CALR

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: Protein folding is a core biological process for calreticulin in the calnexin/calreticulin cycle. Reason: Phylogenetic transfer agrees with extensive evidence that calreticulin assists folding of nascent glycoproteins in the ER. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Calcium-binding chaperone that promotes folding, oligomeric
GO:0036503 ERAD pathway	IBA GO_REF:0000033	ACCEPT	Summary: The calnexin/calreticulin cycle triages terminally misfolded glycoproteins toward ER-associated degradation, supporting participation in the ERAD pathway. Reason: Quality-control retention and triage of non-native clients is an established core role. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Calcium-binding chaperone that promotes folding, oligomeric
GO:0005509 calcium ion binding	IBA GO_REF:0000033	ACCEPT	Summary: Calcium ion binding is a core conserved molecular function; calreticulin is the major high-capacity ER Ca2+-binding protein. Reason: Well-supported by biochemistry and the conserved calreticulin-family Ca2+-binding domains. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0005509 calcium ion binding	IEA GO_REF:0000120	ACCEPT	Summary: Electronic calcium ion binding annotation duplicates the core conserved molecular function. Reason: Consistent with experimental and phylogenetic evidence for Ca2+ binding. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0005737 cytoplasm	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: A cytoplasmic pool of calreticulin exists (cytosolic moonlighting), but it is non-core relative to the ER-luminal chaperone function. Reason: Cytosolic calreticulin is documented for moonlighting roles, but the bulk functional protein is ER-luminal. Supporting Evidence: file:human/CALR/CALR-uniprot.txt cytosol and extracellular matrix (PubMed:10358038)
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000120	ACCEPT	Summary: ER localization is the core compartment for calreticulin. Reason: Calreticulin is a resident ER-luminal protein. Supporting Evidence: file:human/CALR/CALR-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005788 endoplasmic reticulum lumen	IEA GO_REF:0000120	ACCEPT	Summary: ER lumen is the precise core localization of this soluble chaperone. Reason: Calreticulin bears a KDEL retention signal and resides in the ER lumen. Supporting Evidence: file:human/CALR/CALR-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005829 cytosol	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: A cytosolic pool supports moonlighting functions but is non-core. Reason: Cytosolic calreticulin is documented but secondary to the ER chaperone role. Supporting Evidence: file:human/CALR/CALR-uniprot.txt cytosol and extracellular matrix (PubMed:10358038)
GO:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	Summary: Electronic protein folding annotation duplicates the core folding role. Reason: Consistent with experimental and phylogenetic evidence for chaperone-assisted folding. Supporting Evidence: PMID:15474971 Calreticulin is also an important molecular chaperone involved in "quality control" within secretory pathways.
GO:0009986 cell surface	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Cell-surface calreticulin is real (eat-me signal, T-cell surface) but non-core relative to ER function. Reason: Surface exposure is a documented secondary localization linked to phagocytic clearance and immune signaling. Supporting Evidence: PMID:10358038 the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells
GO:0012505 endomembrane system	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Endomembrane system is correct but uninformatively broad; the precise compartment is the ER lumen. Reason: Subsumed by the more specific ER lumen annotation.
GO:0033018 sarcoplasmic reticulum lumen	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Sarcoplasmic reticulum lumen is the muscle-cell equivalent of the ER lumen; a valid specialized localization but non-core. Reason: Reflects the ER/SR continuum in muscle; not distinct from the core ER-luminal role.
GO:0044194 cytolytic granule	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Calreticulin is a major constituent of cytolytic (lytic) granules of CTLs; a real but specialized non-core localization. Reason: Documented localization in lytic granules, secondary to the ER chaperone function. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Cytolytic granule
GO:0060473 cortical granule	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Cortical granule localization (oocytes) is an ortholog-supported specialized pool linked to the block to polyspermy; non-core. Reason: Documented in oocyte cortical granules by similarity; secondary to the ER role. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Cortical granule
GO:0005515 protein binding	IPI PMID:15896298 In cerebrospinal fluid ER chaperones ERp57 and calreticulin ...	MARK AS OVER ANNOTATED	Summary: Bare protein binding (ERp57/beta-amyloid in CSF study) is uninformative. Reason: Per guidelines, generic protein binding does not convey calreticulin function.
GO:0005515 protein binding	IPI PMID:17055437 Redox regulation facilitates optimal peptide selection by MH...	MARK AS OVER ANNOTATED	Summary: This reflects calreticulin's role in redox-regulated MHC I peptide selection, but bare protein binding is uninformative. Reason: The functional content is MHC I peptide loading, captured by PLC terms; generic protein binding adds nothing.
GO:0005515 protein binding	IPI PMID:17215244 Purification and identification of G protein-coupled recepto...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a GPCR-complex study; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:18177377 The chaperone and potential mannan-binding lectin (MBL) co-r...	MARK AS OVER ANNOTATED	Summary: This reflects the calreticulin-MBL interaction (cC1qR/MBL co-receptor), but bare protein binding is uninformative. Reason: The MBL/innate-immune interaction is a non-core extracellular role; generic protein binding does not capture it.
GO:0005515 protein binding	IPI PMID:19154346 Structural framework of the GABARAP-calreticulin interface--...	MARK AS OVER ANNOTATED	Summary: Generic protein binding (GABARAP-calreticulin interface) is uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:20562859 Network organization of the human autophagy system.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from an autophagy-network interactome; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:21900206 A directed protein interaction network for investigating int...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a directed signal-transduction interaction network; uninformative. Reason: High-throughput interaction; bare protein binding adds no functional information.
