenesis, but this is a pleiotropic downstream effect rather than a core molecular function.
Supporting Evidence:
PMID:22170608
genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone
|
|
GO:0042752
regulation of circadian rhythm
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: CRY2 is a core circadian clock component. CRY1 and CRY2 encode inhibitors of the CLOCK:BMAL1 complex and their degradation by SCF(FBXL3) is essential for clock oscillation (PMID:17463251).
Reason: CRY2 is a core component of the circadian clock regulatory mechanism.
Supporting Evidence:
PMID:17463251
Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback loop
|
|
GO:0042754
negative regulation of circadian rhythm
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: CRY2 functions as part of the negative limb of the circadian TTFL, inhibiting CLOCK:BMAL1 activity (PMID:17463251, PMID:10531061).
Reason: CRY2 is a negative regulator in the circadian feedback loop, directly inhibiting the positive limb (CLOCK:BMAL1) of the clock.
Supporting Evidence:
PMID:17463251
Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback loop
|
|
GO:0043153
entrainment of circadian clock by photoperiod
|
IEA
GO_REF:0000107 |
REMOVE |
Summary: Duplicate IEA annotation. Mammalian CRY2 is not involved in photic entrainment of the circadian clock.
Reason: Mammalian CRY2 functions as a light-independent transcriptional repressor (PMID:10531061). Photic entrainment in mammals is mediated by retinal photoreceptors, not by cryptochromes.
Supporting Evidence:
Q49AN0
Transcriptional repressor which forms a core component of the circadian clock
|
|
GO:0045892
negative regulation of DNA-templated transcription
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate IEA annotation. Consistent with IBA and IDA annotations for transcriptional repression.
Reason: Negative regulation of transcription is the primary molecular function of CRY2.
Supporting Evidence:
PMID:12397359
Cry proteins to inhibit Per transcription
|
|
GO:0071949
FAD binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate IEA annotation for FAD binding. Consistent with IBA and ISS annotations.
Reason: FAD binding is experimentally demonstrated for CRY2.
Supporting Evidence:
PMID:8909283
were found to contain FAD and a pterin cofactor
|
|
GO:2000323
negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Cryptochromes interact with the glucocorticoid receptor and broadly oppose GR activation while promoting GR-mediated repression (PMID:22170608). CRY deficiency vastly decreases gene repression and approximately doubles dexamethasone-induced genes.
Reason: While well-supported by PMID:22170608, regulation of glucocorticoid signaling is a downstream function of CRY2 nuclear receptor binding rather than a core clock function. It represents an important secondary output of the circadian clock.
Supporting Evidence:
PMID:22170608
cryptochrome deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone-induced genes, suggesting that cryptochromes broadly oppose glucocorticoid receptor activation and promote repression
|
|
GO:2000850
negative regulation of glucocorticoid secretion
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Loss of cryptochromes leads to constitutively high circulating corticosterone levels, suggesting reduced suppression of the hypothalamic-pituitary-adrenal axis (PMID:22170608).
Reason: While well-supported, regulation of glucocorticoid secretion is a downstream physiological consequence of CRY2 function in the circadian clock and its interaction with the glucocorticoid receptor. This is a secondary output rather than a core molecular function.
Supporting Evidence:
PMID:22170608
genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal axis
|
|
GO:0005829
cytosol
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: HPA immunofluorescence data supports cytosolic localization of CRY2. This is consistent with the broader cytoplasm annotation.
Reason: Cytosolic localization is consistent with the established cytoplasmic/nuclear distribution of CRY2. HPA provides IDA-level evidence from immunofluorescence.
Supporting Evidence:
Q49AN0
Cytoplasm {ECO:0000269|PubMed:9801304}
|
|
GO:0016607
nuclear speck
|
IDA
GO_REF:0000052 |
UNDECIDED |
Summary: HPA immunofluorescence data indicates nuclear speck localization. This is IDA evidence from the Human Protein Atlas. Nuclear specks are subnuclear structures enriched in RNA splicing factors. While the HPA staining pattern may show punctate nuclear signal, nuclear speck localization has not been independently confirmed for CRY2 in the literature.
Reason: The HPA immunofluorescence data may show punctate nuclear staining consistent with nuclear specks, but this has not been validated by independent studies. Without access to the specific HPA images and co-localization data with speck markers, it is difficult to confirm this specific subnuclear localization.
Supporting Evidence:
Q49AN0
Nucleus {ECO:0000269|PubMed:22798407, ECO:0000269|PubMed:9801304}
|
|
GO:0032922
circadian regulation of gene expression
|
NAS
PMID:20840750 Identification of two amino acids in the C-terminal domain o... |
ACCEPT |
Summary: PMID:20840750 identifies CRY2 residues essential for PER2 interaction in the negative arm of the circadian feedback loop (PMID:20840750).
Reason: The study provides direct evidence that CRY2-PER2 interaction is essential for the circadian transcriptional repression mechanism.
Supporting Evidence:
PMID:20840750
negatively regulate the transcription of Per and Cry core clock genes
|
|
GO:0042754
negative regulation of circadian rhythm
|
NAS
PMID:20840750 Identification of two amino acids in the C-terminal domain o... |
ACCEPT |
Summary: CRY2 represses CLOCK:BMAL1 as part of the negative limb of the circadian clock. PMID:20840750 characterizes the CRY2-PER2 interaction interface essential for this repression.
Reason: CRY2 is a well-established negative regulator in the circadian feedback loop.
Supporting Evidence:
PMID:17463251
Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback loop
|
|
GO:0004864
protein phosphatase inhibitor activity
|
IDA
PMID:9383998 Human blue-light photoreceptor hCRY2 specifically interacts ... |
ACCEPT |
Summary: hCRY2 inhibits the phosphatase activity of PP5. Zhao and Sancar 1997 demonstrated that hCRY2, but not the highly homologous (6-4) photolyase, specifically inhibits PP5 phosphatase activity (PMID:9383998).
Reason: This is a well-characterized direct enzymatic inhibition demonstrated by direct assay. CRY2 specifically inhibits PP5, and this interaction is relevant to circadian clock regulation through modulation of CKIepsilon phosphorylation.
Supporting Evidence:
PMID:9383998
hCRY2, but not the highly homologous (6-4) photolyase, inhibits the phosphatase activity of PP5
|
|
GO:0009416
response to light stimulus
|
ISS
GO_REF:0000024 |
REMOVE |
Summary: ISS annotation transferred from mouse CRY2 (Q9R194). Mammalian CRY2 functions as a light-independent transcriptional repressor (PMID:10531061).
Reason: Mammalian CRY2 has a light-independent role in the circadian clock. Response to light stimulus is not a function of human CRY2.
Supporting Evidence:
Q49AN0
Transcriptional repressor which forms a core component of the circadian clock
|
|
GO:0014823
response to activity
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ISS annotation transferred from mouse CRY2. UniProt notes CRY2 represses PPARD in skeletal muscle and limits exercise capacity (by similarity). This is a downstream pleiotropic effect.
Reason: CRY2 may indirectly affect exercise-related physiology through transcriptional repression of PPARD, but this is a secondary downstream effect of circadian regulation.
Supporting Evidence:
Q49AN0
Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (By similarity)
|
|
GO:0005515
protein binding
|
IPI
PMID:30530698 Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modula... |
MODIFY |
Summary: PMID:30530698 demonstrates CRY2 interacts with HNF4A, a nuclear receptor. The specific interaction is better captured by the nuclear receptor binding annotation (GO:0016922).
Reason: The interaction between CRY2 and HNF4A is a specific nuclear receptor binding interaction. Generic protein binding does not convey the functional specificity of this interaction.
Proposed replacements:
nuclear receptor binding
Supporting Evidence:
PMID:30530698
HNF4A strongly transrepresses the transcriptional activity of the CLOCK:BMAL1 heterodimer
|
|
GO:0009416
response to light stimulus
|
IMP
PMID:15751956 Role of structural plasticity in signal transduction by the ... |
REMOVE |
Summary: PMID:15751956 (Partch et al. 2005) demonstrates a light-dependent conformational change in the C-terminal domain of Arabidopsis Cry1, not human CRY2. The paper also characterizes the CRY2 photolyase homology region structure but does not demonstrate a light response for human CRY2. This IMP annotation from CAFA appears to be a misannotation.
Reason: The paper primarily characterizes Arabidopsis Cry1 light-dependent conformational changes. It does not demonstrate a light response function for human CRY2. The IMP evidence code is inappropriate for this reference.
Supporting Evidence:
PMID:15751956
we demonstrate a light-dependent conformational change in the C-terminal domain of Arabidopsis Cry1
|
|
GO:0042752
regulation of circadian rhythm
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ISS annotation from mouse CRY2. CRY2 is a core circadian clock component, well-established as a regulator of circadian rhythm.
Reason: CRY2 is a core component of the circadian clock mechanism.
Supporting Evidence:
PMID:17463251
Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback loop
|
|
GO:0043153
entrainment of circadian clock by photoperiod
|
ISS
GO_REF:0000024 |
REMOVE |
Summary: ISS annotation from mouse CRY2. Mammalian CRY2 is not involved in photic entrainment.
Reason: Mammalian CRY2 functions as a light-independent transcriptional repressor (PMID:10531061). Photic entrainment is not a function of mammalian CRY.
Supporting Evidence:
Q49AN0
Transcriptional repressor which forms a core component of the circadian clock
|
|
GO:0045892
negative regulation of DNA-templated transcription
|
IDA
PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc... |
ACCEPT |
Summary: Dec1 and Dec2 study (Honma et al. 2002) shows Cry proteins together with Per proteins inhibit Per transcription by closing the autoregulatory feedback loop.
Reason: Direct experimental evidence that Cry proteins inhibit Per transcription, a core function of CRY2.
Supporting Evidence:
PMID:12397359
Protein products of Per act together with Cry proteins to inhibit Per transcription, thus closing the autoregulatory feedback loop
|
|
GO:0032922
circadian regulation of gene expression
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ISS annotation from mouse CRY2. Consistent with the well-established role of CRY2 in circadian gene regulation.
Reason: Circadian regulation of gene expression is a core function of CRY2.
Supporting Evidence:
PMID:20840750
negatively regulate the transcription of Per and Cry core clock genes
|
|
GO:0042593
glucose homeostasis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ISS annotation from mouse CRY2. Cryptochrome deficiency causes glucose intolerance (PMID:22170608). This is a downstream metabolic effect.
Reason: Glucose homeostasis is affected by CRY2 through its circadian regulation of glucocorticoid signaling, but this is a pleiotropic downstream effect.
Supporting Evidence:
PMID:22170608
genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance
|
|
GO:2000323
negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ISS annotation from mouse CRY2. Cryptochromes broadly oppose GR activation (PMID:22170608). This is a well-supported secondary function.
Reason: Regulation of glucocorticoid signaling is a downstream output of CRY2 nuclear receptor binding, not a core clock function.
Supporting Evidence:
PMID:22170608
cryptochromes broadly oppose glucocorticoid receptor activation and promote repression
|
|
GO:0000976
transcription cis-regulatory region binding
|
ISS
GO_REF:0000024 |
MODIFY |
Summary: ISS annotation from mouse CRY2. CRY2 binds DNA non-specifically rather than at specific cis-regulatory regions.
Reason: CRY2 does not specifically bind cis-regulatory regions. Its DNA binding is non-specific and weak. A general DNA binding term is more appropriate.
Proposed replacements:
DNA binding
Supporting Evidence:
PMID:12627958
binds to double-stranded DNA weakly and to single-stranded DNA with higher affinity
|
|
GO:0042754
negative regulation of circadian rhythm
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ISS annotation from mouse CRY2. CRY2 functions as a negative regulator in the circadian feedback loop.
