CALCOCO1 (Calcium-binding and coiled-coil domain-containing protein 1; also known as CoCoA/coiled-coil coactivator and calphoglin) is a multidomain protein built from an N-terminal SKICH domain, a central CALCOCO1 domain with several coiled-coil segments, a disordered region, and a C-terminal UBZ1-type zinc finger. It is a soluble selective-autophagy cargo receptor that mediates turnover of the endoplasmic reticulum (reticulophagy/ER-phagy) and of the Golgi apparatus (Golgiphagy). In this role it binds membrane-associated ER/Golgi proteins on one side and members of the ATG8 family (LC3/GABARAP, in particular GABARAPL1 and GABARAPL2) on the other through LIR- and UIM/UDS-type interaction motifs, thereby tethering organelle fragments to the forming autophagosome. CALCOCO1 acts predominantly in the cytoplasm. Independently of autophagy, CALCOCO1 has a long-standing characterization as a nuclear transcriptional coactivator (CoCoA) that shuttles between cytoplasm and nucleus and acts as a secondary/bridging coactivator for nuclear receptors, the aryl hydrocarbon receptor, and the Wnt/beta-catenin (CTNNB1) and LEF1/TCF pathways, cooperating with p160 coactivators (GRIP1/NCOA2), p300/CBP, CARM1, and with CCAR1/MED1 (for example enhancing GATA1-driven transcription during erythroid differentiation). It has also been reported as a component of a calphoglin complex that activates inorganic pyrophosphatase and phosphoglucomutase.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003713 transcription coactivator activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) transfer of the historical CoCoA transcriptional coactivator activity. This is a real but secondary/context-dependent nuclear function rather than the current core selective-autophagy receptor role. Reason: Coactivator activity is supported by human and ortholog experimental data (e.g. beta-catenin/TCF and GATA1/MED1 coactivation), so the term should be retained, but it is a secondary nuclear function distinct from the core autophagy-receptor activity. Supporting Evidence: PMID:16344550 another component of the p160 nuclear receptor coactivator complex, the coiled-coil file:human/CALCOCO1/CALCOCO1-uniprot.txt Functions as a coactivator for aryl hydrocarbon and nuclear |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA transfer of a positive transcriptional regulation role, consistent with the CoCoA coactivator function in beta-catenin/TCF and GATA1-driven transcription. Reason: Supported by experimental coactivation data but represents the secondary nuclear function rather than the core autophagy-receptor activity. Supporting Evidence: PMID:16344550 reduction of the endogenous CoCoA level decreased the ability of TCF/LEF and beta-catenin to activate transcription |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nuclear localization is consistent with the CoCoA coactivator function and with the UniProt note that the protein shuttles between nucleus and cytoplasm. Reason: Nuclear residence is real and supports the coactivator role, but the principal compartment for the core autophagy-receptor activity is the cytoplasm. Supporting Evidence: file:human/CALCOCO1/CALCOCO1-uniprot.txt Shuttles between nucleus |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization is well supported and is the principal compartment for the selective-autophagy receptor activity of CALCOCO1. Reason: The cytoplasm is the main site of action for the core autophagy-receptor function, and UniProt records cytoplasmic localization with nucleocytoplasmic shuttling. Supporting Evidence: file:human/CALCOCO1/CALCOCO1-uniprot.txt Cytoplasm. Nucleus. Note=Shuttles between nucleus |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding annotation from a proteome-scale yeast two-hybrid map; uninformative as to the specific molecular function. Reason: Bare protein binding from a high-throughput interactome screen does not identify a physiologically interpretable function for CALCOCO1. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Generic protein-binding annotation from a proteome-scale interactome map; the partner list includes the ATG8 family member GABARAPL2 but the term itself is uninformative. Reason: Bare protein binding is too general; the more meaningful biology (ATG8/GABARAP binding underlying the autophagy-receptor role) is captured in core_functions and the NEW GO:0160247/GO:0061709 recommendations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Generic protein-binding annotation from the HuRI binary interactome; partners include GABARAPL1 and GABARAPL2, but the GO term conveys no specific function. Reason: Bare protein binding from a high-throughput screen is uninformative for curation. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding annotation from the BioPlex proteome-scale interactome. Reason: Bare protein binding from a high-throughput affinity-purification screen does not establish a specific CALCOCO1 function. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding annotation from a multimodal cell-map interactome study. Reason: Bare protein binding from a high-throughput dataset is uninformative as a molecular function. |