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a proximity-ligation pathway profiling study; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:25277244 The functional landscape of Hsp27 reveals new cellular proce...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from an Hsp27 functional-landscape study; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:26514267 Protein interactome mining defines melatonin MT1 receptors a...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a melatonin MT1 presynaptic interactome; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:28298427 Systematic protein-protein interaction mapping for clinicall...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a GPCR interaction-mapping study; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:30108113 Comprehensive evaluation of coding region point mutations in...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a colorectal-cancer mutation study; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a reference binary interactome; uninformative. Reason: High-throughput interactome hit; bare protein binding adds no functional information.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a neurodegenerative-disease interactome; uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005515 protein binding	IPI PMID:36417879 Calreticulin mutations affect its chaperone function and per...	MARK AS OVER ANNOTATED	Summary: This study shows mutant calreticulin perturbs the glycoproteome, but bare protein binding is uninformative. Reason: The functional content is glycoprotein chaperoning; generic protein binding does not capture it. Supporting Evidence: PMID:36417879 Calreticulin mutations affect its chaperone function and perturb the glycoproteome.
GO:0001669 acrosomal vesicle	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Acrosomal vesicle localization is an ortholog-transferred specialized pool; non-core and weakly supported for human. Reason: Ortholog phenotype/localization transfer; not part of the core ER function.
GO:0002502 peptide antigen assembly with MHC class I protein complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: MHC class I peptide antigen assembly is a well-supported specialized role of calreticulin in the peptide loading complex. Reason: This is a specialized application of the lectin-chaperone function; supported directly (see IDA from PMID:35948544) but secondary to general glycoprotein folding. Supporting Evidence: PMID:35948544 peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan
GO:0003729 mRNA binding	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: mRNA binding reflects cytosolic moonlighting (e.g. p21, C/EBP mRNAs); documented but non-core for an ER lectin chaperone. Reason: Documented cytosolic mRNA-binding moonlighting; secondary to the ER lectin-chaperone role.
GO:0005506 iron ion binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Iron ion binding is an ortholog-transferred metal-binding claim with weak support; not a credible core function. Reason: Poorly supported metal-binding inference; calreticulin's characterized metal ligand is Ca2+.
GO:0005576 extracellular region	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: A secreted/extracellular pool of calreticulin exists but is non-core. Reason: Documented extracellular/secreted localization, secondary to ER function. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Secreted, extracellular space,
GO:0005635 nuclear envelope	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Nuclear envelope localization likely reflects continuity with the ER and a minor nuclear-envelope pool; non-core. Reason: A minor localization, partly reflecting ER/nuclear-envelope continuity.
GO:0005739 mitochondrion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Mitochondrial localization is an ortholog-transferred over-call for a soluble ER-luminal chaperone. Reason: Not supported by direct human evidence; an ER protein is unlikely to be a genuine mitochondrial resident.
GO:0005790 smooth endoplasmic reticulum	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Smooth ER is a sub-compartment of the broader ER localization; subsumed by the core ER annotation. Reason: A specific ER sub-compartment; not distinct from the core ER-luminal role.
GO:0007283 spermatogenesis	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Spermatogenesis is an ortholog-derived phenotype-transfer over-annotation. Reason: Phenotype transfer, not a direct molecular function of human calreticulin.
GO:0009410 response to xenobiotic stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to xenobiotic stimulus is a broad ortholog-transferred response term. Reason: Over-broad phenotype/response transfer, not a core function.
GO:0009897 external side of plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: External side of the plasma membrane corresponds to surface-exposed (eat-me) calreticulin; real but non-core. Reason: Surface exposure is documented; secondary to the ER chaperone role. Supporting Evidence: PMID:10358038 the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells
GO:0010628 positive regulation of gene expression	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Positive regulation of gene expression is an over-broad downstream/ortholog-transferred effect. Reason: Over-broad BP not reflecting a direct calreticulin molecular activity.
GO:0016529 sarcoplasmic reticulum	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Sarcoplasmic reticulum is the muscle ER equivalent; a valid specialized localization but non-core. Reason: Reflects ER/SR continuum in muscle; not distinct from the core ER role.
GO:0030246 carbohydrate binding	IEA GO_REF:0000107	ACCEPT	Summary: Carbohydrate (monoglucosylated N-glycan) binding is a core molecular function underlying the lectin-chaperone activity. Reason: Calreticulin is a lectin that binds monoglucosylated glycans on glycoprotein clients. Supporting Evidence: PMID:15056662 Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin
GO:0031012 extracellular matrix	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Extracellular matrix localization reflects the secreted/extracellular pool; non-core. Reason: Documented extracellular/matrix pool, secondary to ER function. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Secreted, extracellular space,
GO:0032355 response to estradiol	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to estradiol is a broad ortholog-transferred response term. Reason: Over-broad phenotype/response transfer, not a core function.
GO:0032991 protein-containing complex	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Generic protein-containing complex membership is uninformative. Reason: Too general; specific complexes (PLC) are captured elsewhere.
GO:0033574 response to testosterone	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to testosterone is a broad ortholog-transferred response term. Reason: Over-broad phenotype/response transfer, not a core function.
GO:0034504 protein localization to nucleus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Protein localization to nucleus relates to the cytosolic nuclear-export moonlighting role; non-core. Reason: Linked to the documented nuclear-export receptor activity; secondary to ER function.
GO:0042277 peptide binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Peptide binding is consistent with calreticulin's chaperone interactions (e.g. in MHC I peptide loading) but is a broad MF. Reason: Generic peptide binding partially reflects the chaperone/PLC role; retain as non-core rather than core.
GO:0042562 hormone binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Hormone binding is a weakly supported ortholog-transferred MF. Reason: Not a credible core molecular function; likely derived from steroid-receptor moonlighting reports.
GO:0042824 MHC class I peptide loading complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Calreticulin is a bona fide component of the MHC class I peptide loading complex. Reason: Well-supported specialized complex membership; secondary to the general glycoprotein-folding core function. Supporting Evidence: PMID:35948544 peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan
GO:0044322 endoplasmic reticulum quality control compartment	IEA GO_REF:0000107	ACCEPT	Summary: Localization to the ER quality control compartment is consistent with calreticulin's retention/triage role. Reason: Directly aligned with the core ER quality-control function. Supporting Evidence: file:human/CALR/CALR-uniprot.txt Calcium-binding chaperone that promotes folding, oligomeric
GO:0045787 positive regulation of cell cycle	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Positive regulation of cell cycle is an over-broad downstream/ortholog-transferred effect. Reason: Over-broad BP not reflecting a direct calreticulin activity.
