Existing Annotations Review

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)

Core Functions

CALCOCO1 acts as a soluble selective-autophagy cargo receptor that bridges organelle membrane proteins of the endoplasmic reticulum and Golgi to ATG8-family proteins (LC3/GABARAP, notably GABARAPL1 and GABARAPL2) via LIR- and UIM/UDS-type motifs, driving reticulophagy (ER-phagy) and Golgiphagy. This receptor/adaptor activity is supported by direct interactions with the ATG8 family in the UniProt interaction record and by recent autophagy literature. The ER-phagy arm is captured by reticulophagy plus the general autophagy cargo-adaptor MF; the Golgi-associated role remains context-dependent and should not drive a new MF term request.

Molecular Function:

autophagy cargo adaptor activity

Directly Involved In:

reticulophagy

Cellular Locations:

cytoplasm cytosol

Supporting Evidence:

file:human/CALCOCO1/CALCOCO1-uniprot.txt
Q9H0R8: GABARAPL1
file:human/CALCOCO1/CALCOCO1-notes.md
selective-autophagy receptor that functions in reticulophagy (ER-phagy)
PMID:31971854

CALCOCO1/CoCoA functions as a secondary/bridging transcriptional coactivator in the nucleus, cooperating with beta-catenin (CTNNB1) and the p160 coactivator complex (GRIP1/NCOA2, p300/CBP, CARM1) and with CCAR1/MED1 to enhance transcription by nuclear receptors, the aryl hydrocarbon receptor, and the Wnt/beta-catenin (TCF/LEF) and GATA1 pathways. It is recruited to target promoters through protein-protein interactions rather than sequence-specific DNA binding.

Molecular Function:

transcription coactivator activity

Directly Involved In:

positive regulation of transcription by RNA polymerase II

Cellular Locations:

nucleus

Supporting Evidence:

PMID:16344550
directly binds to and cooperates
PMID:24245781
the GATA1 CF domain serves as a docking surface for multiple coactivators, including CoCoA, CCAR1, and MED1

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000054

Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins in living cells

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:16344550

Differential use of functional domains by coiled-coil coactivator in its synergistic coactivator function with beta-catenin or GRIP1.

PMID:24245781

CCAR1/CoCoA pair-mediated recruitment of the Mediator defines a novel pathway for GATA1 function.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:31971854

Mass spectrometry proteomics reveals a function for mammalian CALCOCO1 in MTOR-regulated selective autophagy.

CALCOCO1 physically interacts with the ATG8-family protein MAP1LC3C, and genetic deletion of CALCOCO1 disrupts autophagy of the endoplasmic reticulum (reticulophagy), establishing CALCOCO1 as a selective-autophagy receptor in the MTOR-regulated autophagy axis.
A canonical LIR motif (W47A abolishes LC3-family binding) and a non-canonical CLIR motif (L140A/V142A weakens MAP1LC3C binding) mediate CALCOCO1 association with ATG8-family proteins, with a preference for MAP1LC3C, and CALCOCO1 abundance is regulated by MTOR-dependent autophagy and lysosomal flux.

PMID:18722177

CCAR1, a key regulator of mediator complex recruitment to nuclear receptor transcription complexes.

CCAR1 cooperates with the p160 coactivator complex and CoCoA/CALCOCO1 to recruit the Mediator complex and RNA polymerase II to nuclear-receptor target gene promoters, supporting the CCAR1-CoCoA-Mediator coactivator axis.

PMID:25422592

Distinct, genome-wide, gene-specific selectivity patterns of four glucocorticoid receptor coregulators.

siRNA depletion of CALCOCO1 (alongside CCAR1, CCAR2, and ZNF282) shows that CALCOCO1 acts as a gene-selective glucocorticoid-receptor coregulator with both positive and negative effects on hormone-regulated genes, rather than as a global coactivator.

PMID:38822137

YIPF3 and YIPF4 regulate autophagic turnover of the Golgi apparatus.

In a HeLa Golgiphagy reporter assay, knockdown of CALCOCO1 alone did not decrease Golgiphagy and triple knockdown with YIPF3/YIPF4 retained activity, indicating that CALCOCO1 is not the dominant Golgiphagy receptor in this context and that Golgi turnover involves redundant or context-specific receptors.

PMID:39871880

Join the club: YIPF3 and YIPF4 act as Golgiphagy receptors.

Commentary framing CALCOCO1 as a soluble ER-phagy receptor with a minor Golgi-associated pool that can contribute to Golgiphagy through a mechanism distinct from the YIPF3/YIPF4 transmembrane Golgiphagy receptor complex.

file:human/CALCOCO1/CALCOCO1-uniprot.txt

UniProt entry Q9P1Z2 (CACO1_HUMAN)

file:human/CALCOCO1/CALCOCO1-notes.md

CALCOCO1 research notes

Suggested Experiments

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

Deep Research

Falcon

(CALCOCO1-deep-research-falcon.md)

Research Report: Human CALCOCO1 (UniProt Q9P1Z2) — Functional Annotation Falcon Edison Scientific Literature 31 citations 1 artifacts 2026-06-07T05:17:26.579761

Edison artifact artifact-00 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human CALCOCO1 (UniProt Q9P1Z2) — Functional Annotation

0. Target verification (critical identity check)

The protein described in UniProt as Calcium-binding and coiled-coil domain-containing protein 1 with accession Q9P1Z2 corresponds to the human gene CALCOCO1 and is widely referenced in the literature under the alternative name CoCoA (coiled-coil coactivator), as well as in autophagy literature as CALCOCO1. The sources used here explicitly use these names for the same protein and experimentally interrogate CALCOCO1/CoCoA in human cell systems, matching the requested target context. (stefely2020massspectrometryproteomics pages 8-11, kim2008ccar1akey pages 1-2)

1. Key concepts and definitions (current understanding)

1.1 CALCOCO1 as a selective-autophagy receptor/adaptor

In current autophagy nomenclature, CALCOCO1 is best supported as a soluble selective-autophagy receptor/adaptor that links specific organelle membranes (especially ER subdomains) to the autophagosome machinery via ATG8-family proteins (LC3/GABARAP family). (stefely2020massspectrometryproteomics pages 14-17, stefely2020massspectrometryproteomics pages 11-14)

Operational definition used in key primary studies: CALCOCO1 is considered an ER-selective autophagy (reticulophagy) receptor because genetic deletion reduces ER-phagy reporter flux and because CALCOCO1 physically interacts with LC3-family proteins through short linear motifs (LIR/CLIR). (stefely2020massspectrometryproteomics pages 14-17, stefely2020massspectrometryproteomics pages 11-14)

1.2 ATG8-family binding motifs: LIR and CLIR

A central mechanistic concept for CALCOCO1 function is binding to ATG8-family proteins. Stefely et al. experimentally dissected two classes of motifs:
- A canonical LIR motif (LC3-interacting region), where the W47A mutation abolished detectable binding to MAP1LC3C, MAP1LC3B, and GABARAPL2 in co-immunoprecipitation experiments. (stefely2020massspectrometryproteomics pages 11-14)
- A non-canonical CLIR (MAP1LC3C-interacting region), where L140A/V142A weakened MAP1LC3C binding, consistent with partial contribution to LC3C preference. (stefely2020massspectrometryproteomics pages 11-14)

1.3 CALCOCO1 as a transcriptional coregulator (“CoCoA”)

Independently of autophagy, CALCOCO1 was originally characterized as CoCoA, a transcriptional coactivator/coregulator that integrates signals from transcription factors (including nuclear receptors and GATA1) with the Mediator complex and RNA polymerase II recruitment. (kim2008ccar1akey pages 1-2, mizuta2014ccar1cocoapairmediatedrecruitment pages 13-15)

2. Molecular functions, pathways, and cellular localization (evidence-weighted)

2.1 Subcellular localization

Autophagy-focused experiments indicate CALCOCO1 is predominantly cytoplasmic, with vesicle/light-membrane association and close proximity to ER structures. (stefely2020massspectrometryproteomics pages 8-11, stefely2020massspectrometryproteomics pages 11-14)

Stefely et al. also report detection of CALCOCO1 in cytoplasmic and nuclear fractions in some fractionation experiments, but their imaging and cell-line comparisons support that autophagy-relevant pools are largely cytosolic/vesicle-associated and proximal to ER. (stefely2020massspectrometryproteomics pages 17-21, stefely2020massspectrometryproteomics pages 34-41)

2.2 Core binding partners (experimentally supported)

ATG8/LC3-family proteins. Co-immunoprecipitation experiments show CALCOCO1 binds LC3/GABARAP proteins with a strong preference for MAP1LC3C, and also binds MAP1LC3B and GABARAPL2, with interactions strengthened when autophagy is blocked (e.g., chloroquine). (stefely2020massspectrometryproteomics pages 8-11, stefely2020massspectrometryproteomics pages 11-14)