Reason: CRY2 inhibits CLOCK:BMAL1 in the negative arm of the circadian clock.
Supporting Evidence:
PMID:17463251
Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback loop
|
|
GO:0045892
negative regulation of DNA-templated transcription
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ISS annotation from mouse CRY2. Consistent with the core transcriptional repressor function of CRY2.
Reason: Negative regulation of transcription is the primary molecular function of CRY2.
Supporting Evidence:
PMID:20840750
negatively regulate the transcription of Per and Cry core clock genes
|
|
GO:0071949
FAD binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ISS annotation from mouse CRY2. FAD binding is experimentally confirmed for human CRY2.
Reason: FAD binding is directly demonstrated for purified human CRY2.
Supporting Evidence:
PMID:8909283
were found to contain FAD and a pterin cofactor
|
|
GO:0007623
circadian rhythm
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: CRY2 is a core component of the mammalian circadian clock, essential for generating approximately 24-hour rhythms.
Reason: CRY2 is a well-established core circadian clock component. Mice lacking both CRY1 and CRY2 are completely arrhythmic.
Supporting Evidence:
Q49AN0
Transcriptional repressor which forms a core component of the circadian clock
|
|
GO:0005515
protein binding
|
IPI
PMID:9383998 Human blue-light photoreceptor hCRY2 specifically interacts ... |
MARK AS OVER ANNOTATED |
Summary: PMID:9383998 demonstrates CRY2 specifically interacts with PP5. More informative terms (phosphatase binding, protein phosphatase inhibitor activity) are already annotated for this interaction.
Reason: Generic protein binding does not convey the specific functional interaction. Phosphatase binding (GO:0019902) and protein phosphatase inhibitor activity (GO:0004864) from the same reference are more informative.
Supporting Evidence:
PMID:9383998
protein serine/threonine phosphatase 5 (PP5) that contains the TPR motif specifically interacted with hCRY2
|
|
GO:0019902
phosphatase binding
|
IPI
PMID:9383998 Human blue-light photoreceptor hCRY2 specifically interacts ... |
ACCEPT |
Summary: Zhao and Sancar 1997 demonstrated by yeast two-hybrid that PP5 specifically interacts with hCRY2 (PMID:9383998). This is a well-characterized direct interaction.
Reason: Direct experimental evidence for CRY2-PP5 interaction by yeast two-hybrid assay.
Supporting Evidence:
PMID:9383998
protein serine/threonine phosphatase 5 (PP5) that contains the TPR motif specifically interacted with hCRY2
|
|
GO:0005576
extracellular region
|
IDA
PMID:9753616 Molecular cloning of a second human stanniocalcin homologue ... |
REMOVE |
Summary: PMID:9753616 (Ishibashi et al. 1998) describes the cloning of stanniocalcin-2 (STC2), an unrelated protein. This appears to be a misannotation where the wrong gene was associated with this reference. CRY2 is not an extracellular protein.
Reason: The cited reference is about STC2 (stanniocalcin-2), not CRY2. This is a clear misannotation. CRY2 is an intracellular protein localized to cytoplasm and nucleus.
Supporting Evidence:
PMID:9753616
Molecular cloning of a second human stanniocalcin homologue (STC2)
|
|
GO:2000118
regulation of sodium-dependent phosphate transport
|
IDA
PMID:9753616 Molecular cloning of a second human stanniocalcin homologue ... |
REMOVE |
Summary: PMID:9753616 describes STC2-mediated inhibition of sodium-phosphate cotransporter. This is unrelated to CRY2. This is a clear misannotation.
Reason: The cited reference concerns STC2 (stanniocalcin-2) biology, not CRY2. CRY2 has no demonstrated role in phosphate transport regulation.
Supporting Evidence:
PMID:9753616
STC2-transfected CHO cells inhibited the promoter activity of Na-phosphate cotransporter
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IDA
PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc... |
ACCEPT |
Summary: Honma et al. 2002 demonstrated that Cry proteins act together with Per proteins to inhibit CLOCK:BMAL1-driven transcription from E-box elements in the Per1 promoter (PMID:12397359). This is RNA Pol II-dependent transcription.
Reason: CRY2 inhibits CLOCK:BMAL1-driven transcription from E-box elements, which are RNA polymerase II promoter elements.
Supporting Evidence:
PMID:12397359
Protein products of Per act together with Cry proteins to inhibit Per transcription, thus closing the autoregulatory feedback loop
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IDA
PMID:14672706 A novel autofeedback loop of Dec1 transcription involved in ... |
ACCEPT |
Summary: Kawamoto et al. 2004 showed PERs and CRYs suppressed CLOCK/BMAL-induced expression of Dec1 through E-box elements (PMID:14672706).
Reason: Direct experimental evidence that CRY proteins suppress CLOCK/BMAL-induced transcription from E-box-containing promoters.
Supporting Evidence:
PMID:14672706
PERs and CRYs suppressed the induced expression
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IDA
PMID:15147242 Expression of the gene for Dec2, a basic helix-loop-helix tr... |
ACCEPT |
Summary: Hamaguchi et al. 2004 showed Cry suppressed Clock/Bmal-induced transcription from the Dec2 promoter (PMID:15147242).
Reason: Direct experimental evidence that Cry proteins suppress CLOCK/BMAL-induced transcription of Dec2.
Supporting Evidence:
PMID:15147242
Like Dec, Cry and Per also suppressed Clock/Bmal-induced transcription from the Dec2 promoter
|
|
GO:0005634
nucleus
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: ISS annotation from mouse CRY2 for nuclear localization. Consistent with direct evidence from human cells.
Reason: Nuclear localization is well-established for CRY2 by multiple lines of evidence.
Supporting Evidence:
Q49AN0
Nucleus {ECO:0000269|PubMed:22798407, ECO:0000269|PubMed:9801304}
|
|
GO:0009785
blue light signaling pathway
|
NAS
PMID:8909283 Putative human blue-light photoreceptors hCRY1 and hCRY2 are... |
REMOVE |
Summary: Hsu et al. 1996 initially hypothesized human CRY proteins may function as blue-light photoreceptors (PMID:8909283). However, subsequent work by Griffin et al. 1999 (PMID:10531061) established that mammalian CRYs function as light-independent transcriptional repressors. There is no evidence for blue light signaling by human CRY2.
Reason: The original NAS annotation was based on a hypothesis that has been superseded by definitive evidence that mammalian CRY2 functions as a light-independent repressor. Human CRY2 does not participate in blue light signaling.
Supporting Evidence:
PMID:8909283
may function as blue-light photoreceptors in humans
|
|
GO:0009882
blue light photoreceptor activity
|
NAS
PMID:8909283 Putative human blue-light photoreceptors hCRY1 and hCRY2 are... |
REMOVE |
Summary: Hsu et al. 1996 speculated CRY proteins may be blue-light photoreceptors (PMID:8909283), but Griffin et al. 1999 (PMID:10531061) demonstrated a light-independent role for mammalian CRYs. Human CRY2 has no demonstrated photoreceptor activity.
Reason: The original NAS annotation was speculative. Mammalian CRY2 does not function as a blue light photoreceptor. The annotation should be removed rather than merely marked as over-annotated because the function is not supported by any evidence.
Supporting Evidence:
PMID:8909283
may function as blue-light photoreceptors in humans
|
|
GO:0000719
photoreactive repair
|
IDA
NOT
PMID:12627958 Purification and properties of human blue-light photorecepto... |
ACCEPT |
Summary: Ozgur and Sancar 2003 confirmed that hCRY2 lacks photorepair activity (PMID:12627958). This is a correctly negated annotation documenting the absence of photolyase function.
Reason: The negated annotation is correct and well-supported. CRY2 lacks photorepair activity despite its structural similarity to photolyases.
Supporting Evidence:
PMID:12627958
appear to lack photorepair activity
|
|
GO:0003677
DNA binding
|
IDA
PMID:12627958 Purification and properties of human blue-light photorecepto... |
KEEP AS NON CORE |
Summary: Ozgur and Sancar 2003 demonstrated that purified hCRY2 binds dsDNA weakly and ssDNA with higher affinity (PMID:12627958). This is a residual property from the photolyase ancestor rather than a core functional activity.
Reason: DNA binding is experimentally demonstrated but is not the primary mechanism of CRY2 function. CRY2 represses transcription through protein-protein interactions with CLOCK:BMAL1, not through direct DNA binding.
Supporting Evidence:
PMID:12627958
binds to double-stranded DNA weakly and to single-stranded DNA with higher affinity
|
|
GO:0003684
damaged DNA binding
|
IDA
PMID:12627958 Purification and properties of human blue-light photorecepto... |
KEEP AS NON CORE |
Summary: CRY2 DNA binding is stimulated by the presence of a (6-4) photoproduct (PMID:12627958). This reflects the ancestral photolyase substrate recognition capability retained in the protein structure but without associated repair activity.
Reason: Damaged DNA binding is experimentally demonstrated but is a vestigial property from the photolyase ancestor. CRY2 lacks photolyase activity and damaged DNA binding is not its primary function.
Supporting Evidence:
PMID:12627958
this binding is further stimulated by the presence of a (6-4) photoproduct
|
|
GO:0003697
single-stranded DNA binding
|
IDA
PMID:12627958 Purification and properties of human blue-light photorecepto... |
KEEP AS NON CORE |
Summary: Ozgur and Sancar 2003 showed hCRY2 binds ssDNA with higher affinity than dsDNA (PMID:12627958). This is a vestigial property from the photolyase ancestor.
Reason: Single-stranded DNA binding is experimentally demonstrated but is not the primary mechanism of CRY2 function. It represents a retained ancestral property.
Supporting Evidence:
PMID:12627958
single-stranded DNA with higher affinity
|
|
GO:0003904
deoxyribodipyrimidine photo-lyase activity
|
IDA
NOT
PMID:8909283 Putative human blue-light photoreceptors hCRY1 and hCRY2 are... |
ACCEPT |
Summary: Hsu et al. 1996 demonstrated that purified hCRY2 lacks photolyase activity on cyclobutane pyrimidine dimers (PMID:8909283). Correctly negated annotation.
Reason: The negated annotation is correct. CRY2 lacks CPD photolyase activity despite its structural similarity to DNA photolyases.
Supporting Evidence:
PMID:8909283
lacked photolyase activity on the cyclobutane pyrimidine dimer and the (6-4) photoproduct
|
|
GO:0003914
DNA (6-4) photolyase activity
|
IDA
NOT
PMID:8909283 Putative human blue-light photoreceptors hCRY1 and hCRY2 are... |
ACCEPT |
Summary: Hsu et al. 1996 demonstrated that purified hCRY2 lacks (6-4) photolyase activity (PMID:8909283). Correctly negated annotation.
Reason: The negated annotation is correct. CRY2 lacks (6-4) photolyase activity despite its homology to the Drosophila (6-4) photolyase.
Supporting Evidence:
PMID:8909283
lacked photolyase activity on the cyclobutane pyrimidine dimer and the (6-4) photoproduct
|
|
GO:0005515
protein binding
|
IPI
PMID:17463251 SCFFbxl3 controls the oscillation of the circadian clock by ... |
MARK AS OVER ANNOTATED |
Summary: Busino et al. 2007 identified CRY2 interaction with FBXL3 as part of the SCF(FBXL3) ubiquitin ligase complex that targets CRY proteins for degradation (PMID:17463251). The specific ubiquitin ligase interaction is functionally important but annotated as generic protein binding.
Reason: The CRY2-FBXL3 interaction is a specific ubiquitin ligase substrate recognition event. Generic protein binding does not convey the functional significance of this interaction.
