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: UniProtKB: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: UniProtKB: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 UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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 UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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 UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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: UniProtKB: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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