Functional consequence of variant: a tumor-associated R12H variant reduced MAP1LC3C association, linking a disease-associated residue to impaired ATG8-family binding behavior. (stefely2020massspectrometryproteomics pages 11-14)

Transcriptional cofactors. In transcription contexts, CALCOCO1/CoCoA interacts functionally with p160 coactivators, and its activation domain binds CCAR1, which associates with Mediator; these interactions support Mediator recruitment to nuclear receptor transcription complexes. (kim2008ccar1akey pages 1-2)

2.3 Primary autophagy function: MTOR-regulated ER-phagy/reticulophagy

Pathway context. MTOR inhibition is a canonical autophagy-activating input. Stefely et al. show that the ATP-competitive MTOR inhibitor MLN0128 triggers a decline in CALCOCO1 abundance, while lysosomal/autophagy inhibition (chloroquine or bafilomycin A1) increases CALCOCO1 levels—supporting that CALCOCO1 is itself turned over by autophagy/lysosomes and is responsive to MTOR-regulated autophagy flux. (stefely2020massspectrometryproteomics pages 8-11)

Functional assays and effect sizes. In CRISPR sgCALCOCO1 knockout cells, ER-phagy flux measured by ER-targeted reporters was reduced:
- ~50% reduced ER-phagy signal in a GST-LSCS-GFP-cb5 assay.
- ~25% reduced ER-phagy in a Keima-cb5 assay.
These results support CALCOCO1 as a contributor (but not necessarily the sole mediator) of ER-selective autophagy under the tested conditions. (stefely2020massspectrometryproteomics pages 11-14)

Interpretation: The most evidence-supported “primary function” of CALCOCO1 in the autophagy literature is as a selective ER-phagy adaptor/receptor that couples ER-associated cargo capture to ATG8 proteins, especially via MAP1LC3C. (stefely2020massspectrometryproteomics pages 14-17, stefely2020massspectrometryproteomics pages 11-14)

2.4 Transcriptional coactivator function (mechanistic detail)

CCAR1–CoCoA–Mediator axis. Kim et al. identified CCAR1 as a CoCoA activation-domain-binding protein using GST-CoCoA pull-downs and mass spectrometry, and showed CCAR1 is needed for hormone-induced recruitment of Mediator components and RNA polymerase II to promoters and for estrogen-dependent growth of MCF-7 breast cancer cells. (kim2008ccar1akey pages 1-2)

p53 and GATA1 connections. Kim et al. also show CCAR1 and CoCoA are recruited to the p21 promoter and are required for p53-mediated transcription (qRT-PCR/ChIP contexts described in the excerpt). (kim2008ccar1akey pages 8-8) Mizuta et al. further place CoCoA in erythroid transcription, where CCAR1 and CoCoA support GATA1-dependent transcription and are co-recruited with Mediator components to the c-globin promoter during K562 differentiation; CoCoA knockdown reduced globin expression in this model. (mizuta2014ccar1cocoapairmediatedrecruitment pages 13-15)

Conceptual implication: CALCOCO1 is unusual among selective-autophagy adaptors in having substantial historical evidence as a nuclear transcriptional coactivator, suggesting that CALCOCO1 biology may be bifunctional and context-dependent (nuclear coactivation vs cytosolic selective-autophagy adaptor). (kim2008ccar1akey pages 1-2, mizuta2014ccar1cocoapairmediatedrecruitment pages 13-15)

3. Recent developments and latest research (prioritizing 2023–2024)

3.1 2024: CALCOCO1 and Golgiphagy (selective autophagy of the Golgi)

A 2024 primary study identifying YIPF3/YIPF4 as Golgiphagy receptors tested CALCOCO1 using a Golgiphagy reporter assay and siRNA knockdown in HeLa cells. In that system, CALCOCO1 knockdown alone did not decrease Golgiphagy, and even triple knockdown (YIPF3/YIPF4/CALCOCO1) retained some Golgiphagic activity, supporting redundancy and suggesting CALCOCO1 is not the dominant Golgi receptor in that specific experimental context. (kitta2024yipf3andyipf4 pages 10-11)

A 2024 expert commentary in Life Metabolism frames CALCOCO1 as a soluble ER-phagy receptor that can also act in Golgiphagy via Golgi-associated interactions (e.g., ZDHHC17), but emphasizes that CALCOCO1 and YIPF3/4 likely represent distinct Golgiphagy mechanisms rather than a single unified pathway. (ma2024jointheclub pages 3-3)

3.2 2024: Multi-omics evidence linking CALCOCO1 to Alzheimer’s disease severity

A 2024 multi-omics analysis of 87 Alzheimer’s disease patients reported 170 plasma proteins significantly altered between high vs low ADAS-Cog severity groups and listed CALCOCO1 among the top five significantly downregulated proteins in high-severity ADAS-Cog groups. (meng2024multiomicsanalysisreveals pages 2-4)

While the excerpted text does not provide CALCOCO1-specific effect sizes or p-values, the study supports the hypothesis that plasma CALCOCO1 may track with disease severity in at least one cohort and assay platform (NPX log2-scale proteomics). (meng2024multiomicsanalysisreveals pages 2-4)

3.3 2023: Cancer bioinformatics/prognostic associations (LUAD)

A 2023 lung adenocarcinoma (LUAD) study reports an association between low CALCOCO1 expression and poorer prognosis (log-rank test referenced), consistent with prior literature linking CALCOCO1/CoCoA with CCAR1-mediated p53 coactivation. Numeric hazard ratios/p-values were not present in the excerpt and therefore cannot be stated here. (wei2023npm3asa pages 12-14)

4. Current applications and real-world implementations

4.1 Translational status

Based on the retrieved sources, CALCOCO1 is not currently an established clinical target with approved CALCOCO1-directed therapeutics. Instead, CALCOCO1 appears in translational contexts mainly as:
- A candidate biomarker feature in multi-omics models of disease severity (e.g., plasma proteomics in Alzheimer’s disease). (meng2024multiomicsanalysisreveals pages 2-4)
- A cancer-related factor implicated in stem-like phenotypes in vitro (mammosphere formation) and in expression–prognosis associations in tumor datasets. (stefely2020massspectrometryproteomics pages 8-11, wei2023npm3asa pages 12-14)

4.2 Example of an experimentally demonstrated cancer-relevant phenotype

In MB231 breast cancer cells, CRISPR targeting of CALCOCO1 reduced mammosphere formation by ~50%, supporting a potential role in cancer stem-like traits (preclinical, in vitro). (stefely2020massspectrometryproteomics pages 8-11)

5. Expert opinions and authoritative synthesis

5.1 Expert synthesis on Golgiphagy receptor landscape

The 2024 Life Metabolism commentary interprets the Golgiphagy literature as involving multiple receptor systems. It positions CALCOCO1 as a receptor with a dominant ER-phagy identity and a minor Golgi-localized pool that can contribute to Golgiphagy in some settings, while the YIPF3/YIPF4 complex represents a distinct transmembrane receptor mechanism. (ma2024jointheclub pages 3-3)

5.2 Expert synthesis on coregulator selectivity in transcription

Wu et al. (2014) provide a genome-wide perspective that CALCOCO1/CoCoA acts as a selective glucocorticoid receptor (GR) coregulator, with gene-specific positive and negative effects; most affected genes were unique to each tested coregulator (including CALCOCO1), supporting pathway-selective regulation rather than global coactivation. (wu2014distinctgenomewidegenespecific pages 1-2)

6. Statistics and data highlights from recent studies (2023–2024)

Alzheimer’s disease cohort size: 87 well-phenotyped AD patients (plasma proteomics/metabolomics); CALCOCO1 among the top five downregulated proteins in high vs low ADAS-Cog severity comparisons; 170 proteins significantly altered between high and low groups. (Publication date: Oct 2024; URL: https://doi.org/10.1186/s13195-024-01578-6). (meng2024multiomicsanalysisreveals pages 2-4)
Golgiphagy functional assay replication: n = 4 independent experiments for Golgiphagy reporter cleavage quantification under CALCOCO1 knockdown conditions in HeLa cells (primary EMBO J study). (Publication date: May 2024; URL: https://doi.org/10.1038/s44318-024-00131-3). (kitta2024yipf3andyipf4 pages 10-11)

7. Consolidated evidence map

The table below summarizes the highest-confidence functions, interactions, and translational links for CALCOCO1 based on the retrieved evidence.