Supporting Evidence:
PMID:17463251
both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
|
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gene_id: CRY2
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protein_description: 'RecName: Full=Cryptochrome-2;'
gene_info: Name=CRY2; Synonyms=KIAA0658;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the DNA photolyase class-1 family.
protein_domains: Crypto/Photolyase_FAD-like_sf. (IPR036134); Crypto/Photolyase_N_sf.
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BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'CRY2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene CRY2 (gene ID: CRY2, UniProt: Q49AN0) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'CRY2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene CRY2 (gene ID: CRY2, UniProt: Q49AN0) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Human CRY2 is a flavoprotein of the cryptochrome/photolyase family that acts primarily as a light-independent transcriptional repressor in the mammalian circadian clock transcription–translation feedback loop (TTFL). Its core biochemical role is to assemble with PER proteins, enter the nucleus, and inhibit CLOCK:BMAL1-driven transcription, with CRY2 stability and repression strength governed by FAD-pocket–centered protein interactions with ubiquitin ligases (notably FBXL3/FBXL21) and by PER2-dependent protection from degradation. Recent work (2023–2024) adds mechanistic detail on (i) how specific CRY2 residues enable PER2-mediated repression and adipogenic output programs, (ii) how human CRY2 can undergo noncanonical/lysosomal degradation, and (iii) translational progress of CRY2-selective stabilizers/activators into early clinical testing (Phase I) for glioblastoma as a clock-targeting therapeutic strategy. (li2023transcriptionrepressionof pages 13-15, calloni2023thestructuraland pages 1-2, parlak2023functionalcharacterizationof pages 4-5, chan2024advancingclinicalresponse pages 8-11)
In mammals, CRY1 and CRY2 are essential negative-limb components of the TTFL: CLOCK:BMAL1 activates transcription of PER and CRY genes, and PER/CRY proteins accumulate and form repressive complexes that suppress CLOCK:BMAL1 activity to close the feedback loop. Mammalian cryptochromes are direct suppressors of circadian transcription and act independently of light, in contrast to many insect/plant cryptochromes that function as photoreceptors. (calloni2023thestructuraland pages 1-2, conrady2024identificationandevolution pages 34-37)
CRY2 is a member of the cryptochrome/photolyase (CRY/PL) family, derived from ancestral DNA photolyases. It contains a conserved photolyase homology region (PHR) plus a regulatory C-terminal extension/tail (often called CCT/CCE). The PHR contains a primary pocket homologous to the photolyase FAD/lesion pocket and also a secondary pocket used for regulatory interactions. (khan2025aninsilico pages 1-2, conrady2024identificationandevolution pages 34-37)
A key concept in mammalian cryptochromes is that they often show weak FAD association in vitro, raising the question of whether FAD is essential as a cofactor. However, the FAD-binding pocket remains functionally critical because it is directly tied to ubiquitin-ligase recognition (e.g., FBXL3) and is the binding site for small molecules that stabilize CRYs (e.g., KL001-class compounds). Thus, the “FAD pocket” is best viewed as a regulatory hub, even when FAD occupancy is low. (calloni2023thestructuraland pages 1-2, calloni2023thestructuraland pages 2-3)
CRY2 represses CLOCK:BMAL1-induced transcription as part of a PER–CRY repressor complex that accumulates and translocates to the nucleus. A 2023 review summarizes that CRY and PER proteins form a large nuclear repressor complex with CLOCK:BMAL1 to inhibit transcription, framing CRY2 as a direct transcriptional suppressor rather than a DNA repair enzyme. (calloni2023thestructuraland pages 1-2, calloni2023thestructuraland pages 2-3)
PER2 interaction is central to CRY2 repression and stability. A 2023 mechanistic study identified a conserved CRY2 cysteine (C432) in a loop interfacing with PER2 as critical for PER2 association; mutation of this residue disrupts PER2 binding and is linked to loss of repression while preserving BMAL1 binding, highlighting separable binding determinants for repression complex assembly. (li2023transcriptionrepressionof pages 13-15)
Ubiquitin ligases via the FAD pocket: Reviews emphasize that the cofactor/FAD pocket is a recognition site for the SCF ubiquitin ligase FBXL3, and that related ligases (including FBXL21 discussed in reviews) modulate CRY stability and oscillation properties by competition at this site. (calloni2023thestructuraland pages 2-3, conrady2024identificationandevolution pages 136-139)
CRY2 abundance is tightly regulated by post-translational mechanisms.
PER2-dependent stabilization and half-life control (quantitative): In a 2023 Journal of Biological Chemistry study of human CRY2, PER2 overexpression increased wild-type CRY2 half-life from ~7.9 h to ~12 h, supporting the model that PER2 binding protects CRY2 from degradation and supports repression. (parlak2023functionalcharacterizationof pages 4-5)
Noncanonical degradation pathways (2023 finding): The same 2023 study reports that a human CRY2 variant (p.Ser420Phe) shows markedly reduced stability (half-life ~2 h without PER2), reduced abundance in cytosolic and nuclear fractions, and impaired repression of CLOCK:BMAL1. Notably, proteasome inhibition stabilized wild-type CRY2 but did not stabilize the p.Ser420Phe variant, and the authors provide evidence consistent with lysosomal degradation contributing to CRY2 turnover (e.g., inhibition by lysosomal protease inhibitors). This indicates that human CRY2 turnover can involve proteasomal and lysosomal routes, depending on context/variant. (parlak2023functionalcharacterizationof pages 4-5)
CRY2 function requires dynamic cytosol-to-nucleus shuttling as part of PER:CRY complexes; nuclear accumulation is integral to repression. Impaired nuclear abundance (e.g., destabilizing variants) is associated with impaired repression capacity. (calloni2023thestructuraland pages 1-2, parlak2023functionalcharacterizationof pages 4-5)
A 2023 review synthesizes evidence that mammalian CRYs are light-independent repressors yet retain a photolyase-like pocket that is directly related to ubiquitylation by FBXL3 and is the target for protein-stabilizing small molecules; it also notes that altering cellular FAD supply can stabilize cryptochromes and affect circadian gene expression, reinforcing metabolic coupling to clock protein stability. (Publication date: Jan 2023; https://doi.org/10.3389/fmolb.2022.1081661) (calloni2023thestructuraland pages 1-2, calloni2023thestructuraland pages 2-3)
A 2023 Molecular and Cellular Biology study links CRY2 repression mechanisms to adipocyte biology. It identifies C432 as a PER2-interaction determinant required for repression and reports that CRY2 repression modulates circadian control of Wnt signaling to promote adipogenesis, tying TTFL repression mechanisms to a defined downstream output program. (Publication date: Sep 2023; https://doi.org/10.1080/10985549.2023.2253710) (li2023transcriptionrepressionof pages 13-15)
The 2023 JBC paper on p.Ser420Phe provides mechanistic insight into how specific CRY2 residues can disrupt PER2 interactions, nuclear localization/abundance, and degradation routing, with quantitative half-life measurements demonstrating strong PER2-dependent stabilization and variant-dependent turnover. (Publication date: Dec 2023; https://doi.org/10.1016/j.jbc.2023.105451) (parlak2023functionalcharacterizationof pages 4-5)
A 2024 bioRxiv preprint reports development of SHP1705, described as a CRY2-selective activator intended to inhibit BMAL1–CLOCK transcriptional activity in glioblastoma stem cell (GSC) contexts. It reports a randomized, double-blind Phase I study in healthy volunteers with explicit cohort sizes (see statistics below) and states both single and multiple dosing were well tolerated. (Publication date: Sep 2024; https://doi.org/10.1101/2024.09.17.613520) (chan2024advancingclinicalresponse pages 8-11)
Multiple small molecules target the cryptochrome FAD-pocket region to modulate stability and circadian outputs. A 2025 translational review summarizes that KL001-class compounds bind in the CRY pocket to stabilize CRYs, with derivatives that show CRY2 selectivity (e.g., SHP656/SHP1705, TH301-class) and are being studied across cancer and metabolic indications. (Publication date: Sep 2025; https://doi.org/10.1002/cbin.70087) (toda2025targetingcryptochromesin pages 2-3)
SHP1705 is reported as the first circadian clock–modulating compound in this class to be found safe and well tolerated in Phase I clinical trials (healthy volunteers), and it is positioned for use against GSC-driven glioblastoma based on preclinical efficacy and combination strategies (e.g., with a REV-ERB agonist). (chan2024advancingclinicalresponse pages 1-4, chan2024advancingclinicalresponse pages 8-11)
Visual evidence: The Chan et al. 2024 study includes a TTFL schematic highlighting how CRY stabilizers are proposed to block SCF-FBXL3-mediated degradation of CRY proteins in the repression loop, and a separate schematic of the in vivo experimental timeline in xenograft models. (chan2024advancingclinicalresponse media 0254a939, chan2024advancingclinicalresponse media bc968ea3)
Authoritative reviews emphasize that even with weak FAD binding in vitro, the FAD pocket is a central structural feature because it mediates E3 ligase recognition and provides a binding site for small-molecule stabilizers, making it a practical “handle” for manipulating clock function pharmacologically. This is a prominent theme in 2023 and later syntheses of the field. (calloni2023thestructuraland pages 1-2, calloni2023thestructuraland pages 2-3)
The p.Ser420Phe work illustrates an expert-level caution: CRY2 turnover cannot be treated as exclusively proteasome-mediated. Variant- and context-dependent routing to lysosomal degradation suggests that “degradation pathway” is itself a regulated phenotype, potentially affecting how CRY2-targeting drugs perform across tissues/diseases. (parlak2023functionalcharacterizationof pages 4-5)
Study: Parlak et al., JBC, Dec 2023 (https://doi.org/10.1016/j.jbc.2023.105451)
- WT CRY2 half-life: ~7.9 h (no PER2) vs ~12 h (with PER2 overexpression). (parlak2023functionalcharacterizationof pages 4-5)
- CRY2 p.Ser420Phe half-life: ~2 h (no PER2) and “comparable to WT” when PER2 is overexpressed (indicating rescue via PER2 protection). (parlak2023functionalcharacterizationof pages 4-5)
Study: Chan et al., bioRxiv, Sep 2024 (https://doi.org/10.1101/2024.09.17.613520)
- Randomized, double-blind, placebo-controlled Phase I with SAD and MAD stages. (chan2024advancingclinicalresponse pages 8-11)
- SAD: 56 treated (42 SHP1705; 14 placebo). (chan2024advancingclinicalresponse pages 8-11)
- MAD: 16 treated (12 SHP1705; 4 placebo). (chan2024advancingclinicalresponse pages 8-11)
- Most frequent TEAE: headache (5 SHP1705 vs 2 placebo); diarrhea and nausea each reported in 3 SHP1705 subjects. One discontinuation (ventricular extrasystoles) judged unrelated. (chan2024advancingclinicalresponse pages 8-11)
| Functional Aspect | Key Mechanism / Role | Experimental Evidence & Quantitative Data | Key Sources (2023\u20132025) |
|---|---|---|---|
| Core Clock Function (TTFL) | Transcriptional Repressor: Essential component of the negative limb; heterodimerizes with PER proteins to repress CLOCK:BMAL1-mediated transcription. | Forms a ~1.9 MDa repressor complex in the nucleus. Acts via "displacement" or "blocking" of CLOCK:BMAL1. | Li et al. 2023 Mol Cell Biol (li2023transcriptionrepressionof pages 13-15); Calloni & Vabulas 2023 Front Mol Biosci (calloni2023thestructuraland pages 1-2) |
| Protein Interactions | Key Partners: PER2, CLOCK, BMAL1, FBXL3 (E3 ligase). Specific Interfaces: Cysteine-432 (C432) in CRY2 loop is critical for PER2 binding. |
Quantitative: Mutation of C432 disrupts PER2 binding (without affecting BMAL1 binding) and abolishes repression. Structure: FBXL3 binds the FAD pocket via a C-terminal tryptophan. |
Li et al. 2023 (li2023transcriptionrepressionof pages 13-15); Conrady 2024 (conrady2024identificationandevolution pages 34-37) |
| FAD Binding Pocket | Repurposed Domain: Mammalian CRY2 retains the ancestral photolyase FAD pocket but uses it for E3 ligase (FBXL3) recognition and small-molecule binding rather than light sensing. | Binding: Associates with FAD only weakly in vitro (often purifies empty). Cellular FAD levels can still influence stability. Targeted by stabilizers like KL001. | Calloni & Vabulas 2023 (calloni2023thestructuraland pages 2-3); Toda & Hirota 2025 Cell Biol Int (toda2025targetingcryptochromesin pages 12-12) |
| Stability & Degradation | Regulation: Controlled by SCFFBXL3 (degradation) and SCFFBXL21 (stabilization). Stabilization by PER2 is critical. New Pathway: Lysosomal degradation (via LIR motifs). | Half-life Data: Basal half-life ~7.9 h; extended to ~12 h with PER2. p.Ser420Phe variant is unstable (t1/2 ~2 h) due to loss of PER2 protection. | Parlak et al. 2023 JBC (parlak2023functionalcharacterizationof pages 4-5); Conrady 2024 (conrady2024identificationandevolution pages 136-139) |
| Small Molecule Modulation | Therapeutic Targets: CRY2 stabilizers (KL001 derivatives) mimic FAD/FBXL3 tail to block degradation. | Compounds: SHP1705 (CRY2-selective, Phase I safe/well-tolerated, effective in GBM xenografts). TH301 (CRY2 stabilizer, induces p21/arrest in pancreatic cancer). | Chan et al. 2025 Neuro-Oncology (chan2025advancingclinicalresponse pages 1-2); Toda & Hirota 2025 (toda2025targetingcryptochromesin pages 2-3); Farmakis et al. 2024 (farmakis2024th301emergesas pages 1-2) |
| Physiological Outputs | Adipogenesis: Promotes adipocyte differentiation by repressing Wnt signaling. Cancer: Tumor suppressor or oncogene context-dependently (e.g., low in GBM). |
Mechanism: CRY2 repression of Wnt is required for adipogenesis; C432 mutants fail to support differentiation. KL001 treatment augments adipocyte maturation. | Li et al. 2023 (li2023transcriptionrepressionof pages 13-15); Chan et al. 2024 bioRxiv (chan2024advancingclinicalresponse pages 1-4) |
Table: Overview of human CRY2 molecular functions, interactions, and therapeutic targeting potential based on 2023–2025 research literature.
