Affinage

CALCOCO1

Calcium-binding and coiled-coil domain-containing protein 1 · UniProt Q9P1Z2

Length
691 aa
Mass
77.3 kDa
Annotated
2026-06-09
100 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2003 High

    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

    PMID:14690606

    Open questions at the time
    • Structural basis of the bHLH-PAS interaction not resolved
    • Relationship between the nuclear coactivator role and later-defined cytoplasmic autophagy role unaddressed
  2. 2004 Medium

    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

    PMID:15522220

    Open questions at the time
    • 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
  3. 2020 High

    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

    PMID:31971854 PMID:32525583

    Open questions at the time
    • Selectivity determinants among ATG8 family members not fully resolved
    • Regulation of receptor engagement during the ER-phagy cycle unknown
  4. 2021 High

    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

    PMID:34162311

    Open questions at the time
    • How CALCOCO1 partitions between ER and Golgi targets is unknown
    • Signals selecting Golgiphagy over ER-phagy not defined
  5. 2019 Medium

    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

    PMID:31104316

    Open questions at the time
    • Functional consequence on autophagy or coactivator roles not tested
    • Direct effect attributable to CALCOCO1 versus other miR-574-5p targets unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-74160 Gene expression (Transcription) 1
Partners
GRIP1MAP1LC3CVAPAVAPBZDHHC13ZDHHC17

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 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. Co-immunoprecipitation, pulldown assays, mutagenesis of LIR/UIR motifs, live imaging, siRNA depletion with ER morphology readout, autophagic flux assays The EMBO journal High 32525583
2020 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. Mass spectrometry proteomics, co-immunoprecipitation, CALCOCO1 knockout cell lines with reticulophagy phenotypic readout, MTOR inhibitor treatment Autophagy Medium 31971854
2021 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. Co-immunoprecipitation, mutagenesis of zDABM motif, Golgi morphology analysis upon CALCOCO1 depletion/knockout Autophagy High 34162311
2004 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. Yeast proteomic data, phosphoryl-transfer experiments, co-localization assays, Ca2+-binding assays, microsomal Ca2+ uptake assay, in vitro enzyme activity assays Biochemical and biophysical research communications Medium 15522220
2003 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. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown of endogenous CoCoA, reporter gene transcription assays, domain mapping Molecular cell High 14690606
2019 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. Dual-luciferase reporter assay, qRT-PCR, Western blot, bioinformatics target prediction, in vivo and in vitro migration/invasion assays Journal of cellular biochemistry Medium 31104316

