{"gene":"CALCOCO1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2020,"finding":"CALCOCO1 acts as a soluble ER-phagy receptor that binds directly to ATG8 proteins via LIR and UDS-interacting region (UIR) motifs acting co-dependently, and interacts with VAMP-associated proteins VAPA and VAPB on ER membranes via a conserved FFAT-like motif. CALCOCO1 is a homomeric protein peripherally associated with the ER. Depletion of CALCOCO1 causes expansion of the ER and inefficient basal autophagy flux.","method":"Co-immunoprecipitation, pulldown assays, mutagenesis of LIR/UIR motifs, live imaging, siRNA depletion with ER morphology readout, autophagic flux assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of binding motifs, multiple orthogonal methods (interaction mapping, localization, functional depletion phenotype) in a focused mechanistic study","pmids":["32525583"],"is_preprint":false},{"year":2020,"finding":"CALCOCO1 physically interacts with MAP1LC3C (a key ATG8-family protein in autophagy machinery), and genetic deletion of CALCOCO1 disrupts selective autophagy of the endoplasmic reticulum (reticulophagy). CALCOCO1 abundance is regulated by the MTOR-autophagy axis.","method":"Mass spectrometry proteomics, co-immunoprecipitation, CALCOCO1 knockout cell lines with reticulophagy phenotypic readout, MTOR inhibitor treatment","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification plus Co-IP and KO phenotype, single lab, two orthogonal methods","pmids":["31971854"],"is_preprint":false},{"year":2021,"finding":"CALCOCO1 functions as a Golgiphagy receptor in response to nutrient deprivation. It interacts with cytoplasmic Ankyrin repeat (AR) domains of Golgi-resident ZDHHC17 and ZDHHC13 palmitoyltransferases via a defined zDHHC-AR-binding motif (zDABM) to recruit autophagy machinery. Loss of CALCOCO1 causes impaired Golgiphagy and expansion of the Golgi.","method":"Co-immunoprecipitation, mutagenesis of zDABM motif, Golgi morphology analysis upon CALCOCO1 depletion/knockout","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined binding motif with mutagenesis, interaction mapping with specific Golgi PATs, loss-of-function Golgi expansion phenotype, multiple orthogonal methods","pmids":["34162311"],"is_preprint":false},{"year":2004,"finding":"Calphoglin (CALCOCO1) interacts with inorganic pyrophosphatase (IPP) and activates it; it also enhances phosphoglucomutase (PGM) activity both through activated IPP and independently. The calphoglin-IPP-PGM complex is conserved from bacteria to mammals. Calphoglin co-localizes with the calmodulin/calcineurin signaling complex, binds Ca2+, and its IPP activation is Ca2+-controlled. Calphoglin also enhances microsomal Ca2+ uptake.","method":"Yeast proteomic data, phosphoryl-transfer experiments, co-localization assays, Ca2+-binding assays, microsomal Ca2+ uptake assay, in vitro enzyme activity assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzyme activation assays with multiple substrates, co-localization, Ca2+ binding, single lab with several orthogonal methods","pmids":["15522220"],"is_preprint":false},{"year":2003,"finding":"CoCoA (CALCOCO1) binds to the N-terminal bHLH-PAS domain of p160 coactivators (e.g., GRIP1) and thereby enhances transcriptional activation by the estrogen receptor and other nuclear receptors. Endogenous CoCoA is recruited to the promoter of endogenous estrogen-responsive genes simultaneously with p160 coactivators. Reduction of endogenous CoCoA inhibits estrogen-stimulated gene expression. CoCoA cooperates synergistically with GRIP1, CARM1, and p300 to enhance ER-mediated transcription.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown of endogenous CoCoA, reporter gene transcription assays, domain mapping","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, loss-of-function (siRNA), reporter assays, and domain mapping across multiple orthogonal methods in a single rigorous study","pmids":["14690606"],"is_preprint":false},{"year":2019,"finding":"miR-574-5p directly targets the CALCOCO1 3'UTR to suppress CALCOCO1 expression, as validated by dual-luciferase reporter assay. The lncRNA LINC00052 acts as a sponge for miR-574-5p, thereby relieving miR-574-5p-mediated repression of CALCOCO1, placing CALCOCO1 downstream in the LINC00052/miR-574-5p regulatory axis in colorectal cancer cells.","method":"Dual-luciferase reporter assay, qRT-PCR, Western blot, bioinformatics target prediction, in vivo and in vitro migration/invasion assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter validation of miRNA-target