References
(li2023transcriptionrepressionof pages 13-15): Weini Li, Xuekai Xiong, Tali Kiperman, and Ke Ma. Transcription repression of cry2 via per2 interaction promotes adipogenesis. Molecular and Cellular Biology, 43:500-514, Sep 2023. URL: https://doi.org/10.1080/10985549.2023.2253710, doi:10.1080/10985549.2023.2253710. This article has 8 citations and is from a domain leading peer-reviewed journal.
(calloni2023thestructuraland pages 1-2): Giulia Calloni and R. Martin Vabulas. The structural and functional roles of the flavin cofactor fad in mammalian cryptochromes. Frontiers in Molecular Biosciences, Jan 2023. URL: https://doi.org/10.3389/fmolb.2022.1081661, doi:10.3389/fmolb.2022.1081661. This article has 7 citations.
(parlak2023functionalcharacterizationof pages 4-5): Gizem Cagla Parlak, Ibrahim Baris, Seref Gul, and Ibrahim Halil Kavakli. Functional characterization of the cry2 circadian clock component variant p.ser420phe revealed a new degradation pathway for cry2. Journal of Biological Chemistry, 299:105451, Dec 2023. URL: https://doi.org/10.1016/j.jbc.2023.105451, doi:10.1016/j.jbc.2023.105451. This article has 5 citations and is from a domain leading peer-reviewed journal.
(chan2024advancingclinicalresponse pages 8-11): Priscilla Chan, Yoshiko Nagai, Qiulian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Jiarui Wang, Gevorg Karapetyan, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Rex A. Moats, Tsuyoshi Hirota, Jeremy N. Rich, and Steve A. Kay. Advancing clinical response against glioblastoma: evaluating shp1705 cry2 activator efficacy in preclinical models and safety in phase i trials. bioRxiv, Sep 2024. URL: https://doi.org/10.1101/2024.09.17.613520, doi:10.1101/2024.09.17.613520. This article has 1 citations.
(conrady2024identificationandevolution pages 34-37): MC Conrady. Identification and evolution of protein-protein interactions in circadian gene regulation. Unknown journal, 2024.
(khan2025aninsilico pages 1-2): Auroni Semonti Khan, Mahmuda Akter, Mansura Akter Enni, and Sumaiya Farah Khan. An in silico approach for the identification of detrimental missense snps and their potential impacts on human cry2 protein. Journal of Bangladesh Academy of Sciences, Jun 2025. URL: https://doi.org/10.3329/jbas.v49i1.71914, doi:10.3329/jbas.v49i1.71914. This article has 11 citations.
(calloni2023thestructuraland pages 2-3): Giulia Calloni and R. Martin Vabulas. The structural and functional roles of the flavin cofactor fad in mammalian cryptochromes. Frontiers in Molecular Biosciences, Jan 2023. URL: https://doi.org/10.3389/fmolb.2022.1081661, doi:10.3389/fmolb.2022.1081661. This article has 7 citations.
(conrady2024identificationandevolution pages 136-139): MC Conrady. Identification and evolution of protein-protein interactions in circadian gene regulation. Unknown journal, 2024.
(toda2025targetingcryptochromesin pages 2-3): Takuro Toda and Tsuyoshi Hirota. Targeting cryptochromes in chronic diseases. Cell Biology International, 49(12):1579-1590, Sep 2025. URL: https://doi.org/10.1002/cbin.70087, doi:10.1002/cbin.70087. This article has 0 citations and is from a peer-reviewed journal.
(chan2024advancingclinicalresponse pages 1-4): Priscilla Chan, Yoshiko Nagai, Qiulian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Jiarui Wang, Gevorg Karapetyan, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Rex A. Moats, Tsuyoshi Hirota, Jeremy N. Rich, and Steve A. Kay. Advancing clinical response against glioblastoma: evaluating shp1705 cry2 activator efficacy in preclinical models and safety in phase i trials. bioRxiv, Sep 2024. URL: https://doi.org/10.1101/2024.09.17.613520, doi:10.1101/2024.09.17.613520. This article has 1 citations.
(chan2024advancingclinicalresponse media 0254a939): Priscilla Chan, Yoshiko Nagai, Qiulian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Jiarui Wang, Gevorg Karapetyan, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Rex A. Moats, Tsuyoshi Hirota, Jeremy N. Rich, and Steve A. Kay. Advancing clinical response against glioblastoma: evaluating shp1705 cry2 activator efficacy in preclinical models and safety in phase i trials. bioRxiv, Sep 2024. URL: https://doi.org/10.1101/2024.09.17.613520, doi:10.1101/2024.09.17.613520. This article has 1 citations.
(chan2024advancingclinicalresponse media bc968ea3): Priscilla Chan, Yoshiko Nagai, Qiulian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Jiarui Wang, Gevorg Karapetyan, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Rex A. Moats, Tsuyoshi Hirota, Jeremy N. Rich, and Steve A. Kay. Advancing clinical response against glioblastoma: evaluating shp1705 cry2 activator efficacy in preclinical models and safety in phase i trials. bioRxiv, Sep 2024. URL: https://doi.org/10.1101/2024.09.17.613520, doi:10.1101/2024.09.17.613520. This article has 1 citations.
(toda2025targetingcryptochromesin pages 12-12): Takuro Toda and Tsuyoshi Hirota. Targeting cryptochromes in chronic diseases. Cell Biology International, 49(12):1579-1590, Sep 2025. URL: https://doi.org/10.1002/cbin.70087, doi:10.1002/cbin.70087. This article has 0 citations and is from a peer-reviewed journal.
(chan2025advancingclinicalresponse pages 1-2): Priscilla Chan, Yoshiko Nagai, Qiulian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Jiarui Wang, Gevorg Karapetyan, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Rex A. Moats, Tsuyoshi Hirota, Jeremy N. Rich, and Steve A. Kay. Advancing clinical response against glioblastoma: evaluating shp1705 cry2 activator efficacy in preclinical models and safety in phase i trials. Neuro-oncology, Apr 2025. URL: https://doi.org/10.1093/neuonc/noaf089, doi:10.1093/neuonc/noaf089. This article has 10 citations and is from a domain leading peer-reviewed journal.
(farmakis2024th301emergesas pages 1-2): Danae Farmakis, Dimitrios J. Stravopodis, and Anastasia Prombona. Th301 emerges as a novel anti-oncogenic agent for human pancreatic cancer cells: the dispensable roles of p53, cry2 and bmal1 in th301-induced cdkn1a/p21cip1/waf1 upregulation. International Journal of Molecular Sciences, 26:178, Dec 2024. URL: https://doi.org/10.3390/ijms26010178, doi:10.3390/ijms26010178. This article has 1 citations.
id: Q49AN0
gene_symbol: CRY2
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: Cryptochrome-2 (CRY2) is a flavoprotein member of the cryptochrome/photolyase family that
functions as a light-independent transcriptional repressor in the mammalian circadian clock. CRY2 heterodimerizes
with PER proteins (PER1, PER2, PER3) and translocates to the nucleus where the PER-CRY complex inhibits
CLOCK:BMAL1-driven transcription, forming the negative limb of the transcription-translation feedback
loop (TTFL). CRY2 retains a photolyase homology region with an FAD-binding pocket that serves as a regulatory
hub for ubiquitin ligase recognition (FBXL3, FBXL21) and small-molecule stabilizers rather than for
photoreception. CRY2 lacks DNA photolyase activity but can bind DNA weakly. CRY2 also inhibits protein
phosphatase 5 (PP5) activity, interacts with nuclear receptors (glucocorticoid receptor, HNF4A) in a
ligand-dependent manner, and contributes to glucose and glucocorticoid homeostasis. CRY2 stability is
regulated by phosphorylation-dependent ubiquitination via SCF(FBXL3) and SCF(FBXL21) complexes, and
by PER2-mediated protection from degradation.
alternative_products:
- name: '1'
id: Q49AN0-1
- name: '2'
id: Q49AN0-2
sequence_note: VSP_038970
existing_annotations:
- term:
id: GO:0005634
label: nucleus
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: CRY2 localizes to the nucleus where it functions as a transcriptional repressor. UniProt
curated location confirms nuclear localization (PMID:9801304, PMID:22798407). IBA annotation is
phylogenetically well-supported across cryptochromes.
action: ACCEPT
reason: Nuclear localization is well-established for CRY2 and is essential for its transcriptional
repressor function in the TTFL.
supported_by:
- reference_id: Q49AN0
supporting_text: Nucleus {ECO:0000269|PubMed:22798407, ECO:0000269|PubMed:9801304}
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: CRY2 localizes to the cytoplasm before nuclear translocation as part of the PER-CRY complex.
