Affinage

COPB1

Coatomer subunit beta · UniProt P53618

Length
953 aa
Mass
107.1 kDa
Annotated
2026-06-09
34 papers in source corpus 7 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COPB1 encodes the β-COP subunit of the COPI coatomer and functions in retrograde Golgi-to-ER protein trafficking, where biallelic loss-of-function variants cause a recessive neurodevelopmental disorder (Baralle-Macken syndrome) with intellectual disability, cataracts, and microcephaly (PMID:33632302). Two distinct mutational mechanisms operate: an in-frame deletion disrupts a small β-COP/β'-COP interaction interface, while a missense variant (p.Phe551Val) impairs Golgi-to-ER recycling and retains mutant β-COP in the Golgi, with the phenotype recapitulated by CRISPR modelling in Xenopus tropicalis (PMID:33632302). Beyond its core coatomer role, COPB1 governs the localization of specific cargo through retrograde trafficking: it is required to retrieve STING from the Golgi back to the ER, and its depletion leaves STING in the Golgi to drive type I interferon signaling (PMID:40115189), and it mediates OSBPL2-dependent transport of ATGL from the ER to lipid droplets to support lipolysis (PMID:32650117). COPB1 additionally binds kappa opioid receptor (KOR) mRNA and supports its microtubule-dependent axonal transport and local translation in sensory neurons (PMID:17698811). In osteoblasts, COPB1 loss activates ATF6-mediated ER stress that suppresses SLC7A11 and triggers ferroptosis, and its restoration rescues osteogenic function in osteoporosis models (PMID:40206560).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2007 Medium

    Established that β-COP has an RNA-associated role beyond coatomer assembly by showing it binds KOR mRNA and is required for its microtubule-dependent axonal transport and local translation.

    Evidence Yeast three-hybrid screen, endogenous co-IP, Campenot chamber transport assay, and MS2-GFP tagging in dorsal root ganglion neurons

    PMID:17698811

    Open questions at the time
    • Whether mRNA binding is direct or coatomer-mediated is not resolved
    • The RNA-binding determinant on β-COP is not mapped
    • Single-lab study without independent replication
  2. 2020 Medium

    Defined a cargo-specific trafficking function by showing COPB1 transports ATGL from the ER to lipid droplets in an OSBPL2-dependent manner to regulate lipolysis.

    Evidence Co-immunoprecipitation, siRNA knockdown, and lipid droplet phenotyping

    PMID:32650117

    Open questions at the time
    • Direct versus bridged COPB1-ATGL contact not distinguished
    • Structural basis of the OSBPL2 requirement unknown
    • Single-lab co-IP and knockdown evidence
  3. 2021 High

    Connected COPB1 to human disease and to its molecular interaction interface by demonstrating that biallelic loss-of-function variants cause Baralle-Macken syndrome through disrupted β-COP/β'-COP interaction or defective Golgi-to-ER recycling.

    Evidence Exome/genome sequencing in two families, patient RNA analysis, missense-mutant Golgi-to-ER recycling assays in human cells, and CRISPR/Cas9 Xenopus tropicalis modelling recapitulating microcephaly and cataracts

    PMID:33632302

    Open questions at the time
    • How retrograde trafficking failure produces tissue-specific cataract and brain phenotypes is unresolved
    • No structural model of the disrupted β-COP/β'-COP interface
    • Genotype-phenotype correlation across allele types not defined
  4. 2025 Medium

    Identified a specific retrograde cargo with signaling consequences by showing COPB1 retrieves STING from Golgi to ER, thereby restraining type I interferon output and intracellular pathogen growth.

    Evidence siRNA library screen in HeLa cells against fluorescent C. psittaci, targeted knockdown, STING localization assays, and interferon reporter assays

    PMID:40115189

    Open questions at the time
    • Direct COPB1-STING contact not demonstrated
    • Whether STING retrieval is selective or a bulk consequence of coatomer loss is unclear
    • Single-lab screen
  5. 2025 Medium

    Placed COPB1 in an osteoblast survival pathway by showing its deficiency activates ATF6-mediated ER stress that suppresses SLC7A11 and triggers ferroptosis, with overexpression rescuing osteogenesis in vivo.