| GO:0000785 chromatin | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Chromatin localization transferred by Ensembl Compara from the mouse ortholog; consistent with the coactivator (CoCoA) role and promoter association by ChIP, but it is a secondary nuclear function. Reason: Promoter/chromatin association is supported for the coactivator function but is not the core autophagy-receptor activity. Supporting Evidence: PMID:16344550 CoCoA associated specifically with the promoters |
| GO:0003682 chromatin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Chromatin binding transferred from the mouse ortholog; consistent with the promoter association of the CoCoA coactivator, but a secondary nuclear function. Reason: Supported by ChIP promoter-association data for the coactivator role; not the core autophagy-receptor activity. Supporting Evidence: PMID:16344550 CoCoA associated specifically with the promoters |
| GO:0003713 transcription coactivator activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automated (multi-method IEA) assignment of transcription coactivator activity, consistent with the experimentally supported CoCoA role. Reason: Redundant with the IBA/ISS/IMP coactivator annotations; supported but secondary to the core autophagy-receptor activity. Supporting Evidence: file:human/CALCOCO1/CALCOCO1-uniprot.txt Functions as a coactivator for aryl hydrocarbon and nuclear |
| GO:0007165 signal transduction | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Very broad signal transduction term transferred from the mouse ortholog; too general to be informative for CALCOCO1. Reason: Signal transduction is an over-broad parent term that does not capture either the coactivator or the autophagy-receptor function. |
| GO:0030518 nuclear receptor-mediated steroid hormone signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Steroid-hormone nuclear-receptor signaling transferred from the mouse ortholog; consistent with the CoCoA coactivator role for nuclear receptors such as the androgen receptor, but a secondary function. Reason: The coactivator function for nuclear receptors is supported, but this pathway is secondary to the core autophagy-receptor activity. Supporting Evidence: file:human/CALCOCO1/CALCOCO1-uniprot.txt Functions as a coactivator for aryl hydrocarbon and nuclear |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Automated ortholog transfer of positive regulation of Pol II transcription; redundant with the IBA/ISS coactivator annotations. Reason: Supported by experimental coactivation data but is a secondary nuclear function. Supporting Evidence: PMID:16344550 reduction of the endogenous CoCoA level decreased the ability of TCF/LEF and beta-catenin to activate transcription |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct (immunofluorescence/HPA) evidence for cytosolic localization, consistent with the cytoplasmic site of action of the autophagy-receptor function. Reason: Cytosolic localization is directly observed and matches the principal compartment for the core selective-autophagy receptor activity. Supporting Evidence: file:human/CALCOCO1/CALCOCO1-uniprot.txt Cytoplasm. Nucleus. Note=Shuttles between nucleus |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence/orthology transfer of positive regulation of Pol II transcription; consistent with the CoCoA coactivator role. Reason: Supported but redundant with other coactivator annotations and secondary to the core autophagy-receptor function. Supporting Evidence: PMID:16344550 reduction of the endogenous CoCoA level decreased the ability of TCF/LEF and beta-catenin to activate transcription |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:24245781 CCAR1/CoCoA pair-mediated recruitment of the Mediator define... | MODIFY | Summary: This annotation reads as direct sequence-specific DNA binding, but CALCOCO1/CoCoA is a coactivator recruited to promoters via transcription factors such as GATA1 rather than a sequence-specific DNA-binding protein; the ChIP signal reflects promoter occupancy through protein-protein interactions. Reason: CALCOCO1 lacks a sequence-specific DNA-binding domain and is recruited to the gamma-globin promoter via GATA1/CCAR1/MED1; the evidence supports a transcription coregulator/coactivator role rather than direct cis-regulatory DNA binding. Proposed replacements: transcription coregulator activity Supporting Evidence: PMID:24245781 GATA1, MED1, CCAR1, and CoCoA were all recruited onto the PMID:24245781 the GATA1 CF domain serves as a docking surface for multiple coactivators, including CoCoA, CCAR1, and MED1 |