UniProt curated location confirms cytoplasmic localization (PMID:9801304).
action: ACCEPT
reason: Cytoplasmic localization is well-established; CRY2 accumulates in the cytoplasm and translocates
to the nucleus through interaction with PER2 or BMAL1.
supported_by:
- reference_id: Q49AN0
supporting_text: Cytoplasm {ECO:0000269|PubMed:9801304}
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: CRY2 is a core transcriptional repressor in the mammalian circadian clock. It suppresses
CLOCK:BMAL1-driven transcription of Per, Cry, Dec1, Dec2, and other E-box-containing genes (PMID:12397359,
PMID:14672706, PMID:15147242).
action: ACCEPT
reason: Transcriptional repression is the primary molecular function of CRY2. Multiple independent
studies demonstrate CRY2 suppresses CLOCK:BMAL1-induced transcription.
supported_by:
- reference_id: PMID:12397359
supporting_text: Cry proteins to inhibit Per transcription
- reference_id: PMID:14672706
supporting_text: PERs and CRYs suppressed the induced expression
- term:
id: GO:0003677
label: DNA binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Purified hCRY2 binds dsDNA weakly and ssDNA with higher affinity (PMID:12627958). However,
CRY2 represses transcription primarily through protein-protein interactions with CLOCK:BMAL1 rather
than direct DNA binding. DNA binding is a vestigial property from the photolyase ancestor.
action: KEEP_AS_NON_CORE
reason: DNA binding is experimentally demonstrated but is not the primary mechanism by which CRY2
functions in transcriptional repression. It is a retained ancestral property from the photolyase
family.
supported_by:
- reference_id: PMID:12627958
supporting_text: binds to double-stranded DNA weakly and to single-stranded DNA with higher affinity
- term:
id: GO:0032922
label: circadian regulation of gene expression
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: CRY2 is a core component of the circadian TTFL that regulates rhythmic gene expression through
repression of CLOCK:BMAL1 transcriptional activity (PMID:10531061, PMID:20840750).
action: ACCEPT
reason: Circadian regulation of gene expression is the primary biological process in which CRY2 functions.
This is well-supported by multiple lines of evidence.
supported_by:
- reference_id: PMID:20840750
supporting_text: negatively regulate the transcription of Per and Cry core clock genes
- reference_id: Q49AN0
supporting_text: Transcriptional repressor which forms a core component of the circadian clock
- term:
id: GO:0043153
label: entrainment of circadian clock by photoperiod
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Mammalian CRY proteins function as light-independent transcriptional repressors, not as photoreceptors
for entrainment. Unlike Drosophila and plant cryptochromes, mammalian CRYs do not serve as circadian
photoreceptors (PMID:10531061). The IBA annotation may reflect ancestral function in non-mammalian
family members.
action: REMOVE
reason: Griffin et al. 1999 (PMID:10531061) demonstrated a light-independent role of CRY1 and CRY2
in the mammalian circadian clock. Mammalian CRY2 is not involved in photic entrainment; this function
is mediated by retinal photoreceptors signaling to the SCN.
supported_by:
- reference_id: Q49AN0
supporting_text: Transcriptional repressor which forms a core component of the circadian clock
- term:
id: GO:0071949
label: FAD binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: CRY2 binds FAD, confirmed by purification studies showing FAD and pterin cofactors (PMID:8909283).
However, FAD binding is weak in mammalian CRYs and the FAD pocket primarily serves as a regulatory
hub for FBXL3 recognition and small-molecule binding rather than for catalytic or photochemical
function.
action: ACCEPT
reason: FAD binding is experimentally demonstrated and the FAD pocket is functionally important for
CRY2 regulation, even though FAD occupancy is low.
supported_by:
- reference_id: PMID:8909283
supporting_text: were found to contain FAD and a pterin cofactor
- term:
id: GO:0000166
label: nucleotide binding
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: CRY2 binds FAD, which is a dinucleotide cofactor. The nucleotide binding annotation is a
broader parent of the more informative FAD binding term.
action: ACCEPT
reason: This is a valid broader term that follows from the FAD binding annotation. As an IEA mapped
from the UniProt nucleotide-binding keyword, it is appropriately general.
supported_by:
- reference_id: Q49AN0
supporting_text: Binds 1 FAD per subunit
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Duplicate IEA annotation for nucleus. Consistent with IBA and ISS annotations and UniProt
curated localization.
action: ACCEPT
reason: Nuclear localization is well-established for CRY2.
supported_by:
- reference_id: Q49AN0
supporting_text: Nucleus {ECO:0000269|PubMed:22798407, ECO:0000269|PubMed:9801304}
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: Duplicate IEA annotation for cytoplasm. Consistent with IBA annotation and UniProt curated
localization.
action: ACCEPT
reason: Cytoplasmic localization is well-established for CRY2.
supported_by:
- reference_id: Q49AN0
supporting_text: Cytoplasm {ECO:0000269|PubMed:9801304}
- term:
id: GO:0009881
label: photoreceptor activity
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: Mammalian CRY2 does not function as a photoreceptor. This IEA annotation derives from the
UniProt keyword "Photoreceptor protein" which is a legacy designation based on the photolyase family
membership. Griffin et al. 1999 (PMID:10531061) established the light-independent function of mammalian
CRYs.
action: REMOVE
reason: Mammalian CRY2 functions as a light-independent transcriptional repressor. There is no evidence
that human CRY2 has photoreceptor activity. The UniProt keyword is misleading for the mammalian
protein.
supported_by:
- reference_id: PMID:8909283
supporting_text: may function as blue-light photoreceptors in humans
- reference_id: Q49AN0
supporting_text: Transcriptional repressor which forms a core component of the circadian clock
- term:
id: GO:0019902
label: phosphatase binding
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: hCRY2 specifically interacts with protein serine/threonine phosphatase 5 (PP5) via yeast
two-hybrid and inhibits its phosphatase activity (PMID:9383998). This is a well-characterized direct
interaction.
action: ACCEPT
reason: Direct phosphatase binding is experimentally demonstrated for CRY2 with PP5 (PMID:9383998).
The IEA annotation is consistent with the experimental evidence.
supported_by:
- reference_id: PMID:9383998
supporting_text: protein serine/threonine phosphatase 5 (PP5) that contains the TPR motif specifically
interacted with hCRY2
- term:
id: GO:0048511
label: rhythmic process
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: CRY2 is a core circadian clock component. The rhythmic process annotation is a valid broader
term encompassing its role in circadian rhythms.
action: ACCEPT
reason: CRY2 is a core component of the circadian clock and participates in generating approximately
24-hour rhythms in gene expression and physiology.
supported_by:
- reference_id: Q49AN0
supporting_text: Transcriptional repressor which forms a core component of the circadian clock
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16790549
review:
summary: PMID:16790549 demonstrates CRY2 interacts with PP5 (PPP5C) to modulate CKIepsilon phosphorylation.
The specific interaction is better captured by the phosphatase binding (GO:0019902) and protein
phosphatase inhibitor activity (GO:0004864) annotations already present.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding does not convey the specific functional interaction between CRY2 and
PP5. More informative terms (phosphatase binding, protein phosphatase inhibitor activity) are already
annotated.
supported_by:
- reference_id: PMID:16790549
supporting_text: cryptochrome regulates clock protein phosphorylation by modulating the effect of
PP5 on CKIepsilon
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
review:
summary: Large-scale proteome interactome mapping study. Generic protein binding from high-throughput
screens is uninformative.
action: MARK_AS_OVER_ANNOTATED
reason: High-throughput interactome mapping does not provide functional insight beyond generic protein
binding. More specific interaction terms should be used where validated.
supported_by:
- reference_id: PMID:25416956
supporting_text: A proteome-scale map of the human interactome network
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
review:
summary: Binary interactome reference map study. This is a high-throughput screen reporting many interaction
partners. Generic protein binding from such studies is uninformative.
action: MARK_AS_OVER_ANNOTATED
reason: High-throughput binary interactome mapping provides no functional specificity for CRY2 interactions.
Many of the reported partners (keratin associated proteins, etc.) may represent false positives
or indirect interactions.
supported_by:
- reference_id: PMID:32296183
supporting_text: A reference map of the human binary protein interactome
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32814053
review:
summary: Neurodegenerative disease interactome mapping study. Generic protein binding annotation from
a high-throughput screen.
action: MARK_AS_OVER_ANNOTATED
reason: High-throughput interactome mapping does not provide functional specificity for CRY2 interactions.
supported_by:
- reference_id: PMID:32814053
supporting_text: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
- term:
id: GO:0000976
label: transcription cis-regulatory region binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: This annotation is transferred from mouse CRY2 (Q9R194). CRY2 does not bind cis-regulatory
regions specifically; its DNA binding is non-specific and weak (PMID:12627958). CRY2 represses transcription
through protein-protein interactions with CLOCK:BMAL1 rather than through direct cis-regulatory
element binding.
action: MODIFY
reason: CRY2 binds DNA non-specifically and weakly. The term "transcription cis-regulatory region
binding" implies sequence-specific DNA binding which is not demonstrated for CRY2. A general DNA
binding term is more appropriate.
proposed_replacement_terms:
- id: GO:0003677
label: DNA binding
supported_by:
- reference_id: PMID:12627958
supporting_text: binds to double-stranded DNA weakly and to single-stranded DNA with higher affinity
- term:
id: GO:0005739
label: mitochondrion
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: CRY2 is well-characterized as a cytoplasmic/nuclear protein. Mitochondrial localization is
not supported by any direct evidence for CRY2. UniProt curated localization reports only cytoplasm
and nucleus.
action: REMOVE
reason: No evidence supports mitochondrial localization of CRY2. UniProt curated location indicates
only cytoplasm and nucleus.
supported_by:
- reference_id: Q49AN0
supporting_text: Cytoplasm {ECO:0000269|PubMed:9801304}. Nucleus {ECO:0000269|PubMed:22798407, ECO:0000269|PubMed:9801304}
- term:
id: GO:0009416
label: response to light stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Transferred from mouse CRY2. Mammalian CRY2 functions as a light-independent transcriptional
repressor (PMID:10531061). While CRY2 retains a photolyase-like fold with FAD binding, it does not
function as a light sensor in mammals.
action: REMOVE
reason: Mammalian CRY2 has a well-established light-independent role in the circadian clock. The response
to light stimulus annotation is based on ancestral function from the photolyase family that is not
retained in mammalian cryptochromes.
supported_by:
- reference_id: Q49AN0
supporting_text: Transcriptional repressor which forms a core component of the circadian clock
- term:
id: GO:0014823
label: response to activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Transferred from mouse CRY2. UniProt mentions CRY2 represses PPARD and limits exercise capacity
(by similarity). This would be a downstream pleiotropic effect of circadian clock function rather
than a core function of CRY2.
action: KEEP_AS_NON_CORE
reason: CRY2 may indirectly affect exercise-related physiology through transcriptional repression
of PPARD in skeletal muscle. This is a secondary downstream effect of circadian regulation, not
a core function.
supported_by:
- reference_id: Q49AN0
supporting_text: Represses PPARD and its target genes in the skeletal muscle and limits exercise
capacity (By similarity)
- term:
id: GO:0016922
label: nuclear receptor binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: CRY2 interacts with the glucocorticoid receptor (NR3C1/GR) in a ligand-dependent manner (PMID:22170608)
and with HNF4A (PMID:30530698). UniProt also reports interactions with AR, PPARA, PPARD, PPARG,
NR1I2, NR1I3, and VDR.
action: ACCEPT
reason: Nuclear receptor binding is well-supported by multiple studies demonstrating direct ligand-dependent
interactions between CRY2 and various nuclear receptors including GR, HNF4A, and others.