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Cocoa and chocolate in human health and disease. Antioxidants & redox signaling 233 21470061
2002 Evidence that the antioxidant flavonoids in tea and cocoa are beneficial for cardiovascular health. Current opinion in lipidology 233 11790962
2000 Cocoa inhibits platelet activation and function. The American journal of clinical nutrition 211 10871557
2013 The neuroprotective effects of cocoa flavanol and its influence on cognitive performance. British journal of clinical pharmacology 141 22775434
2012 Cocoa polyphenols and their potential benefits for human health. Oxidative medicine and cellular longevity 125 23150750
2020 CALCOCO1 acts with VAMP-associated proteins to mediate ER-phagy. The EMBO journal 124 32525583
2000 Cocoa and wine polyphenols modulate platelet activation and function. The Journal of nutrition 122 10917933
2013 Cocoa flavonoids attenuate high glucose-induced insulin signalling blockade and modulate glucose uptake and production in human HepG2 cells. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 116 24262486
2005 Cocoa polyphenols and inflammatory mediators. The American journal of clinical nutrition 113 15640495
2002 The effects of flavanol-rich cocoa and aspirin on ex vivo platelet function. Thrombosis research 113 12297125
2003 CoCoA, a nuclear receptor coactivator which acts through an N-terminal activation domain of p160 coactivators. Molecular cell 110 14690606
2003 Food effects on the absorption and pharmacokinetics of cocoa flavanols. Life sciences 108 12798412
2013 Cocoa flavonoids improve insulin signalling and modulate glucose production via AKT and AMPK in HepG2 cells. Molecular nutrition & food research 106 23456781
2013 Chocolate and the brain: neurobiological impact of cocoa flavanols on cognition and behavior. Neuroscience and biobehavioral reviews 105 23810791
2017 Cocoa and Dark Chocolate Polyphenols: From Biology to Clinical Applications. Frontiers in immunology 92 28649251
2012 Cocoa modulatory effect on rat faecal microbiota and colonic crosstalk. Archives of biochemistry and biophysics 85 22663919
2009 Cocoa: antioxidant and immunomodulator. The British journal of nutrition 84 19126261
2013 Influencing cocoa flavour using Pichia kluyveri and Kluyveromyces marxianus in a defined mixed starter culture for cocoa fermentation. International journal of food microbiology 82 23866910
2013 Effects of dark chocolate and cocoa consumption on endothelial function and arterial stiffness in overweight adults. The British journal of nutrition 82 24274771
2013 Inhibition of α-amylase and glucoamylase by tannins extracted from cocoa, pomegranates, cranberries, and grapes. Journal of agricultural and food chemistry 79 23289516
2016 Effect of Cocoa and Its Flavonoids on Biomarkers of Inflammation: Studies of Cell Culture, Animals and Humans. Nutrients 76 27070643
2013 Cocoa flavonoid epicatechin protects pancreatic beta cell viability and function against oxidative stress. Molecular nutrition & food research 75 24115486
2012 Cocoa polyphenols suppress adipogenesis in vitro and obesity in vivo by targeting insulin receptor. International journal of obesity (2005) 73 22641065
2013 Dietary cocoa ameliorates obesity-related inflammation in high fat-fed mice. European journal of nutrition 68 23494741
2016 Antidiabetic actions of cocoa flavanols. Molecular nutrition & food research 67 26824673
2015 Cocoa flavonoids protect hepatic cells against high-glucose-induced oxidative stress: relevance of MAPKs. Molecular nutrition & food research 67 25594685
2009 Polyphenols from cocoa and vascular health-a critical review. International journal of molecular sciences 64 20057946
2009 Cocoa, chocolate, and cardiovascular disease. Journal of cardiovascular pharmacology 62 19701098
2014 Dietary cocoa protects against colitis-associated cancer by activating the Nrf2/Keap1 pathway. BioFactors (Oxford, England) 61 25545372
2000 Cocoa procyanidins and human cytokine transcription and secretion. The Journal of nutrition 61 10917928
2005 Epicatechin and catechin in cocoa inhibit amyloid beta protein induced apoptosis. Journal of agricultural and food chemistry 60 15740021
2013 Potential for preventive effects of cocoa and cocoa polyphenols in cancer. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 59 23439478
2019 Metagenomics analysis of cocoa bean fermentation microbiome identifying species diversity and putative functional capabilities. Heliyon 55 31388591
2013 Molecular mechanisms underlying the potential antiobesity-related diseases effect of cocoa polyphenols. Molecular nutrition & food research 55 24259381
2011 Chemical composition and physical quality characteristics of Ghanaian cocoa beans as affected by pulp pre-conditioning and fermentation. Journal of food science and technology 55 24426021
2008 Cocoa procyanidins suppress transformation by inhibiting mitogen-activated protein kinase kinase. The Journal of biological chemistry 55 18519570