interaction, single lab, functional consequence shown indirectly through lncRNA sponge mechanism","pmids":["31104316"],"is_preprint":false}],"current_model":"CALCOCO1 (calphoglin/CoCoA) is a multifunctional soluble protein that acts as a selective autophagy receptor for both ER-phagy (reticulophagy) and Golgiphagy—binding ATG8 proteins via LIR/UIR motifs, tethering to ER membranes through VAPA/VAPB via an FFAT-like motif, and tethering to Golgi membranes through ZDHHC17/ZDHHC13 palmitoyltransferases via a zDABM motif—while also functioning as a nuclear receptor coactivator by binding the bHLH-PAS domain of p160 coactivators to enhance estrogen receptor-mediated transcription, and as an activator of the metabolic enzymes inorganic pyrophosphatase (IPP) and phosphoglucomutase (PGM) within a Ca2+-regulated complex."},"narrative":{"mechanistic_narrative":"CALCOCO1 is a soluble selective-autophagy receptor that links membrane organelle turnover to the core autophagy machinery [PMID:32525583, PMID:34162311]. It binds ATG8-family proteins directly through co-dependent LIR and UDS-interacting region (UIR) motifs, including an interaction with MAP1LC3C, and its abundance is controlled by the MTOR-autophagy axis [PMID:32525583, PMID:31971854]. As an ER-phagy receptor, CALCOCO1 tethers to the ER by engaging VAPA and VAPB through a conserved FFAT-like motif, and its loss causes ER expansion and inefficient basal autophagic flux [PMID:32525583, PMID:31971854]. As a Golgiphagy receptor active under nutrient deprivation, it docks on Golgi-resident ZDHHC17 and ZDHHC13 palmitoyltransferases via a zDHHC-AR-binding motif (zDABM), with depletion causing impaired Golgiphagy and Golgi expansion [PMID:34162311]. Independently of its autophagy role, CALCOCO1 (CoCoA) functions as a nuclear receptor coactivator, binding the bHLH-PAS domain of p160 coactivators such as GRIP1 and acting synergistically with CARM1 and p300 to enhance estrogen receptor-mediated transcription at endogenous estrogen-responsive promoters [PMID:14690606]. It (as calphoglin) also binds Ca2+ and activates the metabolic enzymes inorganic pyrophosphatase and phosphoglucomutase within a Ca2+-regulated complex [PMID:15522220]. CALCOCO1 expression is repressed by miR-574-5p, which is in turn sponged by the lncRNA LINC00052 [PMID:31104316].","teleology":[{"year":2003,"claim":"Established the first molecular function of CALCOCO1 as a transcriptional coactivator, answering what cellular role this previously uncharacterized protein played.","evidence":"Co-IP, ChIP, siRNA knockdown, reporter assays, and domain mapping in nuclear receptor signaling","pmids":["14690606"],"confidence":"High","gaps":["Structural basis of the bHLH-PAS interaction not resolved","Relationship between the nuclear coactivator role and later-defined cytoplasmic autophagy role unaddressed"]},{"year":2004,"claim":"Linked CALCOCO1 to Ca2+-regulated metabolic enzyme activation, defining a distinct biochemical activity for the protein.","evidence":"In vitro enzyme activity assays with IPP and PGM, Ca2+-binding and microsomal uptake assays, co-localization","pmids":["15522220"],"confidence":"Medium","gaps":["Mechanism by which Ca2+ controls IPP activation not defined","Physiological relevance in mammalian cells not established","No structural model of the calphoglin-IPP-PGM complex"]},{"year":2020,"claim":"Identified CALCOCO1 as a soluble ER-phagy receptor, defining how it bridges the ER to the autophagy machinery via dual ATG8- and VAP-binding motifs.","evidence":"Reciprocal Co-IP, pulldowns, LIR/UIR and FFAT-like motif mutagenesis, siRNA depletion with ER morphology and flux readouts; complemented by MS proteomics and KO reticulophagy phenotype","pmids":["32525583","31971854"],"confidence":"High","gaps":["Selectivity determinants among ATG8 family members not fully resolved","Regulation of receptor engagement during the ER-phagy cycle unknown"]},{"year":2021,"claim":"Extended CALCOCO1's receptor function to the Golgi, showing the same protein mediates Golgiphagy through a distinct membrane-tethering motif.","evidence":"Co-IP, zDABM motif mutagenesis, and Golgi morphology analysis upon depletion/knockout under nutrient deprivation","pmids":["34162311"],"confidence":"High","gaps":["How CALCOCO1 partitions between ER and Golgi targets is unknown","Signals selecting Golgiphagy over ER-phagy not defined"]},{"year":2019,"claim":"Placed CALCOCO1 within a non-coding RNA regulatory axis, defining how its expression is post-transcriptionally controlled in cancer cells.","evidence":"Dual-luciferase