supported_by:
- reference_id: PMID:22170608
supporting_text: cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent
fashion
- reference_id: PMID:30530698
supporting_text: HNF4A strongly transrepresses the transcriptional activity of the CLOCK:BMAL1 heterodimer
- term:
id: GO:0019900
label: kinase binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: CRY2 modulates CKIepsilon (CSNK1E) activity through PP5 interaction (PMID:16790549). UniProt
reports phosphorylation by CSNK1E requires interaction with PER1 or PER2, suggesting indirect rather
than direct kinase binding. However, the circadian core oscillator complex includes CSNK1D/CSNK1E
as components.
action: KEEP_AS_NON_CORE
reason: CRY2 interacts with kinases as part of the circadian repressor complex but direct kinase binding
has not been definitively demonstrated independent of complex partners. The interaction may be mediated
through PER proteins.
supported_by:
- reference_id: PMID:16790549
supporting_text: cryptochrome regulates clock protein phosphorylation by modulating the effect of
PP5 on CKIepsilon
- reference_id: Q49AN0
supporting_text: Phosphorylation by CSKNE requires interaction with PER1 or PER2
- term:
id: GO:0019901
label: protein kinase binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Similar to kinase binding above. CRY2 is part of a complex with CSNK1D/CSNK1E but direct
protein kinase binding independent of PER proteins is not well-demonstrated.
action: KEEP_AS_NON_CORE
reason: CRY2 functions in a complex containing protein kinases (CSNK1D/CSNK1E) but direct binding
may be mediated through PER protein intermediaries.
supported_by:
- reference_id: Q49AN0
supporting_text: Component of the circadian core oscillator, which includes the CRY proteins, CLOCK
or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E
- term:
id: GO:0019915
label: lipid storage
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: UniProt notes CRY2 plays a key role in lipid metabolism modulation through transcriptional
regulation of genes like ACSL4. CRY2 repression via PER2 promotes adipogenesis through circadian
control of Wnt signaling. However, lipid storage per se is a downstream pleiotropic consequence
of circadian regulation.
action: KEEP_AS_NON_CORE
reason: CRY2 contributes to lipid metabolism modulation through transcriptional regulation, which
is a downstream effect of its circadian clock function rather than a direct role in lipid storage.
supported_by:
- reference_id: Q49AN0
supporting_text: 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
- term:
id: GO:0032868
label: response to insulin
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Loss of cryptochromes causes glucose intolerance (PMID:22170608), which relates to insulin
responsiveness. However, this is a downstream metabolic consequence of cryptochrome deficiency affecting
glucocorticoid signaling and glucose homeostasis rather than a direct insulin response function.
action: KEEP_AS_NON_CORE
reason: CRY2 affects insulin sensitivity indirectly through its role in circadian regulation of glucocorticoid
signaling and glucose metabolism. This is a pleiotropic downstream effect rather than a core function.
supported_by:
- reference_id: PMID:22170608
supporting_text: genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively
high levels of circulating corticosterone
- term:
id: GO:0032922
label: circadian regulation of gene expression
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate IEA annotation for circadian regulation of gene expression. Consistent with IBA
and other annotations.
action: ACCEPT
reason: Circadian regulation of gene expression is a core function of CRY2, well-supported across
multiple evidence types.
supported_by:
- reference_id: PMID:20840750
supporting_text: negatively regulate the transcription of Per and Cry core clock genes
- term:
id: GO:0042593
label: glucose homeostasis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Cryptochrome deficiency causes glucose intolerance and elevated corticosterone (PMID:22170608).
CRY2 may mediate circadian regulation of cAMP signaling and gluconeogenesis. This is a downstream
metabolic effect of circadian clock function.
action: KEEP_AS_NON_CORE
reason: Glucose homeostasis is affected by CRY2 through its circadian regulation of glucocorticoid
signaling and gluconeogenesis, but this is a pleiotropic downstream effect rather than a core molecular
function.
supported_by:
- reference_id: PMID:22170608
supporting_text: genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively
high levels of circulating corticosterone
- term:
id: GO:0042752
label: regulation of circadian rhythm
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: CRY2 is a core circadian clock component. CRY1 and CRY2 encode inhibitors of the CLOCK:BMAL1
complex and their degradation by SCF(FBXL3) is essential for clock oscillation (PMID:17463251).
action: ACCEPT
reason: CRY2 is a core component of the circadian clock regulatory mechanism.
supported_by:
- reference_id: PMID:17463251
supporting_text: Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback
loop
- term:
id: GO:0042754
label: negative regulation of circadian rhythm
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: CRY2 functions as part of the negative limb of the circadian TTFL, inhibiting CLOCK:BMAL1
activity (PMID:17463251, PMID:10531061).
action: ACCEPT
reason: CRY2 is a negative regulator in the circadian feedback loop, directly inhibiting the positive
limb (CLOCK:BMAL1) of the clock.
supported_by:
- reference_id: PMID:17463251
supporting_text: Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback
loop
- term:
id: GO:0043153
label: entrainment of circadian clock by photoperiod
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate IEA annotation. Mammalian CRY2 is not involved in photic entrainment of the circadian
clock.
action: REMOVE
reason: Mammalian CRY2 functions as a light-independent transcriptional repressor (PMID:10531061).
Photic entrainment in mammals is mediated by retinal photoreceptors, not by cryptochromes.
supported_by:
- reference_id: Q49AN0
supporting_text: Transcriptional repressor which forms a core component of the circadian clock
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate IEA annotation. Consistent with IBA and IDA annotations for transcriptional repression.
action: ACCEPT
reason: Negative regulation of transcription is the primary molecular function of CRY2.
supported_by:
- reference_id: PMID:12397359
supporting_text: Cry proteins to inhibit Per transcription
- term:
id: GO:0071949
label: FAD binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate IEA annotation for FAD binding. Consistent with IBA and ISS annotations.
action: ACCEPT
reason: FAD binding is experimentally demonstrated for CRY2.
supported_by:
- reference_id: PMID:8909283
supporting_text: were found to contain FAD and a pterin cofactor
- term:
id: GO:2000323
label: negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Cryptochromes interact with the glucocorticoid receptor and broadly oppose GR activation
while promoting GR-mediated repression (PMID:22170608). CRY deficiency vastly decreases gene repression
and approximately doubles dexamethasone-induced genes.
action: KEEP_AS_NON_CORE
reason: While well-supported by PMID:22170608, regulation of glucocorticoid signaling is a downstream
function of CRY2 nuclear receptor binding rather than a core clock function. It represents an important
secondary output of the circadian clock.
supported_by:
- reference_id: PMID:22170608
supporting_text: cryptochrome deficiency vastly decreases gene repression and approximately doubles
the number of dexamethasone-induced genes, suggesting that cryptochromes broadly oppose glucocorticoid
receptor activation and promote repression
- term:
id: GO:2000850
label: negative regulation of glucocorticoid secretion
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Loss of cryptochromes leads to constitutively high circulating corticosterone levels, suggesting
reduced suppression of the hypothalamic-pituitary-adrenal axis (PMID:22170608).
action: KEEP_AS_NON_CORE
reason: While well-supported, regulation of glucocorticoid secretion is a downstream physiological
consequence of CRY2 function in the circadian clock and its interaction with the glucocorticoid
receptor. This is a secondary output rather than a core molecular function.
supported_by:
- reference_id: PMID:22170608
supporting_text: genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively
high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal
axis
- term:
id: GO:0005829
label: cytosol
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: HPA immunofluorescence data supports cytosolic localization of CRY2. This is consistent with
the broader cytoplasm annotation.
action: ACCEPT
reason: Cytosolic localization is consistent with the established cytoplasmic/nuclear distribution
of CRY2. HPA provides IDA-level evidence from immunofluorescence.
supported_by:
- reference_id: Q49AN0
supporting_text: Cytoplasm {ECO:0000269|PubMed:9801304}
- term:
id: GO:0016607
label: nuclear speck
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: HPA immunofluorescence data indicates nuclear speck localization. This is IDA evidence from
the Human Protein Atlas. Nuclear specks are subnuclear structures enriched in RNA splicing factors.
While the HPA staining pattern may show punctate nuclear signal, nuclear speck localization has
not been independently confirmed for CRY2 in the literature.
action: UNDECIDED
reason: The HPA immunofluorescence data may show punctate nuclear staining consistent with nuclear
specks, but this has not been validated by independent studies. Without access to the specific HPA
images and co-localization data with speck markers, it is difficult to confirm this specific subnuclear
localization.
supported_by:
- reference_id: Q49AN0
supporting_text: Nucleus {ECO:0000269|PubMed:22798407, ECO:0000269|PubMed:9801304}
- term:
id: GO:0032922
label: circadian regulation of gene expression
evidence_type: NAS
original_reference_id: PMID:20840750
review:
summary: PMID:20840750 identifies CRY2 residues essential for PER2 interaction in the negative arm
of the circadian feedback loop (PMID:20840750).
action: ACCEPT
reason: The study provides direct evidence that CRY2-PER2 interaction is essential for the circadian
transcriptional repression mechanism.
supported_by:
- reference_id: PMID:20840750
supporting_text: negatively regulate the transcription of Per and Cry core clock genes
- term:
id: GO:0042754
label: negative regulation of circadian rhythm
evidence_type: NAS
original_reference_id: PMID:20840750
review:
summary: CRY2 represses CLOCK:BMAL1 as part of the negative limb of the circadian clock. PMID:20840750
characterizes the CRY2-PER2 interaction interface essential for this repression.
action: ACCEPT
reason: CRY2 is a well-established negative regulator in the circadian feedback loop.
supported_by:
- reference_id: PMID:17463251
supporting_text: Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback
loop
- term:
id: GO:0004864
label: protein phosphatase inhibitor activity
evidence_type: IDA
original_reference_id: PMID:9383998
review:
summary: hCRY2 inhibits the phosphatase activity of PP5. Zhao and Sancar 1997 demonstrated that hCRY2,
but not the highly homologous (6-4) photolyase, specifically inhibits PP5 phosphatase activity (PMID:9383998).
action: ACCEPT
reason: This is a well-characterized direct enzymatic inhibition demonstrated by direct assay. CRY2
specifically inhibits PP5, and this interaction is relevant to circadian clock regulation through
modulation of CKIepsilon phosphorylation.
supported_by:
- reference_id: PMID:9383998
supporting_text: hCRY2, but not the highly homologous (6-4) photolyase, inhibits the phosphatase
activity of PP5
- term:
id: GO:0009416
label: response to light stimulus
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation transferred from mouse CRY2 (Q9R194). Mammalian CRY2 functions as a light-independent
transcriptional repressor (PMID:10531061).
action: REMOVE
reason: Mammalian CRY2 has a light-independent role in the circadian clock. Response to light stimulus
is not a function of human CRY2.
supported_by:
- reference_id: Q49AN0
supporting_text: Transcriptional repressor which forms a core component of the circadian clock
- term:
id: GO:0014823
label: response to activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation transferred from mouse CRY2. UniProt notes CRY2 represses PPARD in skeletal
muscle and limits exercise capacity (by similarity). This is a downstream pleiotropic effect.
action: KEEP_AS_NON_CORE
reason: CRY2 may indirectly affect exercise-related physiology through transcriptional repression
of PPARD, but this is a secondary downstream effect of circadian regulation.
supported_by:
- reference_id: Q49AN0
supporting_text: Represses PPARD and its target genes in the skeletal muscle and limits exercise
capacity (By similarity)
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:30530698
review:
summary: PMID:30530698 demonstrates CRY2 interacts with HNF4A, a nuclear receptor. The specific interaction
is better captured by the nuclear receptor binding annotation (GO:0016922).
action: MODIFY
reason: The interaction between CRY2 and HNF4A is a specific nuclear receptor binding interaction.