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Perinuclear cytoplasm localization reflects the perinuclear ER distribution; non-core descriptive localization. Reason: Consistent with perinuclear ER; not a distinct functional compartment.
GO:0050766 positive regulation of phagocytosis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Surface calreticulin acts as an eat-me signal promoting phagocytosis; a real but non-core role. Reason: Well-documented immunogenic-cell-death/eat-me biology; secondary to the ER chaperone function.
GO:0050821 protein stabilization	IEA GO_REF:0000107	ACCEPT	Summary: Protein stabilization captures calreticulin's chaperone-mediated stabilization of folding clients. Reason: Consistent with experimental evidence (e.g. insulin receptor stabilization) and the core chaperone role. Supporting Evidence: PMID:17563366 calreticulin (CRT) and Hsp90 exert distinct effects on the stability and cell surface levels of native and misfolded forms of the human insulin receptor
GO:0055007 cardiac muscle cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: A cardiac developmental role is documented from calreticulin-knockout mice; an ortholog-supported developmental effect rather than the core human function. Reason: CALR-null mice show essential cardiac developmental defects; retain as non-core developmental role. Supporting Evidence: PMID:15474971 Studies on calreticulin knockout mice indicate that the protein is essential in early cardiac development.
GO:0071257 cellular response to electrical stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Cellular response to electrical stimulus is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:0071285 cellular response to lithium ion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Cellular response to lithium ion is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:0090398 cellular senescence	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Cellular senescence is a downstream/ortholog-transferred effect (cf. p21 translation control); over-broad. Reason: Over-broad downstream BP, not a direct calreticulin function.
GO:0098586 cellular response to virus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Cellular response to virus is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:0098794 postsynapse	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Postsynapse localization/activity is an ortholog-transferred neuronal over-call for an ER chaperone. Reason: Not supported by direct human evidence; not a core function.
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Glutamatergic synapse activity is an ortholog-transferred neuronal over-call. Reason: Not supported by direct human evidence; not a core function.
GO:1901652 response to peptide	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to peptide is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:1903416 response to glycoside	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to glycoside is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:1904614 response to biphenyl	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to biphenyl is an over-broad ortholog-transferred response term. Reason: Phenotype/response transfer, not a core function.
GO:0005783 endoplasmic reticulum	IDA PMID:35948544 Molecular basis of MHC I quality control in the peptide load...	ACCEPT	Summary: Calreticulin is active in the ER as part of the MHC I peptide loading complex; core compartment of action. Reason: Direct evidence of calreticulin acting in the ER within the PLC. Supporting Evidence: PMID:35948544 peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan
GO:0030674 protein-macromolecule adaptor activity	IDA PMID:35948544 Molecular basis of MHC I quality control in the peptide load...	KEEP AS NON CORE	Summary: In the PLC, calreticulin bridges the MHC I glycan to the editing machinery, consistent with an adaptor/scaffolding molecular function. Reason: Supported within the PLC context; a specialized adaptor role secondary to the lectin-chaperone core function. Supporting Evidence: PMID:35948544 peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan
GO:0042824 MHC class I peptide loading complex	IDA PMID:35948544 Molecular basis of MHC I quality control in the peptide load...	KEEP AS NON CORE	Summary: Direct structural evidence places calreticulin in the MHC class I peptide loading complex. Reason: Well-supported specialized complex membership; secondary to general glycoprotein folding. Supporting Evidence: PMID:35948544 we determine the multi-chaperone-client interaction network of the peptide loading complex (PLC)
GO:0005783 endoplasmic reticulum	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence-based ER localization consistent with the core compartment. Reason: Reinforces the established ER localization.
GO:0005788 endoplasmic reticulum lumen	EXP PMID:10358038 Calreticulin is expressed on the cell surface of activated h...	ACCEPT	Summary: Experimental evidence confirms calreticulin in the ER lumen. Reason: Direct support for the core ER-luminal localization. Supporting Evidence: PMID:10358038 Calreticulin is an endoplasmic reticulum resident molecule
GO:0009986 cell surface	EXP PMID:10358038 Calreticulin is expressed on the cell surface of activated h...	KEEP AS NON CORE	Summary: Experimental evidence shows surface calreticulin on activated T cells; a real but non-core localization. Reason: Direct demonstration of surface exposure; secondary to the ER role. Supporting Evidence: PMID:10358038 the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells
GO:0033018 sarcoplasmic reticulum lumen	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence/orthology-transferred SR lumen localization (muscle ER equivalent); non-core. Reason: Reflects the ER/SR continuum; not distinct from the core ER role.
GO:0044194 cytolytic granule	EXP PMID:8418194 The calcium-binding protein calreticulin is a major constitu...	KEEP AS NON CORE	Summary: Calreticulin is experimentally shown to be a major constituent of CTL lytic granules; specialized non-core localization. Reason: Direct evidence for lytic-granule localization; secondary to the ER function. Supporting Evidence: PMID:8418194 The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes.
GO:0005509 calcium ion binding	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	ACCEPT	Summary: Calcium ion binding is a core molecular function; calreticulin regulates ER Ca2+ storage. Reason: Well-supported synthesis source for the core Ca2+-binding function. Supporting Evidence: PMID:15474971 The protein is involved in the regulation of intracellular Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity.