    Evidence siRNA knockdown in MC3T3 cells, conditional knockout mice, RNA-seq, co-IP, ChIP-seq, and AAV overexpression in OVX and Hamp KO models

    PMID:40206560

    Open questions at the time
    • Mechanistic link between trafficking defect and ATF6 activation not detailed
    • Whether the ferroptosis axis is osteoblast-specific is untested
    • Single-lab study
  6. 2026 Low

    Extended the COPB1 disease phenotype by documenting combined immunodeficiency with neutropenia, T cell lymphopenia, and memory B-cell loss in patients with homozygous loss-of-function mutations.

    Evidence Flow cytometry of lymphocyte subsets, cytokine secretion assays, and PBMC proliferation assays in three affected siblings

    PMID:41676145

    Open questions at the time
    • No molecular mechanism linking COPB1 loss to immune cell defects established
    • Limited to three siblings without functional rescue
    • Relationship to the neurodevelopmental phenotype unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single coatomer subunit selectively governs distinct cargoes (STING, ATGL, KOR mRNA, SR-BI) and produces tissue-specific disease phenotypes remains the central open question.
  • No structural model unifying cargo selectivity
  • Mechanism of tissue-specific vulnerability unexplained
  • Direct versus indirect cargo binding undefined across substrates

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-9609507 Protein localization 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ATF6ATGLCOPB2OSBPL2STING
Complex memberships
COPI coatomer

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 COPB1 (β-COP) binds kappa opioid receptor (KOR) mRNA and is required for its axonal transport in dorsal root ganglia neurons. Yeast three-hybrid screening identified COPB1 as a KOR mRNA-associated protein; complexes of endogenous KOR mRNA and COPB1 were colocalized in soma and axons. Axonal transport of biotin-labeled KOR mRNA in Campenot chambers required COPB1 and was blocked by microtubule-disrupting drugs. COPB1 also facilitated local translation of KOR mRNA in soma and axons. Yeast three-hybrid screening, co-immunoprecipitation of endogenous complexes, Campenot chamber axonal transport assay with biotin-labeled mRNA, MS2-GFP mRNA-tagging system, microtubule disruption pharmacology Proceedings of the National Academy of Sciences of the United States of America Medium 17698811
2021 Biallelic loss-of-function variants in COPB1 (encoding β-COP) cause a recessive neurodevelopmental syndrome (Baralle-Macken syndrome) with severe intellectual disability, cataracts, and variable microcephaly. A splice donor variant causes skipping of exon 8, producing a 36 amino acid in-frame deletion that disrupts a small interaction interface between β-COP and β'-COP. A missense variant (p.Phe551Val) causes defective Golgi-to-ER recycling, with the mutant β-COP retarded in the Golgi. CRISPR/Cas9 modelling of the homologous splice variant in Xenopus tropicalis recapitulated microcephaly and cataracts. Whole exome/genome sequencing, patient blood RNA studies, CRISPR/Cas9 modelling in Xenopus tropicalis, transfection of COPB1 expression vectors with missense mutation into human cell lines (RPE and HEK293), Golgi-to-ER recycling assays Genome medicine High 33632302