Generic protein binding does not convey the functional specificity of this interaction.
proposed_replacement_terms:
- id: GO:0016922
label: nuclear receptor binding
supported_by:
- reference_id: PMID:30530698
supporting_text: HNF4A strongly transrepresses the transcriptional activity of the CLOCK:BMAL1 heterodimer
- term:
id: GO:0009416
label: response to light stimulus
evidence_type: IMP
original_reference_id: PMID:15751956
review:
summary: PMID:15751956 (Partch et al. 2005) demonstrates a light-dependent conformational change in
the C-terminal domain of Arabidopsis Cry1, not human CRY2. The paper also characterizes the CRY2
photolyase homology region structure but does not demonstrate a light response for human CRY2. This
IMP annotation from CAFA appears to be a misannotation.
action: REMOVE
reason: The paper primarily characterizes Arabidopsis Cry1 light-dependent conformational changes.
It does not demonstrate a light response function for human CRY2. The IMP evidence code is inappropriate
for this reference.
supported_by:
- reference_id: PMID:15751956
supporting_text: we demonstrate a light-dependent conformational change in the C-terminal domain
of Arabidopsis Cry1
- term:
id: GO:0042752
label: regulation of circadian rhythm
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation from mouse CRY2. CRY2 is a core circadian clock component, well-established
as a regulator of circadian rhythm.
action: ACCEPT
reason: CRY2 is a core component of the circadian clock mechanism.
supported_by:
- reference_id: PMID:17463251
supporting_text: Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback
loop
- term:
id: GO:0043153
label: entrainment of circadian clock by photoperiod
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation from mouse CRY2. Mammalian CRY2 is not involved in photic entrainment.
action: REMOVE
reason: Mammalian CRY2 functions as a light-independent transcriptional repressor (PMID:10531061).
Photic entrainment is not a function of mammalian CRY.
supported_by:
- reference_id: Q49AN0
supporting_text: Transcriptional repressor which forms a core component of the circadian clock
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:12397359
review:
summary: Dec1 and Dec2 study (Honma et al. 2002) shows Cry proteins together with Per proteins inhibit
Per transcription by closing the autoregulatory feedback loop.
action: ACCEPT
reason: Direct experimental evidence that Cry proteins inhibit Per transcription, a core function
of CRY2.
supported_by:
- reference_id: PMID:12397359
supporting_text: Protein products of Per act together with Cry proteins to inhibit Per transcription,
thus closing the autoregulatory feedback loop
- term:
id: GO:0032922
label: circadian regulation of gene expression
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation from mouse CRY2. Consistent with the well-established role of CRY2 in circadian
gene regulation.
action: ACCEPT
reason: Circadian regulation of gene expression is a core function of CRY2.
supported_by:
- reference_id: PMID:20840750
supporting_text: negatively regulate the transcription of Per and Cry core clock genes
- term:
id: GO:0042593
label: glucose homeostasis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation from mouse CRY2. Cryptochrome deficiency causes glucose intolerance (PMID:22170608).
This is a downstream metabolic effect.
action: KEEP_AS_NON_CORE
reason: Glucose homeostasis is affected by CRY2 through its circadian regulation of glucocorticoid
signaling, but this is a pleiotropic downstream effect.
supported_by:
- reference_id: PMID:22170608
supporting_text: genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance
- term:
id: GO:2000323
label: negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation from mouse CRY2. Cryptochromes broadly oppose GR activation (PMID:22170608).
This is a well-supported secondary function.
action: KEEP_AS_NON_CORE
reason: Regulation of glucocorticoid signaling is a downstream output of CRY2 nuclear receptor binding,
not a core clock function.
supported_by:
- reference_id: PMID:22170608
supporting_text: cryptochromes broadly oppose glucocorticoid receptor activation and promote repression
- term:
id: GO:0000976
label: transcription cis-regulatory region binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation from mouse CRY2. CRY2 binds DNA non-specifically rather than at specific cis-regulatory
regions.
action: MODIFY
reason: CRY2 does not specifically bind cis-regulatory regions. Its DNA binding is non-specific and
weak. A general DNA binding term is more appropriate.
proposed_replacement_terms:
- id: GO:0003677
label: DNA binding
supported_by:
- reference_id: PMID:12627958
supporting_text: binds to double-stranded DNA weakly and to single-stranded DNA with higher affinity
- term:
id: GO:0042754
label: negative regulation of circadian rhythm
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation from mouse CRY2. CRY2 functions as a negative regulator in the circadian feedback
loop.
action: ACCEPT
reason: CRY2 inhibits CLOCK:BMAL1 in the negative arm of the circadian clock.
supported_by:
- reference_id: PMID:17463251
supporting_text: Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback
loop
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation from mouse CRY2. Consistent with the core transcriptional repressor function
of CRY2.
action: ACCEPT
reason: Negative regulation of transcription is the primary molecular function of CRY2.
supported_by:
- reference_id: PMID:20840750
supporting_text: negatively regulate the transcription of Per and Cry core clock genes
- term:
id: GO:0071949
label: FAD binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation from mouse CRY2. FAD binding is experimentally confirmed for human CRY2.
action: ACCEPT
reason: FAD binding is directly demonstrated for purified human CRY2.
supported_by:
- reference_id: PMID:8909283
supporting_text: were found to contain FAD and a pterin cofactor
- term:
id: GO:0007623
label: circadian rhythm
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: CRY2 is a core component of the mammalian circadian clock, essential for generating approximately
24-hour rhythms.
action: ACCEPT
reason: CRY2 is a well-established core circadian clock component. Mice lacking both CRY1 and CRY2
are completely arrhythmic.
supported_by:
- reference_id: Q49AN0
supporting_text: Transcriptional repressor which forms a core component of the circadian clock
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9383998
review:
summary: PMID:9383998 demonstrates CRY2 specifically interacts with PP5. More informative terms (phosphatase
binding, protein phosphatase inhibitor activity) are already annotated for this interaction.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding does not convey the specific functional interaction. Phosphatase binding
(GO:0019902) and protein phosphatase inhibitor activity (GO:0004864) from the same reference are
more informative.
supported_by:
- reference_id: PMID:9383998
supporting_text: protein serine/threonine phosphatase 5 (PP5) that contains the TPR motif specifically
interacted with hCRY2
- term:
id: GO:0019902
label: phosphatase binding
evidence_type: IPI
original_reference_id: PMID:9383998
review:
summary: Zhao and Sancar 1997 demonstrated by yeast two-hybrid that PP5 specifically interacts with
hCRY2 (PMID:9383998). This is a well-characterized direct interaction.
action: ACCEPT
reason: Direct experimental evidence for CRY2-PP5 interaction by yeast two-hybrid assay.
supported_by:
- reference_id: PMID:9383998
supporting_text: protein serine/threonine phosphatase 5 (PP5) that contains the TPR motif specifically
interacted with hCRY2
- term:
id: GO:0005576
label: extracellular region
evidence_type: IDA
original_reference_id: PMID:9753616
review:
summary: PMID:9753616 (Ishibashi et al. 1998) describes the cloning of stanniocalcin-2 (STC2), an
unrelated protein. This appears to be a misannotation where the wrong gene was associated with this
reference. CRY2 is not an extracellular protein.
action: REMOVE
reason: The cited reference is about STC2 (stanniocalcin-2), not CRY2. This is a clear misannotation.
CRY2 is an intracellular protein localized to cytoplasm and nucleus.
supported_by:
- reference_id: PMID:9753616
supporting_text: Molecular cloning of a second human stanniocalcin homologue (STC2)
- term:
id: GO:2000118
label: regulation of sodium-dependent phosphate transport
evidence_type: IDA
original_reference_id: PMID:9753616
review:
summary: PMID:9753616 describes STC2-mediated inhibition of sodium-phosphate cotransporter. This is
unrelated to CRY2. This is a clear misannotation.
action: REMOVE
reason: The cited reference concerns STC2 (stanniocalcin-2) biology, not CRY2. CRY2 has no demonstrated
role in phosphate transport regulation.
supported_by:
- reference_id: PMID:9753616
supporting_text: STC2-transfected CHO cells inhibited the promoter activity of Na-phosphate cotransporter
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:12397359
review:
summary: Honma et al. 2002 demonstrated that Cry proteins act together with Per proteins to inhibit
CLOCK:BMAL1-driven transcription from E-box elements in the Per1 promoter (PMID:12397359). This
is RNA Pol II-dependent transcription.
action: ACCEPT
reason: CRY2 inhibits CLOCK:BMAL1-driven transcription from E-box elements, which are RNA polymerase
II promoter elements.
supported_by:
- reference_id: PMID:12397359
supporting_text: Protein products of Per act together with Cry proteins to inhibit Per transcription,
thus closing the autoregulatory feedback loop
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:14672706
review:
summary: Kawamoto et al. 2004 showed PERs and CRYs suppressed CLOCK/BMAL-induced expression of Dec1
through E-box elements (PMID:14672706).
action: ACCEPT
reason: Direct experimental evidence that CRY proteins suppress CLOCK/BMAL-induced transcription from
E-box-containing promoters.
supported_by:
- reference_id: PMID:14672706
supporting_text: PERs and CRYs suppressed the induced expression
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:15147242
review:
summary: Hamaguchi et al. 2004 showed Cry suppressed Clock/Bmal-induced transcription from the Dec2
promoter (PMID:15147242).
action: ACCEPT
reason: Direct experimental evidence that Cry proteins suppress CLOCK/BMAL-induced transcription of
Dec2.
supported_by:
- reference_id: PMID:15147242
supporting_text: Like Dec, Cry and Per also suppressed Clock/Bmal-induced transcription
from the Dec2 promoter
- term:
id: GO:0005634
label: nucleus
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: ISS annotation from mouse CRY2 for nuclear localization. Consistent with direct evidence
from human cells.
action: ACCEPT
reason: Nuclear localization is well-established for CRY2 by multiple lines of evidence.
supported_by:
- reference_id: Q49AN0
supporting_text: Nucleus {ECO:0000269|PubMed:22798407, ECO:0000269|PubMed:9801304}
- term:
id: GO:0009785
label: blue light signaling pathway
evidence_type: NAS
original_reference_id: PMID:8909283
review:
summary: Hsu et al. 1996 initially hypothesized human CRY proteins may function as blue-light photoreceptors
(PMID:8909283). However, subsequent work by Griffin et al. 1999 (PMID:10531061) established that
mammalian CRYs function as light-independent transcriptional repressors. There is no evidence for
blue light signaling by human CRY2.
action: REMOVE
reason: The original NAS annotation was based on a hypothesis that has been superseded by definitive
evidence that mammalian CRY2 functions as a light-independent repressor. Human CRY2 does not participate
in blue light signaling.
supported_by:
- reference_id: PMID:8909283
supporting_text: may function as blue-light photoreceptors in humans
- term:
id: GO:0009882
label: blue light photoreceptor activity
evidence_type: NAS
original_reference_id: PMID:8909283
review:
summary: Hsu et al. 1996 speculated CRY proteins may be blue-light photoreceptors (PMID:8909283),
but Griffin et al. 1999 (PMID:10531061) demonstrated a light-independent role for mammalian CRYs.