2007 Cocoa-enriched diet enhances antioxidant enzyme activity and modulates lymphocyte composition in thymus from young rats. Journal of agricultural and food chemistry 55 17630760
2013 Dietary cocoa reduces metabolic endotoxemia and adipose tissue inflammation in high-fat fed mice. The Journal of nutritional biochemistry 53 24561154
2018 Cocoa Shell: A By-Product with Great Potential for Wide Application. Molecules (Basel, Switzerland) 52 29890752
2017 Cocoa and Grape Seed Byproducts as a Source of Antioxidant and Anti-Inflammatory Proanthocyanidins. International journal of molecular sciences 51 28208630
2020 Mass spectrometry proteomics reveals a function for mammalian CALCOCO1 in MTOR-regulated selective autophagy. Autophagy 48 31971854
2019 Bioavailability and metabolism of selected cocoa bioactive compounds: A comprehensive review. Critical reviews in food science and nutrition 46 31124371
2016 Cocoa tea (Camellia ptilophylla) water extract inhibits adipocyte differentiation in mouse 3T3-L1 preadipocytes. Scientific reports 46 26833256
2020 Co-culturing fructophilic lactic acid bacteria and yeast enhanced sugar metabolism and aroma formation during cocoa beans fermentation. International journal of food microbiology 45 33340944
2017 Monomeric cocoa catechins enhance β-cell function by increasing mitochondrial respiration. The Journal of nutritional biochemistry 45 28863367
2015 Dietary cocoa inhibits colitis associated cancer: a crucial involvement of the IL-6/STAT3 pathway. The Journal of nutritional biochemistry 45 26355019
2020 Cocoa diet modulates gut microbiota composition and improves intestinal health in Zucker diabetic rats. Food research international (Ottawa, Ont.) 44 32331673
2008 Neuroprotective effect of cocoa flavonoids on in vitro oxidative stress. European journal of nutrition 44 19043659
2019 Cocoa tea (Camellia ptilophylla) induces mitochondria-dependent apoptosis in HCT116 cells via ROS generation and PI3K/Akt signaling pathway. Food research international (Ottawa, Ont.) 42 32036895
2013 The effects of cocoa on the immune system. Frontiers in pharmacology 41 23759861
2015 Effect of fermentation and drying on cocoa polyphenols. Journal of agricultural and food chemistry 39 26086521
2012 Preparation, characterization, and induction of cell apoptosis of cocoa procyanidins-gelatin-chitosan nanoparticles. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 38 22641023
2022 From Cocoa to Chocolate: Effect of Processing on Flavanols and Methylxanthines and Their Mechanisms of Action. International journal of molecular sciences 37 36430843
2012 Cocoa, hazelnuts, sterols and soluble fiber cream reduces lipids and inflammation biomarkers in hypertensive patients: a randomized controlled trial. PloS one 36 22383996
2018 Volatile compounds and protein profiles analyses of fermented cocoa beans and chocolates from different hybrids cultivated in Brazil. Food research international (Ottawa, Ont.) 35 29803442
2016 Impact of Cocoa Consumption on Inflammation Processes-A Critical Review of Randomized Controlled Trials. Nutrients 35 27240397
2017 Effects of Cocoa Antioxidants in Type 2 Diabetes Mellitus. Antioxidants (Basel, Switzerland) 34 29088075
2015 Natural cocoa consumption: Potential to reduce atherogenic factors? The Journal of nutritional biochemistry 33 25769436
2015 Cocoa, glucose tolerance, and insulin signaling: cardiometabolic protection. Journal of agricultural and food chemistry 31 26126077
2019 Cocoa Shell Aqueous Phenolic Extract Preserves Mitochondrial Function and Insulin Sensitivity by Attenuating Inflammation between Macrophages and Adipocytes In Vitro. Molecular nutrition & food research 29 31018035
2010 Cocoa-enriched diets enhance expression of phosphatases and decrease expression of inflammatory molecules in trigeminal ganglion neurons. Brain research 28 20138852
2020 Cocoa Flavanols Protect Human Endothelial Cells from Oxidative Stress. Plant foods for human nutrition (Dordrecht, Netherlands) 27 32185628
2022 Supplementation with a Cocoa-Carob Blend, Alone or in Combination with Metformin, Attenuates Diabetic Cardiomyopathy, Cardiac Oxidative Stress and Inflammation in Zucker Diabetic Rats. Antioxidants (Basel, Switzerland) 26 35204314
2019 Cocoa Bean Proteins-Characterization, Changes and Modifications due to Ripening and Post-Harvest Processing. Nutrients 26 30791360
2011 Effect of a cocoa flavonoid-enriched diet on experimental autoimmune arthritis. The British journal of nutrition 26 21771382
2016 Cocoa Diet Prevents Antibody Synthesis and Modifies Lymph Node Composition and Functionality in a Rat Oral Sensitization Model. Nutrients 25 27120615
2012 Effects of a cocoa diet on an intestinal inflammation model in rats. Experimental biology and medicine (Maywood, N.J.) 24 23104506
2021 Dietary cocoa ameliorates non-alcoholic fatty liver disease and increases markers of antioxidant response and mitochondrial biogenesis in high fat-fed mice. The Journal of nutritional biochemistry 23 33711421