Aspect	Evidence-based summary	Key supporting papers
Identity / domains	Human CALCOCO1 corresponds to UniProt Q9P1Z2 and is also known as Calphoglin / Coiled-coil coactivator protein (CoCoA) / NY-SAR-3. Functional/domain analyses place it in the CALCOCO family and support an N-terminal SKICH region, a canonical LIR, a non-canonical CLIR that contributes to MAP1LC3C binding, and C-terminal ubiquitin-associated/zinc-finger features noted in domain annotations and selective-autophagy literature. Mutagenesis of W47A (LIR), L140A/V142A (CLIR), and R12H demonstrated motif-dependent LC3-family interactions. (stefely2020massspectrometryproteomics pages 8-11, stefely2020massspectrometryproteomics pages 11-14, stefely2020massspectrometryproteomics pages 34-41)	Stefely 2020, Autophagy, https://doi.org/10.1080/15548627.2020.1719746; Zhang 2024, PNAS, https://doi.org/10.1073/pnas.2315550121 (stefely2020massspectrometryproteomics pages 8-11, stefely2020massspectrometryproteomics pages 11-14, stefely2020massspectrometryproteomics pages 34-41)
Localization	Experimental fractionation and imaging show CALCOCO1 is predominantly cytoplasmic, associates with vesicular/light membrane fractions, and is proximal to the ER; some studies also detected cytoplasmic and nuclear fractions, whereas other analyses found little nuclear signal in several cell lines, suggesting context-dependent dual localization rather than a primarily nuclear protein in autophagy settings. A minor Golgi-localized pool has been proposed in Golgiphagy models. (stefely2020massspectrometryproteomics pages 17-21, stefely2020massspectrometryproteomics pages 34-41, stefely2020massspectrometryproteomics pages 8-11, ma2024jointheclub pages 3-3)	Stefely 2020, Autophagy, https://doi.org/10.1080/15548627.2020.1719746; Ma & Zhang 2024, Life Metabolism, https://doi.org/10.1093/lifemeta/load049 (stefely2020massspectrometryproteomics pages 17-21, stefely2020massspectrometryproteomics pages 34-41, stefely2020massspectrometryproteomics pages 8-11, ma2024jointheclub pages 3-3)
Key binding partners	Co-immunoprecipitation/mutagenesis support binding to ATG8-family proteins, with strongest reported preference for MAP1LC3C, plus interactions with MAP1LC3B and GABARAPL2 that increase when autophagy is blocked. ER-phagy reviews further place CALCOCO1 in complexes with VAPA/VAPB on the ER, and Golgiphagy commentary links it to ZDHHC17 at the Golgi. In transcriptional settings, CALCOCO1/CoCoA interacts functionally with CCAR1, SRC2/GRIP1, β-catenin, p300, GATA1, and mediator-linked machinery. (stefely2020massspectrometryproteomics pages 34-41, stefely2020massspectrometryproteomics pages 8-11, stefely2020massspectrometryproteomics pages 11-14, ma2024jointheclub pages 3-3, mizuta2014ccar1cocoapairmediatedrecruitment pages 11-12, kim2008ccar1akey pages 1-2, mizuta2014ccar1cocoapairmediatedrecruitment pages 12-13, wu2014distinctgenomewidegenespecific pages 1-2)	Stefely 2020, Autophagy, https://doi.org/10.1080/15548627.2020.1719746; Kim 2008, Molecular Cell, https://doi.org/10.1016/j.molcel.2008.08.001; Mizuta 2014, Genes to Cells, https://doi.org/10.1111/gtc.12104; Wu 2014, Nuclear Receptor Signaling, https://doi.org/10.1621/nrs.12002 (stefely2020massspectrometryproteomics pages 34-41, stefely2020massspectrometryproteomics pages 8-11, stefely2020massspectrometryproteomics pages 11-14, ma2024jointheclub pages 3-3, mizuta2014ccar1cocoapairmediatedrecruitment pages 11-12, kim2008ccar1akey pages 1-2, mizuta2014ccar1cocoapairmediatedrecruitment pages 12-13, wu2014distinctgenomewidegenespecific pages 1-2)
ER-phagy / reticulophagy role	The strongest primary-function evidence supports CALCOCO1 as a soluble selective ER-phagy receptor/adaptor in MTOR-regulated reticulophagy. CRISPR loss of CALCOCO1 reduced reporter-based ER-phagy by about 50% in a GST-LSCS-GFP-cb5 assay and about 25% in a Keima-cb5 assay, while altering ER protein turnover and MAP1LC3C-II accumulation. 2024 work indicates CALCOCO1 functions in parallel with RTN3L and ATL3 to target misfolded ER cargo and maintain ER proteostasis, while neurogenesis studies suggest receptor redundancy and that CALCOCO1 alone is not universally essential for ER maintenance in all developmental contexts. (stefely2020massspectrometryproteomics pages 14-17, stefely2020massspectrometryproteomics pages 11-14, kitta2024yipf3andyipf4 pages 10-11, stefely2020massspectrometryproteomics pages 8-11, stefely2020massspectrometryproteomics pages 34-41)	Stefely 2020, Autophagy, https://doi.org/10.1080/15548627.2020.1719746; Kumar 2024, Autophagy, https://doi.org/10.1080/15548627.2024.2353502; Hoyer 2024, Nature Cell Biology, https://doi.org/10.1038/s41556-024-01356-4 (stefely2020massspectrometryproteomics pages 14-17, stefely2020massspectrometryproteomics pages 11-14, kitta2024yipf3andyipf4 pages 10-11, stefely2020massspectrometryproteomics pages 8-11, stefely2020massspectrometryproteomics pages 34-41)
Golgiphagy role	CALCOCO1 has been proposed as a Golgiphagy receptor under starvation/stress, likely via Golgi-associated interactions such as ZDHHC17. However, 2024 Golgiphagy studies indicate YIPF3/YIPF4 are major Golgiphagy receptors in HeLa cells, and CALCOCO1 knockdown alone did not decrease Golgiphagy in that reporter system; commentary therefore supports a model where CALCOCO1 contributes in a distinct, non-redundant or context-specific pathway rather than serving as the dominant Golgi receptor in all cells. (kitta2024yipf3andyipf4 pages 10-11, ma2024jointheclub pages 3-3)	Kitta 2024, EMBO Journal, https://doi.org/10.1038/s44318-024-00131-3; Ma & Zhang 2024, Life Metabolism, https://doi.org/10.1093/lifemeta/load049 (kitta2024yipf3andyipf4 pages 10-11, ma2024jointheclub pages 3-3)
Transcriptional coactivator role	Independently of autophagy, CALCOCO1 was originally characterized as CoCoA, a transcriptional coactivator/coregulator. Its central coiled-coil binds p160 coactivators, while C-terminal activation regions support transcriptional activation. CALCOCO1/CoCoA cooperates with CCAR1 to help recruit Mediator and RNA polymerase II to target genes, supporting transcription driven by nuclear receptors, p53, β-catenin, and GATA1. In K562 erythroid differentiation, CoCoA expression rose about 4-fold, and knockdown reduced globin-gene expression. (mizuta2014ccar1cocoapairmediatedrecruitment pages 11-12, mizuta2014ccar1cocoapairmediatedrecruitment pages 1-2, mizuta2014ccar1cocoapairmediatedrecruitment pages 7-8, kim2008ccar1akey pages 1-2, mizuta2014ccar1cocoapairmediatedrecruitment pages 13-15, wu2014distinctgenomewidegenespecific pages 1-2, kim2008ccar1akey pages 8-8)	Kim 2008, Molecular Cell, https://doi.org/10.1016/j.molcel.2008.08.001; Mizuta 2014, Genes to Cells, https://doi.org/10.1111/gtc.12104; Wu 2014, Nuclear Receptor Signaling, https://doi.org/10.1621/nrs.12002 (mizuta2014ccar1cocoapairmediatedrecruitment pages 11-12, mizuta2014ccar1cocoapairmediatedrecruitment pages 1-2, mizuta2014ccar1cocoapairmediatedrecruitment pages 7-8, kim2008ccar1akey pages 1-2, mizuta2014ccar1cocoapairmediatedrecruitment pages 13-15, wu2014distinctgenomewidegenespecific pages 1-2, kim2008ccar1akey pages 8-8)
Disease / biomarker links	Evidence for direct disease causality remains limited, but CALCOCO1 has several emerging disease links. It was originally identified as the cancer antigen NY-SAR-3. In breast-cancer models, CALCOCO1 depletion reduced mammosphere formation by about 50%, suggesting a role in cancer stem-like traits. In a 2024 multi-omics study of 87 Alzheimer’s disease patients, CALCOCO1 was among the top five significantly downregulated plasma proteins in the high-severity (high ADAS-Cog) group. A 2023 LUAD bioinformatic study associated low CALCOCO1 expression with poorer prognosis, although exact HRs/p-values were not available in the extracted text. (stefely2020massspectrometryproteomics pages 17-21, stefely2020massspectrometryproteomics pages 8-11, meng2024multiomicsanalysisreveals pages 2-4, wei2023npm3asa pages 12-14)	Stefely 2020, Autophagy, https://doi.org/10.1080/15548627.2020.1719746; Meng 2024, Alzheimer’s Research & Therapy, https://doi.org/10.1186/s13195-024-01578-6; Wei 2023, Hereditas, https://doi.org/10.1186/s41065-023-00289-6 (stefely2020massspectrometryproteomics pages 17-21, stefely2020massspectrometryproteomics pages 8-11, meng2024multiomicsanalysisreveals pages 2-4, wei2023npm3asa pages 12-14)
Regulation	CALCOCO1 is regulated by MTOR-dependent autophagy and lysosomal flux. MLN0128-mediated MTOR inhibition decreased CALCOCO1 abundance, whereas chloroquine or bafilomycin A1 increased it; CALCOCO1 also accumulated in ATG7/ATG3-deficient cells, indicating autophagy-dependent turnover. Cycloheximide chase suggested a half-life of about 24 h. Interactions with LC3-family proteins strengthened when autophagy was blocked, and recent literature places CALCOCO1 within broader nutrient/starvation and organelle-stress response networks affecting ER and Golgi homeostasis. (stefely2020massspectrometryproteomics pages 34-41, stefely2020massspectrometryproteomics pages 8-11, stefely2020massspectrometryproteomics pages 14-17, stefely2020massspectrometryproteomics pages 5-8)	Stefely 2020, Autophagy, https://doi.org/10.1080/15548627.2020.1719746 (stefely2020massspectrometryproteomics pages 34-41, stefely2020massspectrometryproteomics pages 8-11, stefely2020massspectrometryproteomics pages 14-17, stefely2020massspectrometryproteomics pages 5-8)