GO:0002502 peptide antigen assembly with MHC class I protein complex	IDA PMID:35948544 Molecular basis of MHC I quality control in the peptide load...	KEEP AS NON CORE	Summary: Direct evidence supports calreticulin's involvement in MHC class I peptide antigen assembly. Reason: Specialized application of the lectin-chaperone function; well supported but secondary to general glycoprotein folding. Supporting Evidence: PMID:35948544 peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan
GO:0006457 protein folding	IDA PMID:17563366 Calreticulin and Hsp90 stabilize the human insulin receptor ...	ACCEPT	Summary: Direct evidence supports calreticulin's role in folding/maturation of a glycoprotein client (insulin receptor). Reason: Core biological process supported by direct experimental data. Supporting Evidence: PMID:17563366 both CRT and Hsp90 control expression of hIR at its earliest maturation stages and modulate its movement within the ER
GO:0044183 protein folding chaperone	IDA PMID:17563366 Calreticulin and Hsp90 stabilize the human insulin receptor ...	ACCEPT	Summary: Protein folding chaperone is an accurate core molecular function for calreticulin. Reason: Calreticulin is a bona fide molecular chaperone for glycoprotein clients. Supporting Evidence: PMID:17563366 calreticulin (CRT) and Hsp90 exert distinct effects on the stability and cell surface levels of native and misfolded forms of the human insulin receptor
GO:0050821 protein stabilization	IDA PMID:17563366 Calreticulin and Hsp90 stabilize the human insulin receptor ...	ACCEPT	Summary: Calreticulin stabilizes folding clients (insulin receptor variant); core chaperone-related process. Reason: Directly supported stabilization of a misfolded client. Supporting Evidence: PMID:17563366 CRT was unique in stabilizing the disease variant and in augmenting hIR expression when glycolysis was abrogated.
GO:0051604 protein maturation	IDA PMID:17563366 Calreticulin and Hsp90 stabilize the human insulin receptor ...	ACCEPT	Summary: Calreticulin contributes to glycoprotein maturation in the ER; consistent with the core chaperone function. Reason: Directly supported role in early client maturation. Supporting Evidence: PMID:17563366 both CRT and Hsp90 control expression of hIR at its earliest maturation stages and modulate its movement within the ER
GO:0098553 lumenal side of endoplasmic reticulum membrane	TAS Reactome:R-HSA-8863914	ACCEPT	Summary: As a soluble ER-luminal protein, calreticulin functions on the luminal side of the ER membrane. Reason: Consistent with calreticulin's ER-luminal localization.
GO:0098553 lumenal side of endoplasmic reticulum membrane	TAS Reactome:R-HSA-8951499	ACCEPT	Summary: Luminal-side ER membrane localization (MHC I peptide loading pathway) is accurate. Reason: Consistent with calreticulin's ER-luminal localization.
GO:0098553 lumenal side of endoplasmic reticulum membrane	TAS Reactome:R-HSA-983142	ACCEPT	Summary: Luminal-side ER membrane localization (PLC formation) is accurate. Reason: Consistent with calreticulin's ER-luminal localization.
GO:0098553 lumenal side of endoplasmic reticulum membrane	TAS Reactome:R-HSA-983161	ACCEPT	Summary: Luminal-side ER membrane localization (PLC dissociation) is accurate. Reason: Consistent with calreticulin's ER-luminal localization.
GO:0005840 ribosome	IDA PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	KEEP AS NON CORE	Summary: Ribosome association reflects cytosolic calreticulin in mRNA-translation regulation (p21); a moonlighting context, non-core. Reason: Linked to cytosolic translational-control moonlighting; not the core ER localization.
GO:0001849 complement component C1q complex binding	IPI PMID:9922153 Evidence that C1q binds specifically to CH2-like immunoglobu...	KEEP AS NON CORE	Summary: Calreticulin (cC1qR) binds the C1q complex; a documented immune/extracellular molecular function but non-core. Reason: Specific, supported C1q-binding activity relevant to complement and apoptotic-cell clearance; secondary to the ER chaperone role. Supporting Evidence: PMID:9922153 C1q binds specifically to CH2-like immunoglobulin gamma motifs present in the autoantigen calreticulin
GO:0005049 nuclear export signal receptor activity	IDA PMID:11149926 Calreticulin Is a receptor for nuclear export.	KEEP AS NON CORE	Summary: Cytosolic calreticulin was reported to act as a nuclear export receptor for the glucocorticoid receptor; a moonlighting activity, non-core. Reason: Documented but specialized cytosolic moonlighting function distinct from the ER chaperone role. Supporting Evidence: PMID:11149926 Calreticulin Is a receptor for nuclear export.
GO:0005515 protein binding	IPI PMID:17916189 Identification of calreticulin as a ligand of GABARAP by pha...	MARK AS OVER ANNOTATED	Summary: Generic protein binding (GABARAP ligand identification); uninformative. Reason: Bare protein binding is not an informative molecular function.
GO:0005509 calcium ion binding	IMP PMID:21705382 Characterization of unique signature sequences in the diverg...	ACCEPT	Summary: Calcium ion binding is a genuine core function of calreticulin, but the cited reference (PMID:21705382) is a wrong-gene mis-assignment - it concerns Bcl2l10, not CALR, and provides no direct CALR Ca2+-binding measurement. Reason: The GO term (calcium ion binding) is correct and robustly supported by independent evidence (e.g. PMID:15474971), so the annotation is retained; however the original_reference_id PMID:21705382 is misassigned (it is about Bcl2l10) and this reference error should be corrected at source in GOA. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0045787 positive regulation of cell cycle	IGI PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	MARK AS OVER ANNOTATED	Summary: Cell-cycle regulation via competition with CUGBP1 for p21 translation is a cytosolic moonlighting effect; over-broad as a core BP. Reason: Downstream effect of cytosolic mRNA-binding moonlighting, not a core function.
GO:0060473 cortical granule	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence/orthology-transferred cortical granule localization (oocytes); non-core specialized pool. Reason: Documented by similarity; secondary to ER function.
GO:0005783 endoplasmic reticulum	IDA PMID:30188326 Deletion of Tmtc4 activates the unfolded protein response an...	ACCEPT	Summary: Direct ER localization consistent with the core compartment. Reason: Reinforces the established ER localization.