| GO:0003713 transcription coactivator activity | IMP PMID:24245781 CCAR1/CoCoA pair-mediated recruitment of the Mediator define... | KEEP AS NON CORE | Summary: Human experimental (IMP) support for the coactivator function; CoCoA cooperates with CCAR1 to enhance GATA1/MED1-driven gamma-globin transcription, and CoCoA knockdown reduces GATA1 target gene expression. Reason: This is well-supported human experimental evidence for the coactivator function, but it is a secondary/context-dependent nuclear role distinct from the core autophagy-receptor activity. Supporting Evidence: PMID:24245781 Recombinant GATA1, CCAR1, CoCoA and MED1(1-602) formed a PMID:24245781 the GATA1 CF domain serves as a docking surface for multiple coactivators, including CoCoA, CCAR1, and MED1 |
| GO:0005634 nucleus | IDA GO_REF:0000054 | KEEP AS NON CORE | Summary: Direct evidence (expressed fusion protein) for nuclear localization, consistent with the nucleocytoplasmic shuttling and the CoCoA coactivator role. Reason: Nuclear localization is directly observed and supports the coactivator function, but the cytoplasm is the principal site for the core autophagy-receptor activity. Supporting Evidence: file:human/CALCOCO1/CALCOCO1-uniprot.txt Shuttles between nucleus |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:16344550 Differential use of functional domains by coiled-coil coacti... | KEEP AS NON CORE | Summary: CoCoA enhances beta-catenin/TCF-LEF and androgen-receptor transcriptional activation, and its knockdown reduces target-gene transcription; supports a positive transcriptional regulation role. Reason: Supported human experimental evidence for the coactivator function, but secondary to the core autophagy-receptor activity. Supporting Evidence: PMID:16344550 reduction of the endogenous CoCoA level decreased the ability of TCF/LEF and beta-catenin to activate transcription |
| GO:0003712 transcription coregulator activity | IDA PMID:16344550 Differential use of functional domains by coiled-coil coacti... | KEEP AS NON CORE | Summary: Direct evidence that CoCoA acts as a transcriptional coregulator/coactivator synergizing with beta-catenin for AR and TCF/LEF targets. Reason: Well-supported molecular function for the historical CoCoA role; secondary to the core autophagy-receptor activity. Supporting Evidence: PMID:16344550 directly binds to and cooperates |
| GO:0003713 transcription coactivator activity | IMP PMID:16344550 Differential use of functional domains by coiled-coil coacti... | KEEP AS NON CORE | Summary: IMP support for transcription coactivator activity via CoCoA cooperation with beta-catenin for AR and TCF/LEF target genes. Reason: Well-supported coactivator function; secondary to the core autophagy-receptor activity. Supporting Evidence: PMID:16344550 cooperates synergistically with |
| GO:0005515 protein binding | IPI PMID:16344550 Differential use of functional domains by coiled-coil coacti... | MODIFY | Summary: The underlying evidence is a specific direct interaction of CoCoA with beta-catenin (CTNNB1), which is better captured by the more informative beta-catenin binding term that is also annotated from this same paper. Reason: Bare protein binding is uninformative; the specific, supported interaction is with beta-catenin, for which a dedicated GO term exists. Proposed replacements: beta-catenin binding Supporting Evidence: PMID:16344550 directly binds to and cooperates |
| GO:0008013 beta-catenin binding | IPI PMID:16344550 Differential use of functional domains by coiled-coil coacti... | KEEP AS NON CORE | Summary: Direct interaction between CoCoA and beta-catenin (CTNNB1) underpins its synergistic coactivator function in the Wnt/beta-catenin and androgen-receptor pathways. Reason: Specific and well-supported binding for the coactivator role, but part of the secondary nuclear function rather than the core autophagy-receptor activity. Supporting Evidence: PMID:16344550 directly binds to and cooperates |
| GO:0043565 sequence-specific DNA binding | IDA PMID:16344550 Differential use of functional domains by coiled-coil coacti... | MODIFY | Summary: CoCoA is a coactivator recruited to promoters via DNA-bound transcription factors such as TCF/LEF and beta-catenin rather than a sequence-specific DNA-binding protein; the ChIP promoter association reflects recruitment, not intrinsic DNA-sequence recognition. Reason: CALCOCO1 has no sequence-specific DNA-binding domain; the supported activity is transcription coregulator/coactivator function with promoter association mediated by protein-protein interactions. Proposed replacements: transcription coregulator activity Supporting Evidence: PMID:16344550 CoCoA associated specifically with the promoters |