Table: This table summarizes the main experimentally supported functions, localization, interactions, and disease links of human CALCOCO1 (UniProt Q9P1Z2). It is useful as a compact evidence map spanning both its autophagy-receptor and transcriptional-coactivator roles.

8. Conclusions (evidence-weighted functional annotation)

Primary supported cellular role (autophagy context): CALCOCO1 functions as a soluble selective-autophagy receptor/adaptor that promotes ER-phagy/reticulophagy downstream of MTOR-regulated autophagy signaling, in part through motif-mediated binding to ATG8-family proteins, with a reported preference for MAP1LC3C. (stefely2020massspectrometryproteomics pages 14-17, stefely2020massspectrometryproteomics pages 11-14)
Primary supported biochemical mechanism: CALCOCO1 uses a canonical LIR (required for LC3-family binding) and a CLIR that contributes to MAP1LC3C preference; disease-associated residue changes (e.g., R12H) can reduce MAP1LC3C association. (stefely2020massspectrometryproteomics pages 11-14)
Distinct functional axis (nuclear transcription): CALCOCO1 (CoCoA) is also a transcriptional coactivator that cooperates with CCAR1 and Mediator to enhance transcription by nuclear receptors, p53, and GATA1; thus, CALCOCO1 biology plausibly integrates transcriptional regulation and selective autophagy in a context-dependent manner. (kim2008ccar1akey pages 1-2, mizuta2014ccar1cocoapairmediatedrecruitment pages 13-15, kim2008ccar1akey pages 8-8)
Recent (2023–2024) direction of the field: CALCOCO1 is increasingly discussed within a broader selective-organelle autophagy landscape, including Golgiphagy, where current data suggest cell-type- and receptor-specific redundancy, and within omics-driven biomarker discovery (e.g., plasma protein signatures of AD severity). (kitta2024yipf3andyipf4 pages 10-11, ma2024jointheclub pages 3-3, meng2024multiomicsanalysisreveals pages 2-4)

References

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(mizuta2014ccar1cocoapairmediatedrecruitment pages 12-13): Shumpei Mizuta, Tomoya Minami, Haruka Fujita, Chihiro Kaminaga, Keiji Matsui, Ruri Ishino, Azusa Fujita, Kasumi Oda, Asami Kawai, Natsumi Hasegawa, Norinaga Urahama, Robert G. Roeder, and Mitsuhiro Ito. Ccar1/cocoa pair‐mediated recruitment of the mediator defines a novel pathway for gata1 function. Genes to Cells, 19:28-51, Jan 2014. URL: https://doi.org/10.1111/gtc.12104, doi:10.1111/gtc.12104. This article has 14 citations and is from a peer-reviewed journal.
(mizuta2014ccar1cocoapairmediatedrecruitment pages 1-2): Shumpei Mizuta, Tomoya Minami, Haruka Fujita, Chihiro Kaminaga, Keiji Matsui, Ruri Ishino, Azusa Fujita, Kasumi Oda, Asami Kawai, Natsumi Hasegawa, Norinaga Urahama, Robert G. Roeder, and Mitsuhiro Ito. Ccar1/cocoa pair‐mediated recruitment of the mediator defines a novel pathway for gata1 function. Genes to Cells, 19:28-51, Jan 2014. URL: https://doi.org/10.1111/gtc.12104, doi:10.1111/gtc.12104. This article has 14 citations and is from a peer-reviewed journal.
(mizuta2014ccar1cocoapairmediatedrecruitment pages 7-8): Shumpei Mizuta, Tomoya Minami, Haruka Fujita, Chihiro Kaminaga, Keiji Matsui, Ruri Ishino, Azusa Fujita, Kasumi Oda, Asami Kawai, Natsumi Hasegawa, Norinaga Urahama, Robert G. Roeder, and Mitsuhiro Ito. Ccar1/cocoa pair‐mediated recruitment of the mediator defines a novel pathway for gata1 function. Genes to Cells, 19:28-51, Jan 2014. URL: https://doi.org/10.1111/gtc.12104, doi:10.1111/gtc.12104. This article has 14 citations and is from a peer-reviewed journal.
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Artifacts

Edison artifact artifact-00

Citations

stefely2020massspectrometryproteomics pages 11-14
stefely2020massspectrometryproteomics pages 8-11
ma2024jointheclub pages 3-3
meng2024multiomicsanalysisreveals pages 2-4
wu2014distinctgenomewidegenespecific pages 1-2
stefely2020massspectrometryproteomics pages 14-17
stefely2020massspectrometryproteomics pages 17-21
stefely2020massspectrometryproteomics pages 34-41
stefely2020massspectrometryproteomics pages 5-8
https://doi.org/10.1186/s13195-024-01578-6
https://doi.org/10.1038/s44318-024-00131-3
https://doi.org/10.1080/15548627.2020.1719746;
https://doi.org/10.1073/pnas.2315550121
https://doi.org/10.1093/lifemeta/load049
https://doi.org/10.1016/j.molcel.2008.08.001;
https://doi.org/10.1111/gtc.12104;
https://doi.org/10.1621/nrs.12002
https://doi.org/10.1080/15548627.2024.2353502;
https://doi.org/10.1038/s41556-024-01356-4
https://doi.org/10.1038/s44318-024-00131-3;
https://doi.org/10.1186/s13195-024-01578-6;
https://doi.org/10.1186/s41065-023-00289-6
https://doi.org/10.1080/15548627.2020.1719746
https://doi.org/10.1080/15548627.2020.1719746,
https://doi.org/10.1016/j.molcel.2008.08.001,
https://doi.org/10.1111/gtc.12104,
https://doi.org/10.1038/s44318-024-00131-3,
https://doi.org/10.1093/lifemeta/load049,
https://doi.org/10.1186/s13195-024-01578-6,
https://doi.org/10.1186/s41065-023-00289-6,
https://doi.org/10.1621/nrs.12002,

📚 Additional Documentation

Notes

(CALCOCO1-notes.md)

CALCOCO1 (human) research notes

UniProt: Q9P1Z2 (CACO1_HUMAN). Gene: CALCOCO1 (HGNC:29306). 691 aa. Chromosome 12.
Aliases: Calphoglin; Coiled-coil coactivator protein (CoCoA); Sarcoma antigen NY-SAR-3; KIAA1536.

Summary of two distinct narratives for CALCOCO1

CALCOCO1 has two largely separate bodies of literature:

Selective-autophagy receptor (current "core" view). CALCOCO1 is a soluble
selective-autophagy receptor that functions in reticulophagy (ER-phagy) and Golgiphagy.
It bridges ER/Golgi cargo to the ATG8 family (LC3/GABARAP) via LIR (LC3-interacting region)
and UDS (UIM-docking site)-type motifs, and engages ER-phagy machinery (e.g. VAPA/VAPB on
the ER membrane). This is the function emphasised in recent (post-2019) literature and is
reflected in the UniProt IntAct interaction set, which lists direct interactions with
GABARAPL1 (Q9H0R8) and GABARAPL2 (P60520) — the ATG8/LC3-GABARAP family.
Transcriptional coactivator (historical "CoCoA" view). Older work (2003-2014) characterised
CALCOCO1 as "coiled-coil coactivator" (CoCoA), a secondary/bridging coactivator for nuclear
receptors, the aryl hydrocarbon receptor, and the Wnt/beta-catenin (CTNNB1) and LEF1/TCF
pathways, acting in the nucleus via p160 coactivators (GRIP1/NCOA2), p300/CBP, CARM1, and
in association with CCAR1/MED1. A separate "calphoglin" report links it to inorganic
pyrophosphatase (PPA1)/phosphoglucomutase (PGM) activation.