GO:0042824 MHC class I peptide loading complex	IDA PMID:21263072 Distinct functions for the glycans of tapasin and heavy chai...	KEEP AS NON CORE	Summary: Direct evidence supports calreticulin as a PLC component (glycan-dependent MHC I assembly). Reason: Well-supported specialized complex membership; secondary to general glycoprotein folding. Supporting Evidence: PMID:21263072 Distinct functions for the glycans of tapasin and heavy chains in the assembly of MHC class I molecules
GO:0005515 protein binding	IPI PMID:10605026 HLA-F is a predominantly empty, intracellular, TAP-associate...	MARK AS OVER ANNOTATED	Summary: This reflects calreticulin association with HLA-F (an MHC Ib client), but bare protein binding is uninformative. Reason: The functional content is MHC I chaperoning; generic protein binding does not capture it.
GO:0005515 protein binding	IPI PMID:9640257 Calreticulin associates with non-HLA-A,-B class I proteins i...	MARK AS OVER ANNOTATED	Summary: This reflects calreticulin association with non-classical MHC class I proteins, but bare protein binding is uninformative. Reason: The functional content is MHC I chaperoning; generic protein binding does not capture it.
GO:0005509 calcium ion binding	IDA PMID:21590275 Calreticulin-2 is localized in the lumen of the endoplasmic ...	ACCEPT	Summary: Calcium ion binding is a genuine core function of calreticulin, but the cited reference (PMID:21590275) is a wrong-gene mis-assignment - it is about calreticulin-2/CALR3, not CALR. Reason: The GO term (calcium ion binding) is correct and robustly supported by independent evidence (e.g. PMID:15474971), so the annotation is retained; however the original_reference_id PMID:21590275 is misassigned (it concerns CALR3) and this reference error should be corrected at source in GOA. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0005635 nuclear envelope	IDA PMID:21590275 Calreticulin-2 is localized in the lumen of the endoplasmic ...	KEEP AS NON CORE	Summary: Nuclear envelope localization reflects ER/nuclear-envelope continuity; non-core. Reason: A minor localization partly reflecting ER continuity.
GO:0005788 endoplasmic reticulum lumen	IDA PMID:21590275 Calreticulin-2 is localized in the lumen of the endoplasmic ...	ACCEPT	Summary: Direct ER lumen localization consistent with the core compartment. Reason: Reinforces the established ER-luminal localization.
GO:0005576 extracellular region	IMP PMID:22377355 Calreticulin has opposing effects on the migration of human ...	KEEP AS NON CORE	Summary: Extracellular/secreted calreticulin affecting cell migration; non-core extracellular role. Reason: Documented extracellular activity; secondary to ER function. Supporting Evidence: PMID:22377355 Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells.
GO:0010595 positive regulation of endothelial cell migration	IMP PMID:22377355 Calreticulin has opposing effects on the migration of human ...	KEEP AS NON CORE	Summary: Extracellular calreticulin promotes endothelial cell migration; a context-specific non-core role. Reason: Supported context-specific extracellular activity, not the core ER function. Supporting Evidence: PMID:22377355 Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells.
GO:1901164 negative regulation of trophoblast cell migration	IMP PMID:22377355 Calreticulin has opposing effects on the migration of human ...	KEEP AS NON CORE	Summary: Extracellular calreticulin inhibits trophoblast migration; a context-specific non-core role. Reason: Supported context-specific extracellular activity, not the core ER function. Supporting Evidence: PMID:22377355 Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells.
GO:0008284 positive regulation of cell population proliferation	IGI PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	MARK AS OVER ANNOTATED	Summary: Proliferation regulation via p21 translation control is a cytosolic moonlighting effect; over-broad as a core BP. Reason: Downstream effect of cytosolic mRNA-binding moonlighting, not a core function.
GO:0017148 negative regulation of translation	IDA PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	KEEP AS NON CORE	Summary: Cytosolic calreticulin can repress translation of specific mRNAs (p21); a moonlighting activity, non-core. Reason: Documented cytosolic translational-control moonlighting; secondary to the ER role. Supporting Evidence: PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate
GO:0090398 cellular senescence	IGI PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	MARK AS OVER ANNOTATED	Summary: Senescence is a downstream effect of cytosolic p21 translation control; over-broad. Reason: Downstream/indirect effect, not a direct calreticulin function.
GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane	TAS Reactome:R-HSA-8863858	KEEP AS NON CORE	Summary: ERGIC membrane localization reflects trafficking of calreticulin-containing complexes; a minor non-core localization. Reason: Transient trafficking compartment localization; secondary to ER-luminal residence.
GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane	TAS Reactome:R-HSA-8863914	KEEP AS NON CORE	Summary: ERGIC membrane localization (cross-presentation pathway); minor non-core. Reason: Transient trafficking compartment; secondary to ER residence.
GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane	TAS Reactome:R-HSA-8951595	KEEP AS NON CORE	Summary: ERGIC membrane localization (cross-presentation pathway); minor non-core. Reason: Transient trafficking compartment; secondary to ER residence.
GO:0034975 protein folding in endoplasmic reticulum	TAS PMID:22013210 The unfolded protein response: integrating stress signals th...	ACCEPT	Summary: Protein folding in the ER is the precise core biological process for calreticulin. Reason: Most accurate BP term for calreticulin's chaperone activity. Supporting Evidence: PMID:15474971 Calreticulin is also an important molecular chaperone involved in "quality control" within secretory pathways.
GO:0016020 membrane	IDA PMID:22572157 Sensitive detection of idiotypic platelet-reactive alloantib...	MARK AS OVER ANNOTATED	Summary: Generic membrane localization is uninformatively broad. Reason: Subsumed by more specific ER/cell-surface localizations.
GO:0005925 focal adhesion	HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome...	KEEP AS NON CORE	Summary: Focal adhesion localization from a high-throughput proteome; consistent with the integrin-tail interaction but non-core. Reason: Plausible given integrin-tail binding, but high-throughput and secondary to ER function.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: Generic membrane from an NK-cell membrane proteome; uninformatively broad. Reason: Subsumed by more specific localizations.
GO:0005576 extracellular region	HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu...	KEEP AS NON CORE	Summary: Extracellular detection in colostrum proteomics; non-core secreted pool. Reason: Documented secreted/extracellular detection; secondary to ER function.