2020 COPB1 physically interacts with OSBPL2 (ORP2) and ATGL, and OSBPL2 is required for COPB1-mediated transport of ATGL from the ER to the lipid droplet surface to regulate lipolysis. Loss of OSBPL2 disrupts the COPB1–ATGL interaction and impairs lipid droplet lipolysis. Co-immunoprecipitation, siRNA knockdown, lipid droplet phenotyping, Western blot iScience Medium 32650117
1999 Mouse β-COP (Copb) is ubiquitously expressed and its gene maps to mouse chromosome 7 at 53.3 cM. Western blotting confirmed protein expression. The Copb gene was excluded as a candidate for the ruby-eye-2 (ru2) locus (a Hermansky-Pudlak syndrome model) by RH mapping and sequencing of RT-PCR products. RT-PCR, radiation hybrid mapping, Western blotting, sequencing Somatic cell and molecular genetics Low 11441537
2025 COPB1 deficiency in osteoblasts induces ferroptosis and endoplasmic reticulum stress. Mechanistically, loss of COPB1 activates ATF6-mediated ER stress signaling, which suppresses SLC7A11 transcription, reducing cystine uptake and triggering iron-dependent lipid peroxidation (ferroptosis). Co-immunoprecipitation and ChIP-seq confirmed COPB1 involvement in regulating ATF6-SLC7A11 axis. AAV-mediated COPB1 overexpression restored osteogenic function in osteoporosis mouse models. siRNA knockdown in MC3T3 cells, conditional knockout mice, RNA-seq, co-immunoprecipitation, ChIP-seq, transmission electron microscopy, flow cytometry, AAV overexpression in OVX and Hamp KO mouse models, Western blot, ALP/Alizarin Red staining Journal of orthopaedic translation Medium 40206560
2025 COPB1 knockdown prevents retrieval of STING from the Golgi back to the ER, thereby activating type I interferon signaling. This mechanism restricts intracellular Chlamydia psittaci proliferation, establishing COPB1 as required for STING homeostasis in the Golgi-ER retrograde trafficking pathway. siRNA library screen in HeLa cells with fluorescently labeled C. psittaci, targeted COPB1 knockdown, type I interferon pathway reporter assays, STING localization assays Frontiers in microbiology Medium 40115189
2025 Knockdown of COPB1 (and five other COPI subunits) in Huh-7 hepatocytes decreased uptake of HDL holoparticles, reduced cell surface abundance of SR-BI (scavenger receptor BI), decreased APOA1 expression and apoA-I secretion, but increased cell surface ABCA1 abundance and cholesterol efflux. This places COPB1 as required for SR-BI glycosylation and surface trafficking, and for APOA1/apoA-I production in hepatocytes. Genome-wide RNAi screen, targeted siRNA knockdown validation, fluorescent HDL uptake assays, flow cytometry for surface receptor abundance, cholesterol efflux assays bioRxivpreprint Low
2026 Patients with homozygous COPB1 loss-of-function mutations exhibit combined immunodeficiency characterized by neutropenia, T cell lymphopenia, profound reduction in switched and unswitched memory B cells, and absent specific antibody responses, establishing a role for COPB1 in lymphocyte and immune cell development/function. Flow cytometry for lymphocyte subsets, cytokine secretion assays after stimulation, PBMC proliferation assays with dye labeling and CD3/CD28 activation Frontiers in immunology Low 41676145