The GOA/UniProt annotation set assigned to this gene (the existing_annotations being reviewed)
is dominated entirely by the transcription coactivator / CoCoA / beta-catenin narrative plus
generic high-throughput protein-binding entries. The modern autophagy-receptor function is NOT
represented in the curated GO annotations and is therefore captured in description, core_functions,
and proposed_new_terms.

Evidence from the UniProt record (file:human/CALCOCO1/CALCOCO1-uniprot.txt)

Domain architecture: N-terminal SKICH domain (Pfam PF17751), CALCOCO1 domain (PF07888),
three coiled-coil regions (145-205, 232-339, 417-514), a disordered region (514-606), and a
C-terminal UBZ1-type zinc finger (653-679; Zn coordinated by C656, C659, H675, H679).
[file:human/CALCOCO1/CALCOCO1-uniprot.txt "ZN_FING 653..679 /note=\"UBZ1-type\""]
FUNCTION (coactivator): "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." [file:human/CALCOCO1/CALCOCO1-uniprot.txt "Functions as a coactivator for aryl hydrocarbon and nuclear"]
FUNCTION (Wnt): "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."
[file:human/CALCOCO1/CALCOCO1-uniprot.txt "Involved in the\nCC transcriptional activation of target genes in the Wnt/CTNNB1"]
FUNCTION (calphoglin): "Seems to enhance inorganic pyrophosphatase thus activating
phosphogluomutase (PMG). Probably functions as a component of the calphoglin complex"
[file:human/CALCOCO1/CALCOCO1-uniprot.txt "Seems to enhance inorganic pyrophosphatase thus activating"]
SUBCELLULAR LOCATION: "Cytoplasm. Nucleus. Note=Shuttles between nucleus and cytoplasm."
[file:human/CALCOCO1/CALCOCO1-uniprot.txt "Shuttles between nucleus"]
IntAct partners include the ATG8 family: GABARAPL1 (Q9H0R8) and GABARAPL2 (P60520),
consistent with an autophagy-receptor / ATG8-binding function.
[file:human/CALCOCO1/CALCOCO1-uniprot.txt "Q9H0R8: GABARAPL1"]
Keywords: Activator, Wnt signaling pathway, Zinc, Zinc-finger, Transcription, Nucleus, Cytoplasm.

Note: the UniProt FUNCTION text for the coactivator role is heavily "By similarity"
(ECO:0000250 from mouse ortholog Q8CGU1); only the GATA1/CCAR1 erythroid result is human
experimental (ECO:0000269|PubMed:24245781).

Evidence from cached publications

PMID:16344550 (Yang, Kim, Li, Stallcup 2006, J Biol Chem) — CoCoA / beta-catenin

"another component of the p160 nuclear receptor coactivator complex, the coiled-coil
coactivator (CoCoA), directly binds to and cooperates synergistically with beta-catenin as a
coactivator for AR and TCF/LEF."
PMID:16344550
"CoCoA associated specifically with the promoters of transiently transfected and endogenous
target genes of TCF/LEF, and reduction of the endogenous CoCoA level decreased the ability of
TCF/LEF and beta-catenin to activate transcription"
PMID:16344550
Supports: beta-catenin binding (GO:0008013), transcription coregulator/coactivator activity,
sequence-specific DNA binding (promoter association via ChIP), positive regulation of
transcription. These are real but are the historical/secondary nuclear function.

PMID:24245781 (Mizuta et al. 2014, Genes Cells) — CCAR1/CoCoA + GATA1/MED1

"Recombinant GATA1, CCAR1, CoCoA and MED1(1-602) formed a complex in vitro, and GATA1, CCAR1,
CoCoA and MED1 were recruited to the gamma-globin promoter in K562 cells during erythroid
differentiation."
PMID:24245781
"CoCoA AD2 may interact with GATA1, CoCoA AD1 interacts with CCAR1 ... and that the GATA1 CF
domain serves as a docking surface for multiple coactivators, including CoCoA, CCAR1, and MED1."
PMID:24245781
"GATA1, MED1, CCAR1, and CoCoA were all recruited onto the gamma-globin promoter at the
GATA1-binding sites after 2 and 3 days during erythroid differentiation"
PMID:24245781
This is the strongest human experimental support for the coactivator role; supports
transcription coactivator activity (IMP) and promoter/cis-regulatory DNA binding (IDA via ChIP).

High-throughput interactome papers (all generic "protein binding", GO:0005515)

PMID:16189514 (Rual et al., proteome-scale Y2H map) — WITH NDC80 (O14777).
PMID:25416956 (Rolland et al., human interactome) — many partners (GABARAPL2 P60520, etc.).
PMID:32296183 (Luck et al., HuRI binary interactome) — includes GABARAPL1 (Q9H0R8),
GABARAPL2 (P60520).
PMID:33961781 (Huttlin et al., BioPlex) — NDC80, BFSP2.
PMID:40205054 (Schaffer et al. 2025, multimodal cell maps) — NDC80, BFSP2.
These are uninformative as "protein binding" per curation guidelines. They do, however,
collectively corroborate the ATG8/GABARAP interactions underlying the autophagy-receptor role.

Falcon deep research findings (2026-06-07)

The Falcon report (Edison) adds primary-literature support for several claims that the
existing review previously sourced only from UniProt/notes, plus some new disease/biomarker
links. Distinguishing CONFIRMS / NEW / PROVISIONAL:

CONFIRMS + key NEW primary reference for the core function. The foundational ER-phagy
paper Stefely et al. 2020 (Autophagy) PMID:31971854 was MISSING from the existing references: even though the
review's whole "core" autophagy-receptor narrative rests on it. It provides the direct
experimental basis: a canonical LIR (W47A abolishes LC3-family binding), a non-canonical
CLIR (L140A/V142A weakens MAP1LC3C binding) explaining MAP1LC3C preference, MTOR-regulated
turnover (MLN0128 lowers, chloroquine/bafilomycin raise CALCOCO1), and ER-phagy reporter
flux reduced ~50% (GST-LSCS-GFP-cb5) / ~25% (Keima-cb5) in knockouts. NOTE: this is a
mouse/MEF + human cell study; the genetic ER-phagy data are largely in mouse cells.
Now added to the review as a statement-only reference.
NEW primary reference for the historical coactivator (non-core) role. Kim et al. 2008
(Mol Cell) PMID:18722177 is the original CCAR1/CoCoA paper underpinning the
CCAR1-CoCoA-Mediator axis already described; previously only Mizuta 2014 (PMID:24245781) was
cited. Added as statement-only reference.
NEW: direct experimental test of CALCOCO1 as a glucocorticoid-receptor coregulator.
Wu et al. 2014 (Nucl Recept Signal) PMID:25422592 shows CALCOCO1 is a gene-selective GR coregulator with both positive and negative
effects - i.e. not a global coactivator. Reinforces the KEEP_AS_NON_CORE coactivator calls
and the steroid-hormone-signaling annotations. Added as statement-only reference.
NEW / nuancing the Golgiphagy proposed term. Kitta et al. 2024 (EMBO J) PMID:38822137 tested CALCOCO1 in a HeLa Golgiphagy
reporter: CALCOCO1 knockdown alone did NOT decrease Golgiphagy, and triple YIPF3/YIPF4/CALCOCO1
knockdown retained activity - arguing CALCOCO1 is not the dominant Golgi receptor in that
context (redundancy / context-specific). This tempers the "Golgiphagy receptor activity"
proposed term: keep proposed but flag redundancy. Commentary Ma & Zhang 2024 (Life Metab)
PMID:39871880 frames CALCOCO1 as a soluble ER-phagy receptor with a minor Golgi pool
(possibly via ZDHHC17), distinct from the YIPF3/4 mechanism. Both added as statement-only refs.
PROVISIONAL / low-confidence disease links (NOT used to change annotations).
(i) A tumor-associated R12H variant reduced MAP1LC3C association (Stefely 2020) - a
mechanistic, not disease-causal, observation. (ii) Meng et al. 2024 AD multi-omics
(DOI:10.1186/s13195-024-01578-6) reportedly lists CALCOCO1 among downregulated plasma proteins
in high-severity AD, but the abstract's top features are SKAP1/NEFL and CALCOCO1 is not named
there - treat as weak, association-only. (iii) Wei et al. 2023 (DOI:10.1186/s41065-023-00289-6)
is actually an NPM3/LUAD paper; CALCOCO1 appears only peripherally, so it is NOT a
CALCOCO1-focused reference and is intentionally kept out of the YAML.
No change to existing annotation actions. Falcon confirms the existing two-narrative
framing (cytoplasmic ER-phagy/Golgiphagy receptor = core; nuclear CoCoA coactivator =
non-core; generic protein binding = over-annotated). It adds primary citations and one
redundancy caveat (Golgiphagy) but does not contradict any existing action.