GO:0005515 protein binding	IPI PMID:15056662 Major histocompatibility complex class I molecules expressed...	MARK AS OVER ANNOTATED	Summary: This reflects calreticulin binding monoglucosylated MHC I glycans, more informatively captured as carbohydrate binding than bare protein binding. Reason: The functional content is glycan-dependent MHC I binding, captured by carbohydrate-binding/PLC terms; generic protein binding adds nothing. Supporting Evidence: PMID:15056662 Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	KEEP AS NON CORE	Summary: Nuclear detection in a sperm-nucleus proteome; non-core moonlighting/contaminant-prone localization. Reason: A minor nuclear pool consistent with nuclear moonlighting reports; secondary to ER function.
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	MARK AS OVER ANNOTATED	Summary: RNA binding from a global mRNA-interactome capture; not a credible core molecular function. Reason: High-throughput RNA-capture; not a genuine primary function for an ER lectin chaperone.
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	KEEP AS NON CORE	Summary: Exosome detection in parotid-gland proteomics; non-core, likely incidental. Reason: High-throughput exosome detection; secondary to ER function.
GO:0005783 endoplasmic reticulum	IDA PMID:23395171 Tmem64 modulates calcium signaling during RANKL-mediated ost...	ACCEPT	Summary: Direct ER localization consistent with the core compartment. Reason: Reinforces the established ER localization.
GO:0005783 endoplasmic reticulum	IDA PMID:23011799 ORMDL3 is an inducible lung epithelial gene regulating metal...	ACCEPT	Summary: Direct ER localization consistent with the core compartment. Reason: Reinforces the established ER localization.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2247514	KEEP AS NON CORE	Summary: Extracellular calreticulin in scavenger-receptor (SCARF1) clearance pathway; non-core. Reason: Reflects extracellular eat-me/clearance biology; secondary to ER function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2507854	KEEP AS NON CORE	Summary: Extracellular calreticulin in scavenger-receptor (MSR1) clearance pathway; non-core. Reason: Reflects extracellular eat-me/clearance biology; secondary to ER function.
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-8951595	KEEP AS NON CORE	Summary: Phagocytic vesicle membrane localization in cross-presentation; non-core specialized localization. Reason: Specialized immune-pathway localization; secondary to ER function.
GO:0071682 endocytic vesicle lumen	TAS Reactome:R-HSA-2247514	KEEP AS NON CORE	Summary: Endocytic vesicle lumen localization in scavenger-receptor clearance; non-core. Reason: Reflects extracellular/endocytic clearance biology; secondary to ER function.
GO:0071682 endocytic vesicle lumen	TAS Reactome:R-HSA-2507854	KEEP AS NON CORE	Summary: Endocytic vesicle lumen localization in scavenger-receptor clearance; non-core. Reason: Reflects extracellular/endocytic clearance biology; secondary to ER function.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-1791082	ACCEPT	Summary: ER lumen localization (calreticulin expression); accurate core compartment. Reason: Consistent with the core ER-luminal localization.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-535717	ACCEPT	Summary: ER lumen localization for the chaperone-client binding step; accurate. Reason: Consistent with the core ER-luminal localization and function.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-548890	ACCEPT	Summary: ER lumen localization for the glucosidase II/release step; accurate. Reason: Consistent with the core ER-luminal localization and the CNX/CRT cycle.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-901047	ACCEPT	Summary: ER lumen localization for ERp57 binding; accurate and functionally central. Reason: Consistent with calreticulin's ERp57-recruiting role in the ER lumen.
GO:1900026 positive regulation of substrate adhesion-dependent cell spreading	IMP PMID:11859136 Cooperation of C1q receptors and integrins in C1q-mediated e...	KEEP AS NON CORE	Summary: Calreticulin (with C1q receptors/integrins) promotes endothelial cell adhesion/spreading; a context-specific extracellular role, non-core. Reason: Supported context-specific surface/extracellular activity; secondary to ER function. Supporting Evidence: PMID:11859136 Cooperation of C1q receptors and integrins in C1q-mediated endothelial cell adhesion and spreading
GO:2000510 positive regulation of dendritic cell chemotaxis	IMP PMID:16140380 Chemotaxis of human monocyte-derived dendritic cells to comp...	KEEP AS NON CORE	Summary: Calreticulin (cC1qR) mediates dendritic cell chemotaxis to C1q; a context-specific extracellular immune role, non-core. Reason: Supported context-specific extracellular activity; secondary to ER function. Supporting Evidence: PMID:16140380 Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR
GO:0034504 protein localization to nucleus	IDA PMID:15998798 Calreticulin signals upstream of calcineurin and MEF2C in a ...	KEEP AS NON CORE	Summary: Linked to the calreticulin/calcineurin/MEF2C signaling cascade affecting nuclear localization of downstream factors; cytosolic moonlighting, non-core. Reason: Part of the cytosolic Ca2+-signaling moonlighting; secondary to ER function. Supporting Evidence: PMID:15998798 Calreticulin signals upstream of calcineurin and MEF2C in a critical Ca(2+)-dependent signaling cascade.
GO:0005509 calcium ion binding	ISS GO_REF:0000024	ACCEPT	Summary: Sequence/orthology-transferred calcium ion binding consistent with the core conserved function. Reason: Matches the well-supported core Ca2+-binding function. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0050821 protein stabilization	ISS GO_REF:0000024	ACCEPT	Summary: Sequence/orthology-transferred protein stabilization consistent with the core chaperone role. Reason: Matches the supported chaperone-mediated stabilization function. Supporting Evidence: PMID:17563366 CRT was unique in stabilizing the disease variant and in augmenting hIR expression when glycolysis was abrogated.
GO:0031625 ubiquitin protein ligase binding	IPI PMID:8666824 Calreticulin binds hYRNA and the 52-kDa polypeptide componen...	KEEP AS NON CORE	Summary: Binding to the TRIM21/Ro52 (an E3 ligase) autoantigen; a specific but non-core interaction. Reason: Specific documented interaction (Ro/SS-A context); secondary to the ER chaperone role. Supporting Evidence: PMID:8666824 Calreticulin binds hYRNA and the 52-kDa polypeptide component of the Ro/SS-A ribonucleoprotein autoantigen.