reporter assay, qRT-PCR, Western blot, migration/invasion assays in colorectal cancer cells","pmids":["31104316"],"confidence":"Medium","gaps":["Functional consequence on autophagy or coactivator roles not tested","Direct effect attributable to CALCOCO1 versus other miR-574-5p targets unresolved"]},{"year":null,"claim":"How CALCOCO1's distinct activities—organelle-selective autophagy, nuclear receptor coactivation, and metabolic enzyme regulation—are coordinated or regulated within a single cell remains unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying mechanism connecting nuclear and cytoplasmic functions","No structural data on full-length CALCOCO1","Tissue- and signal-specific switching between functions uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4]}],"complexes":[],"partners":["VAPA","VAPB","MAP1LC3C","ZDHHC17","ZDHHC13","GRIP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P1Z2","full_name":"Calcium-binding and coiled-coil domain-containing protein 1","aliases":["Calphoglin","Coiled-coil coactivator protein","Sarcoma antigen NY-SAR-3"],"length_aa":691,"mass_kda":77.3,"function":"Functions as a coactivator for aryl hydrocarbon and nuclear receptors (NR). Recruited to promoters through its contact with the N-terminal basic helix-loop-helix-Per-Arnt-Sim (PAS) domain of transcription factors or coactivators, such as NCOA2. During ER-activation acts synergistically in combination with other NCOA2-binding proteins, such as EP300, CREBBP and CARM1. Involved in the transcriptional activation of target genes in the Wnt/CTNNB1 pathway. Functions as a secondary coactivator in LEF1-mediated transcriptional activation via its interaction with CTNNB1. Coactivator function for nuclear receptors and LEF1/CTNNB1 involves differential utilization of two different activation regions (By similarity). In association with CCAR1 enhances GATA1- and MED1-mediated transcriptional activation from the gamma-globin promoter during erythroid differentiation of K562 erythroleukemia cells (PubMed:24245781) Seems to enhance inorganic pyrophosphatase thus activating phosphogluomutase (PMG). Probably functions as a component of the calphoglin complex, which is involved in linking cellular metabolism (phosphate and glucose metabolism) with other core functions including protein synthesis and degradation, calcium signaling and cell growth","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9P1Z2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CALCOCO1","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"AP2B1","stoichiometry":0.2},{"gene":"CYP51A1","stoichiometry":0.2},{"gene":"GRK2","stoichiometry":0.2},{"gene":"SRP14","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CALCOCO1","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CALCOCO1"},"hgnc":{"alias_symbol":["KIAA1536","calphoglin","Cocoa"],"prev_symbol":[]},"alphafold":{"accession":"Q9P1Z2","domains":[{"cath_id":"2.60.40.2840","chopping":"15-122","consensus_level":"high","plddt":88.7638,"start":15,"end":122}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P1Z2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P1Z2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P1Z2-F1-predicted_aligned_error_v6.png","plddt_mean":76.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CALCOCO1","jax_strain_url":"https://www.jax.org/strain/search?query=CALCOCO1"},"sequence":{"accession":"Q9P1Z2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P1Z2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P1Z2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P1Z2"}},"corpus_meta":[{"pmid":"21470061","id":"PMC_21470061","title":"Cocoa 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CALCOCO1 is a homomeric protein peripherally associated with the ER. Depletion of CALCOCO1 causes expansion of the ER and inefficient basal autophagy flux.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, mutagenesis of LIR/UIR motifs, live imaging, siRNA depletion with ER morphology readout, autophagic flux assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of binding motifs, multiple orthogonal methods (interaction mapping, localization, functional depletion phenotype) in a focused mechanistic study\",\n      \"pmids\": [\"32525583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CALCOCO1 physically interacts with MAP1LC3C (a key ATG8-family protein in autophagy machinery), and genetic deletion of CALCOCO1 disrupts selective autophagy of the endoplasmic reticulum (reticulophagy). CALCOCO1 abundance is regulated by the MTOR-autophagy axis.