Conclusion on core vs non-core

Core (current understanding, not in GOA): selective-autophagy receptor / cargo receptor
bridging ER and Golgi membranes to ATG8 (LC3/GABARAP) family for reticulophagy and Golgiphagy;
ATG8-family protein binding (LIR/UIM-type). Cytoplasmic.
Non-core (historical, well-cited): transcriptional coactivator (CoCoA) for nuclear
receptors / AhR / Wnt-beta-catenin/LEF1 / GATA1; nuclear localization and promoter association.
Real but secondary/context-dependent and largely "by similarity" at the human level.
Over-annotated / uninformative: generic "protein binding" (GO:0005515) from interactome
screens; broad "signal transduction"; the calphoglin/PPA1-PGM activity (single old report).

Pn Notes

(CALCOCO1-pn-notes.md)

CALCOCO1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9P1Z2
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/CALCOCO1/CALCOCO1-ai-review.yaml
AIGR review HTML: present - genes/human/CALCOCO1/CALCOCO1-ai-review.html
Gene notes: present - genes/human/CALCOCO1/CALCOCO1-notes.md
GOA TSV: present - genes/human/CALCOCO1/CALCOCO1-goa.tsv
UniProt record: present - genes/human/CALCOCO1/CALCOCO1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/CALCOCO1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/CALCOCO1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/CALCOCO1/CALCOCO1-deep-research-falcon.md

AIGR Review Snapshot

Description: 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.
Existing/core annotation action counts: ACCEPT: 2; KEEP_AS_NON_CORE: 18; MARK_AS_OVER_ANNOTATED: 7; MODIFY: 3; NEW: 2

PN Consistency Summary

Consistency: Consistent. Deep research, notes, and review YAML all frame CALCOCO1 as a dual-function protein: (core) soluble selective-autophagy receptor for ER (reticulophagy) and Golgi (Golgiphagy) binding ATG8/GABARAP via LIR/UDS motifs; (non-core, historical) CoCoA transcriptional coactivator. The PN ERphagy mapping aligns with the review's core function. The notes explicitly flag that the autophagy-receptor role is absent from curated GOA, matching the review's GOA set (dominated by coactivator + generic protein-binding terms).
PN story / NEW pressure: Strong, defensible ADD pressure for the core receptor role, which is genuinely absent from GOA. GO:0061709 reticulophagy (BP, verified real) is the PN projection and is new_to_goa — should be added. Review proposes NEW MF "reticulophagy receptor activity" / "Golgiphagy receptor activity"; however an existing MF term GO:0160247 autophagy cargo adaptor activity ("brings together a cargo, targeted for degradation via autophagy, to a phagophore"; verified real) plus GO:0038024 cargo receptor activity already capture this — so the bespoke MF terms over-reach as proposed-new. Recommend annotating existing GO:0160247 + GO:0061709 (and BP GO:0061709-Golgi analog if available) rather than minting new MF terms.
Evidence alignment: Partial overlap. PN cites the EMBO ER-phagy paper (CALCOCO1+VAP) and an ER-phagy review; the review's foundational autophagy reference is Stefely 2020 (PMID:31971854, full_text_unavailable, statement-only) plus Golgiphagy papers PMID:38822137/39871880. The specific EMBO "CALCOCO1 acts with VAMP-associated proteins to mediate ER-phagy" paper named in the PN dossier is NOT cited by PMID in the review — a gap.
Verdict: Consistent; ADD reticulophagy is warranted. Avoid minting new MF terms — existing GO:0160247 covers the receptor MF.

Full Consistency Review

UniProt: Q9P1Z2 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (thorough)
PN placement: ALP|Autophagy substrate selection|Selective autophagy receptor|ERphagy; ...|Golgiphagy; UPS|Ubiquitin and UBL binding|trafficking|selective autophagy|UBZ1-type ZnF. PN-node mappings: ERphagy type=mapped/propagation GO:0061709 reticulophagy; Golgiphagy type=no_mapping; UPS ancestors=no_mapping/context_only (GO:0140036).
Consistency: Consistent. Deep research, notes, and review YAML all frame CALCOCO1 as a dual-function protein: (core) soluble selective-autophagy receptor for ER (reticulophagy) and Golgi (Golgiphagy) binding ATG8/GABARAP via LIR/UDS motifs; (non-core, historical) CoCoA transcriptional coactivator. The PN ERphagy mapping aligns with the review's core function. The notes explicitly flag that the autophagy-receptor role is absent from curated GOA, matching the review's GOA set (dominated by coactivator + generic protein-binding terms).
PN story / NEW pressure: Strong, defensible ADD pressure for the core receptor role, which is genuinely absent from GOA. GO:0061709 reticulophagy (BP, verified real) is the PN projection and is new_to_goa — should be added. Review proposes NEW MF "reticulophagy receptor activity" / "Golgiphagy receptor activity"; however an existing MF term GO:0160247 autophagy cargo adaptor activity ("brings together a cargo, targeted for degradation via autophagy, to a phagophore"; verified real) plus GO:0038024 cargo receptor activity already capture this — so the bespoke MF terms over-reach as proposed-new. Recommend annotating existing GO:0160247 + GO:0061709 (and BP GO:0061709-Golgi analog if available) rather than minting new MF terms.
Mapping strategy: PN ERphagy=mapped/propagation GO:0061709 is correct and not too broad (reticulophagy is a specific leaf process). Golgiphagy=no_mapping is the right call given Kitta 2024 (PMID:38822137) shows CALCOCO1 is NOT the dominant Golgi receptor (YIPF3/4 are) — propagating Golgiphagy would over-reach. No mapping change needed.
Evidence alignment: Partial overlap. PN cites the EMBO ER-phagy paper (CALCOCO1+VAP) and an ER-phagy review; the review's foundational autophagy reference is Stefely 2020 (PMID:31971854, full_text_unavailable, statement-only) plus Golgiphagy papers PMID:38822137/39871880. The specific EMBO "CALCOCO1 acts with VAMP-associated proteins to mediate ER-phagy" paper named in the PN dossier is NOT cited by PMID in the review — a gap.
Verdict: Consistent; ADD reticulophagy is warranted. Avoid minting new MF terms — existing GO:0160247 covers the receptor MF.

Recommended edits: [YAML] Add GO:0061709 reticulophagy (BP, involved_in) to CALCOCO1 existing/core annotations — currently new_to_goa and the validated core process. [YAML] Replace proposed_new_terms "reticulophagy/Golgiphagy receptor activity" with existing GO:0160247 autophagy cargo adaptor activity (and GO:0038024 cargo receptor activity) as the molecular_function for the core receptor role. [REF] Add the EMBO J "CALCOCO1 acts with VAMP-associated proteins to mediate ER-phagy" PMID (named in PN dossier) to the review references.
- 2026-06-18 follow-up: Implemented the high-confidence YAML edits: added GO:0061709 reticulophagy and GO:0160247 autophagy cargo adaptor activity, updated the core receptor function, and removed the bespoke reticulophagy/Golgiphagy receptor NTR block. The separate EMBO J reference gap remains a follow-up.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/CALCOCO1/CALCOCO1-ai-review.yaml
PN workbook rows: 3

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | ERphagy

UniProt: Q9P1Z2
In branches: ALP, UPS
Notes: Adapter for selective autophagy. Binds to ATG8 and ubiquitinated or degron-contaning substrates. Active in ERphagy
PN references (titles):
- Regulatory events controlling ER-phagy - ScienceDirect
- CALCOCO1 acts with VAMP‐associated proteins to mediate ER‐phagy | The EMBO Journal (embopress.org)
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|ERphagy
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061709 reticulophagy]
  rationale: The PN uses the community label ERphagy for selective autophagy of the endoplasmic reticulum, while GO uses the synonym reticulophagy. Receptor members of this PN category are suitable for propagation to the GO reticulophagy process.
- [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | Golgiphagy

UniProt: Q9P1Z2
In branches: ALP, UPS
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Golgiphagy
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | trafficking | selective autophagy | UBZ1-type ZnF

UniProt: Q9P1Z2
In branches: ALP, UPS
Signature domains: IPR041641
Auxiliary domains: (none)
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking|selective autophagy|UBZ1-type ZnF
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a selective-autophagy or trafficking subdivision under a UPS binding context. The autophagy context is real, but this node is too indirect for automatic GO propagation.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking|selective autophagy
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
  status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
  rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:0061709 reticulophagy | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|ERphagy