| GO:0010628 positive regulation of gene expression | IDA PMID:16344550 Differential use of functional domains by coiled-coil coacti... | KEEP AS NON CORE | Summary: Broad positive-regulation-of-gene-expression term supported by the coactivator activity of CoCoA on beta-catenin/TCF-LEF and AR target genes; more specifically captured by the positive regulation of Pol II transcription annotations. Reason: Supported but broad; redundant with the more specific transcription-regulation terms and secondary to the core autophagy-receptor activity. Supporting Evidence: PMID:16344550 reduction of the endogenous CoCoA level decreased the ability of TCF/LEF and beta-catenin to activate transcription |
| GO:0003713 transcription coactivator activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence/orthology transfer of transcription coactivator activity, consistent with the experimentally supported CoCoA role. Reason: Redundant with the IBA/IEA/IMP coactivator annotations; supported but secondary to the core autophagy-receptor activity. Supporting Evidence: file:human/CALCOCO1/CALCOCO1-uniprot.txt Functions as a coactivator for aryl hydrocarbon and nuclear |
| GO:0007165 signal transduction | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Very broad signal transduction term transferred by orthology; too general to be informative for CALCOCO1. Reason: Over-broad parent term that does not capture the coactivator or autophagy-receptor function. |
| GO:0030518 nuclear receptor-mediated steroid hormone signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Orthology transfer of steroid-hormone nuclear-receptor signaling, consistent with the CoCoA coactivator role for nuclear receptors such as the androgen receptor. Reason: Supported for the coactivator function but secondary to the core autophagy-receptor activity. Supporting Evidence: PMID:16344550 the androgen receptor (AR), a nuclear |
| GO:0160247 autophagy cargo adaptor activity | IDA PMID:31971854 Mass spectrometry proteomics reveals a function for mammalia... | NEW | Summary: CALCOCO1 acts as an autophagy cargo adaptor/receptor, binding ATG8-family proteins and linking ER cargo to the autophagy machinery. Reason: The PN review showed that the proposed reticulophagy/Golgiphagy receptor MF requests duplicate an existing GO term. GO:0160247 captures the cargo-adaptor activity without minting a bespoke receptor term. Supporting Evidence: PMID:31971854 CALCOCO1 physically interacts with MAP1LC3C, a key protein in the machinery of autophagy file:human/CALCOCO1/CALCOCO1-uniprot.txt Q9H0R8: GABARAPL1 |
| GO:0061709 reticulophagy | IMP PMID:31971854 Mass spectrometry proteomics reveals a function for mammalia... | NEW | Summary: Genetic deletion of CALCOCO1 disrupts autophagy of the endoplasmic reticulum, supporting a specific reticulophagy process annotation. Reason: PN correctly projected the ER-phagy node to existing GO:0061709. This is more precise than generic selective autophagy and avoids treating the Golgi-associated report as a broad propagating assertion. Supporting Evidence: PMID:31971854 Genetic deletion of CALCOCO1 disrupted autophagy of the endoplasmic reticulum (reticulophagy) |
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Download this section (compressed HTML)Q: Which ER and Golgi membrane proteins does CALCOCO1 recognize as cargo, and what are the precise LIR/UDS motifs that mediate ATG8-family (LC3/GABARAP) binding?
Q: How is CALCOCO1 partitioned between its cytoplasmic autophagy-receptor function and its nuclear coactivator (CoCoA) function, and is the nucleocytoplasmic shuttling regulated by autophagy or stress signaling?
Q: Is the historical calphoglin activity (activation of inorganic pyrophosphatase and phosphoglucomutase) a genuine independent function of CALCOCO1, or an artifact of the original complex preparation?
Experiment: Map the CALCOCO1 LIR/UDS motifs by mutagenesis and quantify binding to each ATG8-family member (LC3A/B/C, GABARAP, GABARAPL1, GABARAPL2) using isothermal titration calorimetry or pulldown, and test whether motif mutants abolish reticulophagy/Golgiphagy in cells.
Hypothesis: CALCOCO1 engages GABARAP-subfamily ATG8 proteins through defined LIR/UDS motifs that are required for ER-phagy and Golgiphagy.
Type: biochemical interaction mapping and cell-based autophagy flux assay
Experiment: Use CALCOCO1 knockout and rescue (wild-type vs ATG8-binding-deficient mutant) cells with ER- and Golgi-targeted autophagy flux reporters to quantify the contribution of CALCOCO1 to reticulophagy and Golgiphagy under basal and stress conditions.
Hypothesis: Loss of CALCOCO1 selectively impairs ER-phagy and Golgiphagy without affecting bulk autophagy.
Type: genetic loss-of-function with organelle-specific autophagy reporters
Experiment: Determine the subcellular distribution and functional separability of the autophagy-receptor versus coactivator roles by domain-swap and localization mutants, testing reticulophagy flux and TCF/LEF or GATA1 reporter activity in parallel.
Hypothesis: The cytoplasmic autophagy-receptor function and the nuclear coactivator function are mediated by distinct domains and can be uncoupled.
Type: structure-function and dual-readout reporter assays
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