GO:0044183 protein folding chaperone	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	ACCEPT	Summary: Protein folding chaperone is an accurate core molecular function for calreticulin. Reason: Calreticulin is a bona fide molecular chaperone. Supporting Evidence: PMID:15474971 Calreticulin is also an important molecular chaperone involved in "quality control" within secretory pathways.
GO:0003729 mRNA binding	IDA PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of...	KEEP AS NON CORE	Summary: mRNA binding (p21 mRNA) reflects cytosolic moonlighting; non-core molecular function. Reason: Documented cytosolic mRNA-binding moonlighting; secondary to the ER lectin-chaperone role. Supporting Evidence: PMID:14726956 Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate
GO:0017148 negative regulation of translation	TAS PMID:12242300 Calreticulin interacts with C/EBPalpha and C/EBPbeta mRNAs a...	KEEP AS NON CORE	Summary: Cytosolic calreticulin represses translation of C/EBP mRNAs; a moonlighting activity, non-core. Reason: Documented cytosolic translational-repression moonlighting; secondary to the ER role. Supporting Evidence: PMID:12242300 Calreticulin interacts with C/EBPalpha and C/EBPbeta mRNAs and represses translation of C/EBP proteins.
GO:0050821 protein stabilization	TAS PMID:10581245 Calreticulin functions in vitro as a molecular chaperone for...	ACCEPT	Summary: Protein stabilization via in vitro chaperone activity (glycosylated and non-glycosylated substrates); consistent with the core chaperone role. Reason: Supported chaperone-mediated stabilization function. Supporting Evidence: PMID:10581245 Calreticulin functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins.
GO:0001849 complement component C1q complex binding	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	KEEP AS NON CORE	Summary: C1q complex binding is a documented immune/extracellular function but non-core. Reason: Specific supported interaction relevant to complement/clearance; secondary to the ER role. Supporting Evidence: PMID:15474971 The protein also plays an important role in autoimmunity and cancer.
GO:0002502 peptide antigen assembly with MHC class I protein complex	ISS PMID:11825569 Assembly and antigen-presenting function of MHC class I mole...	KEEP AS NON CORE	Summary: MHC class I peptide antigen assembly is supported; CALR-null cells have impaired MHC I assembly. Reason: Specialized application of the lectin-chaperone function; well supported but secondary to general glycoprotein folding. Supporting Evidence: PMID:11825569 Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin
GO:0008270 zinc ion binding	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	MARK AS OVER ANNOTATED	Summary: Zinc ion binding has been reported but is weakly supported relative to the well-characterized Ca2+-binding function; not a core function. Reason: Minor/uncertain metal-binding property; not a credible core molecular function.
GO:0009986 cell surface	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	KEEP AS NON CORE	Summary: Cell-surface localization is real (eat-me signal) but non-core. Reason: Documented surface exposure; secondary to ER function. Supporting Evidence: PMID:10358038 the 60-kDa calreticulin was labeled by cell surface biotinylation and precipitated from the surface of activated T cells
GO:0030246 carbohydrate binding	TAS PMID:15474971 Calreticulin, a Ca2+-binding chaperone of the endoplasmic re...	ACCEPT	Summary: Carbohydrate (monoglucosylated N-glycan) binding is a core lectin molecular function. Reason: Underlies the lectin-chaperone activity of calreticulin. Supporting Evidence: PMID:15056662 Major histocompatibility complex class I molecules expressed with monoglucosylated N-linked glycans bind calreticulin
GO:0042824 MHC class I peptide loading complex	ISS PMID:11825569 Assembly and antigen-presenting function of MHC class I mole...	KEEP AS NON CORE	Summary: Calreticulin is a component of the MHC class I peptide loading complex. Reason: Well-supported specialized complex membership; secondary to general glycoprotein folding. Supporting Evidence: PMID:11825569 Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin
GO:0050766 positive regulation of phagocytosis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Surface calreticulin promotes phagocytosis (eat-me signal); a real but non-core role. Reason: Documented immunogenic-cell-death/eat-me biology; secondary to ER function.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	MARK AS OVER ANNOTATED	Summary: Derives from in vitro inhibition of nuclear hormone receptor activity via the KxFFKR DNA-binding-domain motif; a moonlighting effect rather than direct transcriptional regulation. Reason: Calreticulin is not a transcription factor; the effect is indirect via receptor sequestration and is non-core. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0005178 integrin binding	IPI PMID:1911778 In vitro interaction of a polypeptide homologous to human Ro...	KEEP AS NON CORE	Summary: In vitro binding to the conserved KLGFFKR integrin alpha cytoplasmic-tail motif; a biochemically documented but cytosolic non-core interaction. Reason: Specific documented binding; cytosolic and not the conserved ER function. Supporting Evidence: PMID:1911778 a highly conserved motif in the cytoplasmic domain adjacent to the transmembrane domain of the alpha subunit of integrins
GO:0005634 nucleus	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	KEEP AS NON CORE	Summary: Nuclear localization linked to the steroid-receptor moonlighting reports; a minor non-core pool. Reason: Minor nuclear pool tied to moonlighting; secondary to ER function.
GO:0005737 cytoplasm	IDA PMID:1911778 In vitro interaction of a polypeptide homologous to human Ro...	KEEP AS NON CORE	Summary: Cytoplasmic localization supports cytosolic moonlighting functions; non-core. Reason: Documented cytoplasmic pool; secondary to ER function.