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q9P1Z2
gene_symbol: CALCOCO1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
    judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,
    accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations of expressed fusion
    proteins in living cells
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
    Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:16344550
  title: Differential use of functional domains by coiled-coil coactivator in its synergistic coactivator
    function with beta-catenin or GRIP1.
  findings: []
- id: PMID:24245781
  title: CCAR1/CoCoA pair-mediated recruitment of the Mediator defines a novel pathway for GATA1 function.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:31971854
  title: Mass spectrometry proteomics reveals a function for mammalian CALCOCO1 in MTOR-regulated
    selective autophagy.
  full_text_unavailable: true
  findings:
  - statement: CALCOCO1 physically interacts with the ATG8-family protein MAP1LC3C, and genetic
      deletion of CALCOCO1 disrupts autophagy of the endoplasmic reticulum (reticulophagy),
      establishing CALCOCO1 as a selective-autophagy receptor in the MTOR-regulated autophagy
      axis.
  - statement: A canonical LIR motif (W47A abolishes LC3-family binding) and a non-canonical
      CLIR motif (L140A/V142A weakens MAP1LC3C binding) mediate CALCOCO1 association with
      ATG8-family proteins, with a preference for MAP1LC3C, and CALCOCO1 abundance is regulated
      by MTOR-dependent autophagy and lysosomal flux.
- id: PMID:18722177
  title: CCAR1, a key regulator of mediator complex recruitment to nuclear receptor transcription
    complexes.
  full_text_unavailable: true
  findings:
  - statement: CCAR1 cooperates with the p160 coactivator complex and CoCoA/CALCOCO1 to recruit
      the Mediator complex and RNA polymerase II to nuclear-receptor target gene promoters,
      supporting the CCAR1-CoCoA-Mediator coactivator axis.
- id: PMID:25422592
  title: Distinct, genome-wide, gene-specific selectivity patterns of four glucocorticoid receptor
    coregulators.
  full_text_unavailable: true
  findings:
  - statement: siRNA depletion of CALCOCO1 (alongside CCAR1, CCAR2, and ZNF282) shows that
      CALCOCO1 acts as a gene-selective glucocorticoid-receptor coregulator with both positive
      and negative effects on hormone-regulated genes, rather than as a global coactivator.
- id: PMID:38822137
  title: YIPF3 and YIPF4 regulate autophagic turnover of the Golgi apparatus.
  full_text_unavailable: true
  findings:
  - statement: In a HeLa Golgiphagy reporter assay, knockdown of CALCOCO1 alone did not decrease
      Golgiphagy and triple knockdown with YIPF3/YIPF4 retained activity, indicating that
      CALCOCO1 is not the dominant Golgiphagy receptor in this context and that Golgi turnover
      involves redundant or context-specific receptors.
- id: PMID:39871880
  title: 'Join the club: YIPF3 and YIPF4 act as Golgiphagy receptors.'
  full_text_unavailable: true
  findings:
  - statement: Commentary framing CALCOCO1 as a soluble ER-phagy receptor with a minor Golgi-associated
      pool that can contribute to Golgiphagy through a mechanism distinct from the YIPF3/YIPF4
      transmembrane Golgiphagy receptor complex.
- id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
  title: UniProt entry Q9P1Z2 (CACO1_HUMAN)
  findings: []
- id: file:human/CALCOCO1/CALCOCO1-notes.md
  title: CALCOCO1 research notes
  findings: []
existing_annotations:
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: another component of the p160 nuclear receptor coactivator complex, the coiled-coil
      reference_section_type: ABSTRACT
    - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
      supporting_text: Functions as a coactivator for aryl hydrocarbon and nuclear
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: IBA transfer of a positive transcriptional regulation role, consistent with the CoCoA coactivator
      function in beta-catenin/TCF and GATA1-driven transcription.
    action: KEEP_AS_NON_CORE
    reason: Supported by experimental coactivation data but represents the secondary nuclear function
      rather than the core autophagy-receptor activity.
    supported_by: &id003
    - reference_id: PMID:16344550
      supporting_text: reduction of the endogenous CoCoA level decreased the ability of TCF/LEF and beta-catenin
        to activate transcription
      reference_section_type: ABSTRACT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization is consistent with the CoCoA coactivator function and with the UniProt
      note that the protein shuttles between nucleus and cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: Nuclear residence is real and supports the coactivator role, but the principal compartment
      for the core autophagy-receptor activity is the cytoplasm.
    supported_by: &id005
    - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
      supporting_text: Shuttles between nucleus
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic localization is well supported and is the principal compartment for the selective-autophagy
      receptor activity of CALCOCO1.
    action: ACCEPT
    reason: The cytoplasm is the main site of action for the core autophagy-receptor function, and UniProt
      records cytoplasmic localization with nucleocytoplasmic shuttling.
    supported_by: &id004
    - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
      supporting_text: Cytoplasm. Nucleus. Note=Shuttles between nucleus
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a proteome-scale yeast two-hybrid map; uninformative
      as to the specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome screen does not identify a physiologically
      interpretable function for CALCOCO1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from the HuRI binary interactome; partners include GABARAPL1
      and GABARAPL2, but the GO term conveys no specific function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput screen is uninformative for curation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from the BioPlex proteome-scale interactome.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput affinity-purification screen does not establish
      a specific CALCOCO1 function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a multimodal cell-map interactome study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput dataset is uninformative as a molecular function.
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Promoter/chromatin association is supported for the coactivator function but is not the core
      autophagy-receptor activity.
    supported_by: &id001
    - reference_id: PMID:16344550
      supporting_text: CoCoA associated specifically with the promoters
      reference_section_type: ABSTRACT
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Chromatin binding transferred from the mouse ortholog; consistent with the promoter association
      of the CoCoA coactivator, but a secondary nuclear function.
    action: KEEP_AS_NON_CORE
    reason: Supported by ChIP promoter-association data for the coactivator role; not the core autophagy-receptor
      activity.
    supported_by: *id001
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated (multi-method IEA) assignment of transcription coactivator activity, consistent
      with the experimentally supported CoCoA role.
    action: KEEP_AS_NON_CORE
    reason: Redundant with the IBA/ISS/IMP coactivator annotations; supported but secondary to the core
      autophagy-receptor activity.
    supported_by: &id002
    - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
      supporting_text: Functions as a coactivator for aryl hydrocarbon and nuclear
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Very broad signal transduction term transferred from the mouse ortholog; too general to be
      informative for CALCOCO1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Signal transduction is an over-broad parent term that does not capture either the coactivator
      or the autophagy-receptor function.
- term:
    id: GO:0030518
    label: nuclear receptor-mediated steroid hormone signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: The coactivator function for nuclear receptors is supported, but this pathway is secondary
      to the core autophagy-receptor activity.
    supported_by: *id002
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated ortholog transfer of positive regulation of Pol II transcription; redundant with
      the IBA/ISS coactivator annotations.
    action: KEEP_AS_NON_CORE
    reason: Supported by experimental coactivation data but is a secondary nuclear function.
    supported_by: *id003
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct (immunofluorescence/HPA) evidence for cytosolic localization, consistent with the
      cytoplasmic site of action of the autophagy-receptor function.
    action: ACCEPT
    reason: Cytosolic localization is directly observed and matches the principal compartment for the
      core selective-autophagy receptor activity.
    supported_by: *id004
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence/orthology transfer of positive regulation of Pol II transcription; consistent with
      the CoCoA coactivator role.
    action: KEEP_AS_NON_CORE
    reason: Supported but redundant with other coactivator annotations and secondary to the core autophagy-receptor
      function.
    supported_by: *id003
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:24245781
  qualifier: enables
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0003712
      label: transcription coregulator activity
    supported_by:
    - reference_id: PMID:24245781
      supporting_text: GATA1, MED1, CCAR1, and CoCoA were all recruited onto the
      reference_section_type: RESULTS
    - reference_id: PMID:24245781
      supporting_text: the GATA1 CF domain serves as a docking surface for multiple coactivators, including
        CoCoA, CCAR1, and MED1
      reference_section_type: RESULTS
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IMP
  original_reference_id: PMID:24245781
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:24245781
      supporting_text: Recombinant GATA1, CCAR1, CoCoA and MED1(1-602) formed a
      reference_section_type: ABSTRACT
    - reference_id: PMID:24245781
      supporting_text: the GATA1 CF domain serves as a docking surface for multiple coactivators, including
        CoCoA, CCAR1, and MED1
      reference_section_type: RESULTS
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: Direct evidence (expressed fusion protein) for nuclear localization, consistent with the
      nucleocytoplasmic shuttling and the CoCoA coactivator role.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is directly observed and supports the coactivator function, but the cytoplasm
      is the principal site for the core autophagy-receptor activity.
    supported_by: *id005
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:16344550
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Supported human experimental evidence for the coactivator function, but secondary to the core
      autophagy-receptor activity.
    supported_by: *id003
- term:
    id: GO:0003712
    label: transcription coregulator activity
  evidence_type: IDA
  original_reference_id: PMID:16344550
  qualifier: enables
  review:
    summary: Direct evidence that CoCoA acts as a transcriptional coregulator/coactivator synergizing
      with beta-catenin for AR and TCF/LEF targets.
    action: KEEP_AS_NON_CORE
    reason: Well-supported molecular function for the historical CoCoA role; secondary to the core autophagy-receptor
      activity.
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: directly binds to and cooperates
      reference_section_type: ABSTRACT
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IMP
  original_reference_id: PMID:16344550
  qualifier: enables
  review:
    summary: IMP support for transcription coactivator activity via CoCoA cooperation with beta-catenin
      for AR and TCF/LEF target genes.
    action: KEEP_AS_NON_CORE
    reason: Well-supported coactivator function; secondary to the core autophagy-receptor activity.
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: cooperates synergistically with
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16344550
  qualifier: enables
  review:
    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.
    action: MODIFY
    reason: Bare protein binding is uninformative; the specific, supported interaction is with beta-catenin,
      for which a dedicated GO term exists.
    proposed_replacement_terms:
    - id: GO:0008013
      label: beta-catenin binding
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: directly binds to and cooperates
      reference_section_type: ABSTRACT
- term:
    id: GO:0008013
    label: beta-catenin binding
  evidence_type: IPI
  original_reference_id: PMID:16344550
  qualifier: enables
  review:
    summary: Direct interaction between CoCoA and beta-catenin (CTNNB1) underpins its synergistic coactivator
      function in the Wnt/beta-catenin and androgen-receptor pathways.
    action: KEEP_AS_NON_CORE
    reason: Specific and well-supported binding for the coactivator role, but part of the secondary nuclear
      function rather than the core autophagy-receptor activity.
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: directly binds to and cooperates
      reference_section_type: ABSTRACT
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:16344550
  qualifier: enables
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0003712
      label: transcription coregulator activity
    supported_by: *id001
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IDA
  original_reference_id: PMID:16344550
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Supported but broad; redundant with the more specific transcription-regulation terms and secondary
      to the core autophagy-receptor activity.
    supported_by: *id003
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence/orthology transfer of transcription coactivator activity, consistent with the experimentally
      supported CoCoA role.
    action: KEEP_AS_NON_CORE
    reason: Redundant with the IBA/IEA/IMP coactivator annotations; supported but secondary to the core
      autophagy-receptor activity.
    supported_by: *id002
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Very broad signal transduction term transferred by orthology; too general to be informative
      for CALCOCO1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-broad parent term that does not capture the coactivator or autophagy-receptor function.
- term:
    id: GO:0030518
    label: nuclear receptor-mediated steroid hormone signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Orthology transfer of steroid-hormone nuclear-receptor signaling, consistent with the CoCoA
      coactivator role for nuclear receptors such as the androgen receptor.
    action: KEEP_AS_NON_CORE
    reason: Supported for the coactivator function but secondary to the core autophagy-receptor activity.
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: the androgen receptor (AR), a nuclear
      reference_section_type: ABSTRACT
- term:
    id: GO:0160247
    label: autophagy cargo adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:31971854
  qualifier: enables
  review:
    summary: CALCOCO1 acts as an autophagy cargo adaptor/receptor, binding ATG8-family proteins and linking ER cargo to the autophagy machinery.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:31971854
      supporting_text: CALCOCO1 physically interacts with MAP1LC3C, a key protein in the machinery of autophagy
      reference_section_type: ABSTRACT
    - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
      supporting_text: 'Q9H0R8: GABARAPL1'
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IMP
  original_reference_id: PMID:31971854
  qualifier: involved_in
  review:
    summary: Genetic deletion of CALCOCO1 disrupts autophagy of the endoplasmic reticulum, supporting a specific reticulophagy process annotation.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:31971854
      supporting_text: Genetic deletion of CALCOCO1 disrupted autophagy of the endoplasmic reticulum (reticulophagy)
      reference_section_type: ABSTRACT
core_functions:
- description: CALCOCO1 acts as a soluble selective-autophagy cargo receptor that bridges organelle membrane
    proteins of the endoplasmic reticulum and Golgi to ATG8-family proteins (LC3/GABARAP, notably GABARAPL1
    and GABARAPL2) via LIR- and UIM/UDS-type motifs, driving reticulophagy (ER-phagy) and Golgiphagy.
    This receptor/adaptor activity is supported by direct interactions with the ATG8 family in the UniProt
    interaction record and by recent autophagy literature. The ER-phagy arm is captured by reticulophagy
    plus the general autophagy cargo-adaptor MF; the Golgi-associated role remains context-dependent and
    should not drive a new MF term request.
  molecular_function:
    id: GO:0160247
    label: autophagy cargo adaptor activity
  supported_by:
  - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
    supporting_text: 'Q9H0R8: GABARAPL1'
    reference_section_type: DATABASE_ENTRY
  - reference_id: file:human/CALCOCO1/CALCOCO1-notes.md
    supporting_text: selective-autophagy receptor that functions in reticulophagy (ER-phagy)
    reference_section_type: OTHER
  - reference_id: PMID:31971854
    full_text_unavailable: true
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005829
    label: cytosol
  directly_involved_in:
  - id: GO:0061709
    label: reticulophagy
- description: CALCOCO1/CoCoA functions as a secondary/bridging transcriptional coactivator in the nucleus,
    cooperating with beta-catenin (CTNNB1) and the p160 coactivator complex (GRIP1/NCOA2, p300/CBP, CARM1)
    and with CCAR1/MED1 to enhance transcription by nuclear receptors, the aryl hydrocarbon receptor,
    and the Wnt/beta-catenin (TCF/LEF) and GATA1 pathways. It is recruited to target promoters through
    protein-protein interactions rather than sequence-specific DNA binding.
  supported_by:
  - reference_id: PMID:16344550
    supporting_text: directly binds to and cooperates
    reference_section_type: ABSTRACT
  - reference_id: PMID:24245781
    supporting_text: the GATA1 CF domain serves as a docking surface for multiple coactivators, including
      CoCoA, CCAR1, and MED1
    reference_section_type: RESULTS
  molecular_function:
    id: GO:0003713
    label: transcription coactivator activity
  directly_involved_in:
  - id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  locations:
  - id: GO:0005634
    label: nucleus
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: 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?
- question: 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?
suggested_experiments:
- description: 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.
  experiment_type: biochemical interaction mapping and cell-based autophagy flux assay
- description: 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.
  experiment_type: genetic loss-of-function with organelle-specific autophagy reporters
- description: 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.
  experiment_type: structure-function and dual-readout reporter assays