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Archaeoglobus fulgidus CopB is a thermophilic Cu2+-ATPase: functional role of its histidine-rich-N-terminal metal binding domain. The Journal of biological chemistry 85 12876283
1996 Expression of the CopB outer membrane protein by Moraxella catarrhalis is regulated by iron and affects iron acquisition from transferrin and lactoferrin. Infection and immunity 58 8675303
2007 Copb1-facilitated axonal transport and translation of kappa opioid-receptor mRNA. Proceedings of the National Academy of Sciences of the United States of America 53 17698811
2001 Structure-function analysis of purified Enterococcus hirae CopB copper ATPase: effect of Menkes/Wilson disease mutation homologues. The Biochemical journal 45 11415452
2012 The ATPases CopA and CopB both contribute to copper resistance of the thermoacidophilic archaeon Sulfolobus solfataricus. Microbiology (Reading, England) 39 22361944
1998 Mapping of a protective epitope of the CopB outer membrane protein of Moraxella catarrhalis. Infection and immunity 39 9453607
1982 Molecular cloning and functional characterization of a copy number control gene (copB) of plasmid R1. Journal of bacteriology 37 7050078
2021 Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly. Genome medicine 32 33632302
1986 Purification and characterization of the CopB replication control protein, and precise mapping of its target site in the R1 plasmid. Plasmid 32 3520615
1982 Expression of a copy number control gene (copB) of plasmid R1 is constitutive and growth rate dependent. Journal of bacteriology 30 7050077
2020 OSBPL2 Is Required for the Binding of COPB1 to ATGL and the Regulation of Lipid Droplet Lipolysis. iScience 29 32650117
2010 Investigation of LDHA and COPB1 as candidate genes for muscle development in the MYOD1 region of pig chromosome 2. Molecular biology reports 25 19830590
1997 Antigenic heterogeneity and molecular analysis of CopB of Moraxella (Branhamella) catarrhalis. Infection and immunity 23 9284135
2007 Sulfate acts as phosphate analog on the monomeric catalytic fragment of the CPx-ATPase CopB from Sulfolobus solfataricus. Journal of molecular biology 20 17434529
1985 Control of replication of FII plasmids: comparison of the basic replicons and of the copB systems of plasmids R100 and R1. Plasmid 19 3889949
2011 Biochemical and localization analyses of putative type III secretion translocator proteins CopB and CopB2 of Chlamydia trachomatis reveal significant distinctions. Infection and immunity 18 21606186
2004 Expression, isolation, and crystallization of the catalytic domain of CopB, a putative copper transporting ATPase from the thermoacidophilic archaeon Sulfolobus solfataricus. Journal of bioenergetics and biomembranes 14 15168619
2004 Effect of the CopB auxiliary replication control system on stability of maintenance of Par(+) plasmid R1. Journal of bacteriology 13 14679240
2021 An integrative pan-cancer analysis of COPB1 based on data mining. Cancer biomarkers : section A of Disease markers 12 32986658
2006 Polymorphism of the major surface epitope of the CopB outer membrane protein of Moraxella catarrhalis. FEMS immunology and medical microbiology 11 16872370
2025 COPB1 deficiency triggers osteoporosis with elevated iron stores by inducing osteoblast ferroptosis. Journal of orthopaedic translation 9 40206560
2009 Spectroscopic investigation of the reaction mechanism of CopB-B, the catalytic fragment from an archaeal thermophilic ATP-driven heavy metal transporter. The FEBS journal 9 19780839
2025 Interfacial CoS bond-enhanced Mn0.3Cd0.7S/CoPB Schottky junction for photothermal-assisted photocatalytic hydrogen evolution. Journal of colloid and interface science 7 41061367
2021 The Role of the Moraxella catarrhalis CopB Protein in Facilitating Iron Acquisition From Human Transferrin and Lactoferrin. Frontiers in microbiology 7 34630348
2018 Xenon-inhibition of the MscL mechano-sensitive channel and the CopB copper ATPase under different conditions suggests direct effects on these proteins. PloS one 6 29864148
2012 Conformations of the apo-, substrate-bound and phosphate-bound ATP-binding domain of the Cu(II) ATPase CopB illustrate coupling of domain movement to the catalytic cycle. Bioscience reports 6 22663904
2024 Isolation and crystallization of copper resistance protein B (CopB) from Acinetobacter baumannii. Protein expression and purification 3 39608619
2014 Investigation of four candidate genes (IGF2, JHDM1A, COPB1 and TEF1) for growth rate and backfat thickness traits on SSC2q in Large White pigs. Molecular biology reports 3 24234674
2025 COPB1-knockdown induced type I interferon signaling activation inhibits Chlamydia psittaci intracellular proliferation. Frontiers in microbiology 2 40115189
2025 Exploring Baralle-Macken Syndrome: A Novel COPB1 Mutation in Consanguineous Pakistani Siblings. American journal of medical genetics. Part A 2 40396222
1999 cDNA sequence and mapping of the mouse Copb gene encoding the beta subunit of the COPI coatomer complex. Somatic cell and molecular genetics 1 11441537
2026 Expanding the clinical and immunological phenotypes of COPB1 deficiency. Frontiers in immunology 0 41676145
2026 The copB Is a Key Copper Resistance Gene in Xanthomonas citri pv. mangiferaeindicae GXBS06. Genes 0 42074526
1990 Comparison of the CopB systems of plasmids R1 and ColV2-K94: a single base alteration in CopB gene is responsible for the increased copy number of the low copy number plasmid ColV2-K94. Molecular & general genetics : MGG 0 2325626

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