Human CRY2 has no demonstrated photoreceptor activity.
action: REMOVE
reason: The original NAS annotation was speculative. Mammalian CRY2 does not function as a blue light
photoreceptor. The annotation should be removed rather than merely marked as over-annotated because
the function is not supported by any evidence.
supported_by:
- reference_id: PMID:8909283
supporting_text: may function as blue-light photoreceptors in humans
- term:
id: GO:0000719
label: photoreactive repair
evidence_type: IDA
original_reference_id: PMID:12627958
negated: true
review:
summary: Ozgur and Sancar 2003 confirmed that hCRY2 lacks photorepair activity (PMID:12627958). This
is a correctly negated annotation documenting the absence of photolyase function.
action: ACCEPT
reason: The negated annotation is correct and well-supported. CRY2 lacks photorepair activity despite
its structural similarity to photolyases.
supported_by:
- reference_id: PMID:12627958
supporting_text: appear to lack photorepair activity
- term:
id: GO:0003677
label: DNA binding
evidence_type: IDA
original_reference_id: PMID:12627958
review:
summary: Ozgur and Sancar 2003 demonstrated that purified hCRY2 binds dsDNA weakly and ssDNA with
higher affinity (PMID:12627958). This is a residual property from the photolyase ancestor rather
than a core functional activity.
action: KEEP_AS_NON_CORE
reason: DNA binding is experimentally demonstrated but is not the primary mechanism of CRY2 function.
CRY2 represses transcription through protein-protein interactions with CLOCK:BMAL1, not through
direct DNA binding.
supported_by:
- reference_id: PMID:12627958
supporting_text: binds to double-stranded DNA weakly and to single-stranded DNA with higher affinity
- term:
id: GO:0003684
label: damaged DNA binding
evidence_type: IDA
original_reference_id: PMID:12627958
review:
summary: CRY2 DNA binding is stimulated by the presence of a (6-4) photoproduct (PMID:12627958). This
reflects the ancestral photolyase substrate recognition capability retained in the protein structure
but without associated repair activity.
action: KEEP_AS_NON_CORE
reason: Damaged DNA binding is experimentally demonstrated but is a vestigial property from the photolyase
ancestor. CRY2 lacks photolyase activity and damaged DNA binding is not its primary function.
supported_by:
- reference_id: PMID:12627958
supporting_text: this binding is further stimulated by the presence of a (6-4) photoproduct
- term:
id: GO:0003697
label: single-stranded DNA binding
evidence_type: IDA
original_reference_id: PMID:12627958
review:
summary: Ozgur and Sancar 2003 showed hCRY2 binds ssDNA with higher affinity than dsDNA (PMID:12627958).
This is a vestigial property from the photolyase ancestor.
action: KEEP_AS_NON_CORE
reason: Single-stranded DNA binding is experimentally demonstrated but is not the primary mechanism
of CRY2 function. It represents a retained ancestral property.
supported_by:
- reference_id: PMID:12627958
supporting_text: single-stranded DNA with higher affinity
- term:
id: GO:0003904
label: deoxyribodipyrimidine photo-lyase activity
evidence_type: IDA
original_reference_id: PMID:8909283
negated: true
review:
summary: Hsu et al. 1996 demonstrated that purified hCRY2 lacks photolyase activity on cyclobutane
pyrimidine dimers (PMID:8909283). Correctly negated annotation.
action: ACCEPT
reason: The negated annotation is correct. CRY2 lacks CPD photolyase activity despite its structural
similarity to DNA photolyases.
supported_by:
- reference_id: PMID:8909283
supporting_text: lacked photolyase activity on the cyclobutane pyrimidine dimer and the (6-4) photoproduct
- term:
id: GO:0003914
label: DNA (6-4) photolyase activity
evidence_type: IDA
original_reference_id: PMID:8909283
negated: true
review:
summary: Hsu et al. 1996 demonstrated that purified hCRY2 lacks (6-4) photolyase activity (PMID:8909283).
Correctly negated annotation.
action: ACCEPT
reason: The negated annotation is correct. CRY2 lacks (6-4) photolyase activity despite its homology
to the Drosophila (6-4) photolyase.
supported_by:
- reference_id: PMID:8909283
supporting_text: lacked photolyase activity on the cyclobutane pyrimidine dimer and the (6-4) photoproduct
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17463251
review:
summary: Busino et al. 2007 identified CRY2 interaction with FBXL3 as part of the SCF(FBXL3) ubiquitin
ligase complex that targets CRY proteins for degradation (PMID:17463251). The specific ubiquitin
ligase interaction is functionally important but annotated as generic protein binding.
action: MARK_AS_OVER_ANNOTATED
reason: The CRY2-FBXL3 interaction is a specific ubiquitin ligase substrate recognition event. Generic
protein binding does not convey the functional significance of this interaction.
supported_by:
- reference_id: PMID:17463251
supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin
ligase complex
core_functions:
- molecular_function:
id: GO:0004864
label: protein phosphatase inhibitor activity
directly_involved_in:
- id: GO:0032922
label: circadian regulation of gene expression
- id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
- id: GO:0042754
label: negative regulation of circadian rhythm
locations:
- id: GO:0005634
label: nucleus
description: CRY2 functions as a transcriptional corepressor in the mammalian circadian clock. It partners
with PER proteins (PER1/2/3) to form nuclear repressor complexes that inhibit CLOCK:BMAL1-driven transcription
of E-box containing genes including Per, Cry, Dec1, Dec2, and other clock-controlled genes. CRY2 also
inhibits PP5 phosphatase activity, modulating CKIepsilon-dependent phosphorylation of clock proteins.
CRY2 repression and stability are regulated through the FAD pocket, which mediates FBXL3-dependent
ubiquitination and degradation.
supported_by:
- reference_id: PMID:12397359
supporting_text: Protein products of Per act together with Cry proteins to inhibit Per transcription,
thus closing the autoregulatory feedback loop
- reference_id: PMID:17463251
supporting_text: Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback
loop
- reference_id: PMID:9383998
supporting_text: hCRY2, but not the highly homologous (6-4) photolyase, inhibits the phosphatase activity
of PP5
- molecular_function:
id: GO:0071949
label: FAD binding
description: CRY2 binds FAD as a cofactor in its photolyase homology region. Although FAD occupancy
is low in mammalian CRYs, the FAD-binding pocket is functionally critical as a regulatory hub for
ubiquitin ligase (FBXL3) recognition, PER2 competitive binding, and small-molecule stabilizer binding.
supported_by:
- reference_id: PMID:8909283
supporting_text: were found to contain FAD and a pterin cofactor
- molecular_function:
id: GO:0016922
label: nuclear receptor binding
directly_involved_in:
- id: GO:2000323
label: negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway
locations:
- id: GO:0005634
label: nucleus
description: CRY2 interacts with nuclear receptors including the glucocorticoid receptor (NR3C1/GR),
androgen receptor (AR), HNF4A, PPARA, PPARD, PPARG, NR1I2, NR1I3, and VDR in a ligand-dependent manner.
Through these interactions, CRY2 mediates circadian modulation of nuclear receptor target gene expression,
including rhythmic repression of glucocorticoid-responsive genes.
supported_by:
- reference_id: PMID:22170608
supporting_text: cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent
fashion and globally alter the transcriptional response to glucocorticoids
- reference_id: PMID:30530698
supporting_text: HNF4A strongly transrepresses the transcriptional activity of the CLOCK:BMAL1 heterodimer
references:
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,
accompanied by conservative changes to GO terms applied by UniProt
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
Compara
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:8909283
title: Putative human blue-light photoreceptors hCRY1 and hCRY2 are flavoproteins.
findings:
- statement: hCRY1 and hCRY2 contain FAD and pterin cofactors but lack photolyase activity on cyclobutane
pyrimidine dimers and (6-4) photoproducts.
supporting_text: were found to contain FAD and a pterin cofactor. Like the plant blue-light photoreceptors,
both hCRY1 and hCRY2 lacked photolyase activity on the cyclobutane pyrimidine dimer and the (6-4)
photoproduct
- id: PMID:9383998
title: Human blue-light photoreceptor hCRY2 specifically interacts with protein serine/threonine phosphatase
5 and modulates its activity.
findings:
- statement: hCRY2 specifically interacts with PP5 and inhibits its phosphatase activity.
supporting_text: protein serine/threonine phosphatase 5 (PP5) that contains the TPR motif specifically
interacted with hCRY2
- id: PMID:9753616
title: Molecular cloning of a second human stanniocalcin homologue (STC2).
findings:
- statement: This paper is about STC2, not CRY2. Annotations citing this reference for CRY2 are misannotations.
- id: PMID:10531061
title: Light-independent role of CRY1 and CRY2 in the mammalian circadian clock.
findings:
- statement: CRY1 and CRY2 function as light-independent components of the mammalian circadian clock,
inhibiting CLOCK:BMAL1-mediated transcription.
- id: PMID:12397359
title: Dec1 and Dec2 are regulators of the mammalian molecular clock.
findings:
- statement: Cry proteins act together with Per proteins to inhibit Per transcription and close the
autoregulatory feedback loop.
supporting_text: Protein products of Per act together with Cry proteins to inhibit Per transcription,
thus closing the autoregulatory feedback loop
- id: PMID:12627958
title: Purification and properties of human blue-light photoreceptor cryptochrome 2.
findings:
- statement: Purified hCRY2 binds dsDNA weakly and ssDNA with higher affinity, stimulated by (6-4) photoproducts.
CRY2 lacks photorepair activity.
supporting_text: binds to double-stranded DNA weakly and to single-stranded DNA with higher affinity,
and this binding is further stimulated by the presence of a (6-4) photoproduct
- id: PMID:14672706
title: A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation.
findings:
- statement: PERs and CRYs suppress CLOCK/BMAL-induced Dec1 expression through E-box elements.
supporting_text: PERs and CRYs suppressed the induced expression
- id: PMID:15147242
title: Expression of the gene for Dec2, a basic helix-loop-helix transcription factor, is regulated
by a molecular clock system.
findings:
- statement: Cry and Per proteins suppress Clock/Bmal-induced transcription from the Dec2 promoter.
- id: PMID:15751956
title: Role of structural plasticity in signal transduction by the cryptochrome blue-light photoreceptor.
findings:
- statement: Light-dependent conformational change demonstrated for Arabidopsis Cry1, not human CRY2.
The paper characterizes CRY structure but does not demonstrate light response function for human
CRY2.
supporting_text: we demonstrate a light-dependent conformational change in the C-terminal domain of
Arabidopsis Cry1
- id: PMID:16790549
title: Posttranslational regulation of the mammalian circadian clock by cryptochrome and protein phosphatase
5.
findings:
- statement: Cryptochrome regulates clock protein phosphorylation by modulating the effect of PP5 on
CKIepsilon.
supporting_text: cryptochrome regulates clock protein phosphorylation by modulating the effect of
PP5 on CKIepsilon
- id: PMID:17463251
title: SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome
proteins.
findings:
- statement: CRY1 and CRY2 are ubiquitinated and degraded by SCF(FBXL3), which is essential for clock
oscillation.
supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin
ligase complex
- id: PMID:20840750
title: Identification of two amino acids in the C-terminal domain of mouse CRY2 essential for PER2 interaction.
findings:
- statement: CRY2 residues R501 and K503 are essential for PER2 interaction and circadian transcriptional
repression.
supporting_text: negatively regulate the transcription of Per and Cry core clock genes
- id: PMID:22170608
title: Cryptochromes mediate rhythmic repression of the glucocorticoid receptor.
findings:
- statement: CRY1 and CRY2 interact with the glucocorticoid receptor in a ligand-dependent manner, globally
altering glucocorticoid transcriptional response. Cryptochrome deficiency causes glucose intolerance
and constitutively high corticosterone.
supporting_text: cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent
fashion and globally alter the transcriptional response to glucocorticoids
- id: PMID:25416956
title: A proteome-scale map of the human interactome network.
findings: []
- id: PMID:30530698
title: Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks.
findings:
- statement: HNF4A interacts with CRY2 and modulates tissue-specific circadian networks.
supporting_text: HNF4A strongly transrepresses the transcriptional activity of the CLOCK:BMAL1 heterodimer
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:32814053
title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread
Protein Aggregation in Affected Brains.
findings: []