CALCOCO1

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human CALCOCO1 (UniProt Q9P1Z2) — Functional Annotation

0. Target verification (critical identity check)

1. Key concepts and definitions (current understanding)

1.1 CALCOCO1 as a selective-autophagy receptor/adaptor

1.2 ATG8-family binding motifs: LIR and CLIR

1.3 CALCOCO1 as a transcriptional coregulator (“CoCoA”)

2. Molecular functions, pathways, and cellular localization (evidence-weighted)

2.1 Subcellular localization

2.2 Core binding partners (experimentally supported)

2.3 Primary autophagy function: MTOR-regulated ER-phagy/reticulophagy

2.4 Transcriptional coactivator function (mechanistic detail)

3. Recent developments and latest research (prioritizing 2023–2024)

3.1 2024: CALCOCO1 and Golgiphagy (selective autophagy of the Golgi)

3.2 2024: Multi-omics evidence linking CALCOCO1 to Alzheimer’s disease severity

3.3 2023: Cancer bioinformatics/prognostic associations (LUAD)

4. Current applications and real-world implementations

4.1 Translational status

4.2 Example of an experimentally demonstrated cancer-relevant phenotype

5. Expert opinions and authoritative synthesis

5.1 Expert synthesis on Golgiphagy receptor landscape

5.2 Expert synthesis on coregulator selectivity in transcription

6. Statistics and data highlights from recent studies (2023–2024)

7. Consolidated evidence map

8. Conclusions (evidence-weighted functional annotation)

Artifacts

Citations

📚 Additional Documentation

Notes

CALCOCO1 (human) research notes

Summary of two distinct narratives for CALCOCO1

Evidence from the UniProt record (file:human/CALCOCO1/CALCOCO1-uniprot.txt)

Evidence from cached publications

PMID:16344550 (Yang, Kim, Li, Stallcup 2006, J Biol Chem) — CoCoA / beta-catenin

PMID:24245781 (Mizuta et al. 2014, Genes Cells) — CCAR1/CoCoA + GATA1/MED1

High-throughput interactome papers (all generic "protein binding", GO:0005515)

Falcon deep research findings (2026-06-07)

Conclusion on core vs non-core

Pn Notes

CALCOCO1 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | ERphagy

PN row 2: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | Golgiphagy

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | trafficking | selective autophagy | UBZ1-type ZnF

Projected GO annotations (1)

Note

📄 View Raw YAML