GO:0033144 negative regulation of intracellular steroid hormone receptor signaling pathway	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	KEEP AS NON CORE	Summary: In vitro inhibition of steroid receptor signaling via the KxFFKR motif; a documented but non-core moonlighting activity. Reason: Specific documented effect on steroid-receptor signaling; secondary to the ER chaperone function. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0042921 nuclear receptor-mediated glucocorticoid signaling pathway	TAS PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	KEEP AS NON CORE	Summary: Related to the glucocorticoid-receptor inhibition moonlighting role; non-core. Reason: Documented GR-related effect; secondary to the ER function. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0045665 negative regulation of neuron differentiation	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	MARK AS OVER ANNOTATED	Summary: Derives from inhibition of retinoic-acid/nuclear-receptor signaling in the same in vitro study; over-broad downstream effect. Reason: Indirect downstream developmental effect of receptor inhibition; not a core function.
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	MARK AS OVER ANNOTATED	Summary: Indirect transcriptional effect via nuclear-receptor sequestration; over-broad. Reason: Calreticulin is not a transcription factor; the effect is indirect and non-core. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0048387 negative regulation of retinoic acid receptor signaling pathway	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	KEEP AS NON CORE	Summary: In vitro inhibition of retinoic-acid receptor signaling via the KxFFKR motif; documented but non-core moonlighting. Reason: Specific documented effect on a nuclear receptor; secondary to the ER function. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0048471 perinuclear region of cytoplasm	IDA PMID:1911778 In vitro interaction of a polypeptide homologous to human Ro...	KEEP AS NON CORE	Summary: Perinuclear cytoplasm localization reflects the perinuclear ER distribution; descriptive non-core localization. Reason: Consistent with perinuclear ER; not a distinct functional compartment.
GO:0050681 nuclear androgen receptor binding	IDA PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticu...	KEEP AS NON CORE	Summary: Calreticulin binds the androgen receptor DNA-binding domain (KxFFKR motif) in vitro; a specific but non-core moonlighting interaction. Reason: Specific documented binding underlying the steroid-receptor inhibition; secondary to the ER function. Supporting Evidence: PMID:8107809 Inhibition of nuclear hormone receptor activity by calreticulin.
GO:0042981 regulation of apoptotic process	TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied...	MARK AS OVER ANNOTATED	Summary: Apoptosis regulation is an over-broad downstream association from an apoptosis proteomics study. Reason: Over-broad BP; not a direct calreticulin molecular function.
GO:0005783 endoplasmic reticulum	TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied...	ACCEPT	Summary: ER localization consistent with the core compartment. Reason: Matches the established ER localization.
GO:0003677 DNA binding	NAS PMID:11149926 Calreticulin Is a receptor for nuclear export.	MARK AS OVER ANNOTATED	Summary: DNA binding is a non-authored-statement claim with weak support; not a credible core molecular function. Reason: Poorly supported; calreticulin is not a bona fide DNA-binding protein.
GO:0005509 calcium ion binding	TAS PMID:11149926 Calreticulin Is a receptor for nuclear export.	ACCEPT	Summary: Calcium ion binding is a core conserved molecular function. Reason: Well-supported core Ca2+-binding function. Supporting Evidence: PMID:15474971 Calreticulin is a 46-kDa Ca2+-binding chaperone found across a diverse range of species.
GO:0005788 endoplasmic reticulum lumen	IDA PMID:11149926 Calreticulin Is a receptor for nuclear export.	ACCEPT	Summary: Direct ER lumen localization consistent with the core compartment. Reason: Reinforces the established ER-luminal localization.
GO:0005829 cytosol	IDA PMID:11149926 Calreticulin Is a receptor for nuclear export.	KEEP AS NON CORE	Summary: A cytosolic pool supports the nuclear-export moonlighting role; non-core. Reason: Documented cytosolic pool; secondary to ER function.
GO:0006611 protein export from nucleus	IDA PMID:11149926 Calreticulin Is a receptor for nuclear export.	KEEP AS NON CORE	Summary: Cytosolic calreticulin mediates nuclear export of the glucocorticoid receptor; a moonlighting activity, non-core. Reason: Documented nuclear-export moonlighting; secondary to the ER chaperone role. Supporting Evidence: PMID:11149926 Calreticulin Is a receptor for nuclear export.
GO:0006874 intracellular calcium ion homeostasis	TAS PMID:11149926 Calreticulin Is a receptor for nuclear export.	ACCEPT	Summary: Regulation of intracellular calcium homeostasis is a core biological process for calreticulin. Reason: Calreticulin is the major ER Ca2+ store and regulates ER/intracellular Ca2+ handling. Supporting Evidence: PMID:15474971 The protein is involved in the regulation of intracellular Ca2+ homeostasis and endoplasmic reticulum (ER) Ca2+ storage capacity.
GO:0006355 regulation of DNA-templated transcription	TAS PMID:8107808 Modulation of gene expression by calreticulin binding to the...	MARK AS OVER ANNOTATED	Summary: Broad transcription-regulation claim from the glucocorticoid-receptor modulation study; indirect and over-broad. Reason: Calreticulin is not a transcription factor; the effect is indirect via receptor binding. Supporting Evidence: PMID:8107808 Modulation of gene expression by calreticulin binding to the glucocorticoid receptor.
GO:0005509 calcium ion binding	TAS PMID:7841019 Human placental calreticulin: purification, characterization...	ACCEPT	Summary: Calcium ion binding established in placental calreticulin characterization; core molecular function. Reason: Supports the well-established core Ca2+-binding function. Supporting Evidence: PMID:7841019 Human placental calreticulin: purification, characterization and association with other proteins.

Gene Description

Existing Annotations Review

Core Functions

Lectin chaperone that binds monoglucosylated N-glycans on nascent glycoproteins in the ER lumen and, with ERp57 and cyclophilin B recruited via its P domain, promotes their folding and oligomeric assembly as part of the calnexin/calreticulin cycle.

Lectin that recognizes monoglucosylated N-glycans, providing the carbohydrate-binding specificity that underlies glycoprotein quality control and retention of incompletely folded clients.

High-capacity calcium-binding protein that buffers ER calcium and regulates intracellular calcium homeostasis and ER calcium storage capacity.

References

Suggested Questions for Experts

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📚 Additional Documentation

Notes

Pn Notes

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