2021 Enhancement of fine flavour cocoa attributes under a controlled postharvest process. Food research international (Ottawa, Ont.) 23 33992349
2020 Chemical and flavor profile changes of cocoa beans (Theobroma cacao L.) during primary fermentation. Food science & nutrition 23 32884693
2018 Expression of cocoa genes in Saccharomyces cerevisiae improves cocoa butter production. Microbial cell factories 23 29370801
2015 Anti-influenza virus effects of cocoa. Journal of the science of food and agriculture 22 25847473
2021 Behavioral, Biochemical and Histopathological effects of Standardised Pomegranate extract with Vinpocetine, Propolis or Cocoa in a rat model of Parkinson's disease. Experimental aging research 21 34384037
2020 Advances in Metabolic Engineering of Saccharomyces cerevisiae for Cocoa Butter Equivalent Production. Frontiers in bioengineering and biotechnology 21 33178680
2019 Long noncoding RNA LINC00052 inhibits colorectal cancer metastasis by sponging microRNA-574-5p to modulate CALCOCO1 expression. Journal of cellular biochemistry 21 31104316
2021 Neurocognitive Effects of Cocoa and Red-Berries Consumption in Healthy Adults. Nutrients 20 35010877
2016 Cocoa and cocoa fibre differentially modulate IgA and IgM production at mucosal sites. The British journal of nutrition 20 26975903
2024 Cocoa flavanols, Nrf2 activation, and oxidative stress in peripheral artery disease: mechanistic findings in muscle based on outcomes from a randomized trial. American journal of physiology. Cell physiology 19 38189132
2021 Cocoa Coproducts-Based and Walnut Oil Gelled Emulsion as Animal Fat Replacer and Healthy Bioactive Source in Beef Burgers. Foods (Basel, Switzerland) 19 34828987
2018 Cocoa beans improve mitochondrial biogenesis via PPARγ/PGC1α dependent signalling pathway in MPP+ intoxicated human neuroblastoma cells (SH-SY5Y). Nutritional neuroscience 19 30207204
2023 Radical Scavenging and Cellular Antioxidant Activity of the Cocoa Shell Phenolic Compounds after Simulated Digestion. Antioxidants (Basel, Switzerland) 18 37237874
2009 Cocoa flavanols and procyanidins can modulate the lipopolysaccharide activation of polymorphonuclear cells in vitro. Journal of medicinal food 18 19298189
2020 Antioxidant Effect of Cocoa By-Product and Cherry Polyphenol Extracts: A Comparative Study. Antioxidants (Basel, Switzerland) 17 32028655
2019 Cocoa-specific flavor components and their peptide precursors. Food research international (Ottawa, Ont.) 17 31284999
2014 Optimized preparation and characterization of CLEA-lipase from cocoa pod husk. Journal of biotechnology 17 25481099
2022 Cocoa Extract Provides Protection against 6-OHDA Toxicity in SH-SY5Y Dopaminergic Neurons by Targeting PERK. Biomedicines 16 36009556
2021 The soluble reticulophagy receptor CALCOCO1 is also a Golgiphagy receptor. Autophagy 16 34162311
2020 Functional Biodiversity of Yeasts Isolated from Colombian Fermented and Dry Cocoa Beans. Microorganisms 16 32708172
2023 Spray-drying microencapsulation of blackcurrant and cocoa polyphenols using underexplored plant-based protein sources. Journal of food science 15 37158305
2023 Effects of adding cocoa fermentation medium on cigar leaves in agricultural fermentation stage. Frontiers in bioengineering and biotechnology 15 37662435
2023 Integrating shotgun metagenomics and metabolomics to elucidate the dynamics of microbial communities and metabolites in fine flavor cocoa fermentation in Hainan. Food research international (Ottawa, Ont.) 15 38225124
2021 Metagenome-Assembled Genomes Contribute to Unraveling of the Microbiome of Cocoa Fermentation. Applied and environmental microbiology 15 34105982
2020 NMR-based Lavado cocoa chemical characterization and comparison with fermented cocoa varieties: Insights on cocoa's anti-amyloidogenic activity. Food chemistry 15 33038804
2018 Cocoa procyanidins modulate transcriptional pathways linked to inflammation and metabolism in human dendritic cells. Food & function 15 29714395
2016 Cocoa and Whey Protein Differentially Affect Markers of Lipid and Glucose Metabolism and Satiety. Journal of medicinal food 15 26987021
2010 Antioxidant effects of cocoa and cocoa products ex vivo and in vivo: is there evidence from controlled intervention studies? Current opinion in clinical nutrition and metabolic care 14 20736821
2004 Cellular signaling mediated by calphoglin-induced activation of IPP and PGM. Biochemical and biophysical research communications 14 15522220
2023 Cocoa Polyphenol Extract Inhibits Cellular Senescence via Modulation of SIRT1 and SIRT3 in Auditory Cells. Nutrients 13 36771251
2020 Phytophthora palmivora-Cocoa Interaction. Journal of fungi (Basel, Switzerland) 13 32916858
1995 Nutrient and antinutrient profiles of raw and fermented cocoa beans. Plant foods for human nutrition (Dordrecht, Netherlands) 13 8833428

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