\",\n      \"method\": \"Mass spectrometry proteomics, co-immunoprecipitation, CALCOCO1 knockout cell lines with reticulophagy phenotypic readout, MTOR inhibitor treatment\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification plus Co-IP and KO phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"31971854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CALCOCO1 functions as a Golgiphagy receptor in response to nutrient deprivation. It interacts with cytoplasmic Ankyrin repeat (AR) domains of Golgi-resident ZDHHC17 and ZDHHC13 palmitoyltransferases via a defined zDHHC-AR-binding motif (zDABM) to recruit autophagy machinery. Loss of CALCOCO1 causes impaired Golgiphagy and expansion of the Golgi.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of zDABM motif, Golgi morphology analysis upon CALCOCO1 depletion/knockout\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined binding motif with mutagenesis, interaction mapping with specific Golgi PATs, loss-of-function Golgi expansion phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"34162311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Calphoglin (CALCOCO1) interacts with inorganic pyrophosphatase (IPP) and activates it; it also enhances phosphoglucomutase (PGM) activity both through activated IPP and independently. The calphoglin-IPP-PGM complex is conserved from bacteria to mammals. Calphoglin co-localizes with the calmodulin/calcineurin signaling complex, binds Ca2+, and its IPP activation is Ca2+-controlled. Calphoglin also enhances microsomal Ca2+ uptake.\",\n      \"method\": \"Yeast proteomic data, phosphoryl-transfer experiments, co-localization assays, Ca2+-binding assays, microsomal Ca2+ uptake assay, in vitro enzyme activity assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzyme activation assays with multiple substrates, co-localization, Ca2+ binding, single lab with several orthogonal methods\",\n      \"pmids\": [\"15522220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CoCoA (CALCOCO1) binds to the N-terminal bHLH-PAS domain of p160 coactivators (e.g., GRIP1) and thereby enhances transcriptional activation by the estrogen receptor and other nuclear receptors. Endogenous CoCoA is recruited to the promoter of endogenous estrogen-responsive genes simultaneously with p160 coactivators. Reduction of endogenous CoCoA inhibits estrogen-stimulated gene expression. CoCoA cooperates synergistically with GRIP1, CARM1, and p300 to enhance ER-mediated transcription.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown of endogenous CoCoA, reporter gene transcription assays, domain mapping\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, loss-of-function (siRNA), reporter assays, and domain mapping across multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"14690606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-574-5p directly targets the CALCOCO1 3'UTR to suppress CALCOCO1 expression, as validated by dual-luciferase reporter assay. The lncRNA LINC00052 acts as a sponge for miR-574-5p, thereby relieving miR-574-5p-mediated repression of CALCOCO1, placing CALCOCO1 downstream in the LINC00052/miR-574-5p regulatory axis in colorectal cancer cells.\",\n      \"method\": \"Dual-luciferase reporter assay, qRT-PCR, Western blot, bioinformatics target prediction, in vivo and in vitro migration/invasion assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter validation of miRNA-target interaction, single lab, functional consequence shown indirectly through lncRNA sponge mechanism\",\n      \"pmids\": [\"31104316\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CALCOCO1 (calphoglin/CoCoA) is a multifunctional soluble protein that acts as a selective autophagy receptor for both ER-phagy (reticulophagy) and Golgiphagy—binding ATG8 proteins via LIR/UIR motifs, tethering to ER membranes through VAPA/VAPB via an FFAT-like motif, and tethering to Golgi membranes through ZDHHC17/ZDHHC13 palmitoyltransferases via a zDABM motif—while also functioning as a nuclear receptor coactivator by binding the bHLH-PAS domain of p160 coactivators to enhance estrogen receptor-mediated transcription, and as an activator of the metabolic enzymes inorganic pyrophosphatase (IPP) and phosphoglucomutase (PGM) within a Ca2+-regulated complex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CALCOCO1 is a soluble selective-autophagy receptor that links membrane organelle turnover to the core autophagy machinery [#0, #2]. It binds ATG8-family proteins directly through co-dependent LIR and UDS-interacting region (UIR) motifs, including an interaction with MAP1LC3C, and its abundance is controlled by the MTOR-autophagy axis [#0, #1]. As an ER-phagy receptor, CALCOCO1 tethers to the ER by engaging VAPA and VAPB through a conserved FFAT-like motif, and its loss causes ER expansion and inefficient basal autophagic flux [#0, #1]. As a Golgiphagy receptor active under nutrient deprivation, it docks on Golgi-resident ZDHHC17 and ZDHHC13 palmitoyltransferases via a zDHHC-AR-binding motif (zDABM), with depletion causing impaired Golgiphagy and Golgi expansion [#2]. Independently of its autophagy role, CALCOCO1 (CoCoA) functions as a nuclear receptor coactivator, binding the bHLH-PAS domain of p160 coactivators such as GRIP1 and acting synergistically with CARM1 and p300 to enhance estrogen receptor-mediated transcription at endogenous estrogen-responsive promoters [#4]. It (as calphoglin) also binds Ca2+ and activates the metabolic enzymes inorganic pyrophosphatase and phosphoglucomutase within a Ca2+-regulated complex [#3]. CALCOCO1 expression is repressed by miR-574-5p, which is in turn sponged by the lncRNA LINC00052 [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the first molecular function of CALCOCO1 as a transcriptional coactivator, answering what cellular role this previously uncharacterized protein played.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA knockdown, reporter assays, and domain mapping in nuclear receptor signaling\",\n      \"pmids\": [\"14690606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the bHLH-PAS interaction not resolved\", \"Relationship between the nuclear coactivator role and later-defined cytoplasmic autophagy role unaddressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked CALCOCO1 to Ca2+-regulated metabolic enzyme activation, defining a distinct biochemical activity for the protein.\",\n      \"evidence\": \"In vitro enzyme activity assays with IPP and PGM, Ca2+-binding and microsomal uptake assays, co-localization\",\n      \"pmids\": [\"15522220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Ca2+ controls IPP activation not defined\", \"Physiological relevance in mammalian cells not established\", \"No structural model of the calphoglin-IPP-PGM complex\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified CALCOCO1 as a soluble ER-phagy receptor, defining how it bridges the ER to the autophagy machinery via dual ATG8- and VAP-binding motifs.\",\n      \"evidence\": \"Reciprocal Co-IP, pulldowns, LIR/UIR and FFAT-like motif mutagenesis, siRNA depletion with ER morphology and flux readouts; complemented by MS proteomics and KO reticulophagy phenotype\",\n      \"pmids\": [\"32525583\", \"31971854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity determinants among ATG8 family members not fully resolved\", \"Regulation of receptor engagement during the ER-phagy cycle unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended CALCOCO1's receptor function to the Golgi, showing the same protein mediates Golgiphagy through a distinct membrane-tethering motif.\",\n      \"evidence\": \"Co-IP, zDABM motif mutagenesis, and Golgi morphology analysis upon depletion/knockout under nutrient deprivation\",\n      \"pmids\": [\"34162311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CALCOCO1 partitions between ER and Golgi targets is unknown\", \"Signals selecting Golgiphagy over ER-phagy not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed CALCOCO1 within a non-coding RNA regulatory axis, defining how its expression is post-transcriptionally controlled in cancer cells.\",\n      \"evidence\": \"Dual-luciferase reporter assay, qRT-PCR, Western blot, migration/invasion assays in colorectal cancer cells\",\n      \"pmids\": [\"31104316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence on autophagy or coactivator roles not tested\", \"Direct effect attributable to CALCOCO1 versus other miR-574-5p targets unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CALCOCO1's distinct activities\\u2014organelle-selective autophagy, nuclear receptor coactivation, and metabolic enzyme regulation\\u2014are coordinated or regulated within a single cell remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying mechanism connecting nuclear and cytoplasmic functions\", \"No structural data on full-length CALCOCO1\", \"Tissue- and signal-specific switching between functions uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VAPA\", \"VAPB\", \"MAP1LC3C\", \"ZDHHC17\", \"ZDHHC13\", \"GRIP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}