id: Q96A33
gene_symbol: CCDC47
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'CCDC47 (also called calumin) is a widely conserved, single-pass type
  I endoplasmic reticulum membrane protein with a small cytosolic domain, a single
  transmembrane helix, and a large luminal domain ending in a disordered, basic, coiled-coil
  region. It is the scaffold subunit of the PAT (protein associated with the ER translocon)
  complex, an obligate heterodimer with WDR83OS/Asterix. The PAT complex is one of
  three accessory subcomplexes (GEL, BOS, PAT) of the ribosome-associated multi-pass
  translocon (MPT) that assembles around the Sec61 channel during synthesis of multi-pass
  membrane proteins. Within this assembly CCDC47 occludes the lateral gate of Sec61
  and stabilizes Asterix, which directly engages and shields hydrophilic transmembrane
  segments of nascent multi-pass clients until they fold, thereby promoting the biogenesis
  of GPCRs, channels, transporters and other polytopic membrane proteins. CCDC47 binds
  Ca2+ with low affinity and high capacity and contributes to ER calcium storage and
  signaling, and it has been linked to ER-associated degradation (ERAD) and to maintenance
  of ER organization during embryogenesis. Biallelic loss-of-function variants cause
  an autosomal recessive trichohepatoneurodevelopmental syndrome (woolly hair, liver
  dysfunction, dysmorphic features, hypotonia, developmental delay).'
alternative_products:
- name: '1'
  id: Q96A33-1
- name: '2'
  id: Q96A33-2
  sequence_note: VSP_018478
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ER localization is well supported and is the compartment where CCDC47
      performs its core membrane-biogenesis scaffold function.
    action: ACCEPT
    reason: CCDC47 is an ER-resident membrane protein, directly demonstrated by multiple
      experimental studies; ER residence is required for its role in the multi-pass
      translocon.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: OTHER
    - reference_id: PMID:32814900
      supporting_text: CCDC47 is an ER-resident single-pass membrane protein with a
        well-conserved cytosolic domain
      reference_section_type: RESULTS
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: CCDC47/calumin binds calcium with low affinity and high capacity, consistent
      with an ER calcium-buffering property, but this is secondary to its membrane-biogenesis
      role.
    action: KEEP_AS_NON_CORE
    reason: Calcium binding is a genuine biochemical property supporting ER calcium
      storage, but the central, conserved function of CCDC47 is as the PAT/MPT scaffold;
      retain as non-core.
    supported_by:
    - reference_id: PMID:30401460
      supporting_text: CCDC47, also known as calumin, has been shown to bind Ca2+ with
        low affinity and high capacity.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated transfer of calcium ion binding agrees with experimental low-affinity,
      high-capacity Ca2+ binding by CCDC47/calumin.
    action: KEEP_AS_NON_CORE
    reason: Consistent with experimental evidence; retained as non-core relative to
      the membrane-biogenesis scaffold function.
    supported_by:
    - reference_id: PMID:30401460
      supporting_text: CCDC47, also known as calumin, has been shown to bind Ca2+ with
        low affinity and high capacity.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Automated ER localization is consistent with direct experimental evidence.
    action: ACCEPT
    reason: ER residence is well established and is core to CCDC47 function.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: OTHER
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ER membrane localization is the precise, well-supported compartment for
      this single-pass type I membrane protein.
    action: ACCEPT
    reason: Direct experimental and structural evidence place CCDC47 in the ER membrane
      as part of the translocon; this is the correct specific localization term.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: OTHER
    - reference_id: PMID:32814900
      supporting_text: CCDC47 is an ER-resident single-pass membrane protein with a
        well-conserved cytosolic domain
      reference_section_type: RESULTS
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Generic protein folding understates CCDC47's specific role; the PAT/MPT
      function is membrane protein biogenesis/insertion, best captured by the specific
      multi-pass insertion term.
    action: MODIFY
    reason: CCDC47 acts as an intramembrane chaperone in multi-pass membrane protein
      biogenesis rather than in generic (soluble) protein folding; replace with the
      specific process term.
    proposed_replacement_terms:
    - id: GO:0160063
      label: multi-pass transmembrane protein insertion into ER membrane
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: Thus, the PAT complex is an intramembrane chaperone that protects
        TMDs during assembly to minimize misfolding of multi-spanning membrane proteins
        and maintain cellular protein homeostasis.
      reference_section_type: ABSTRACT
- term:
    id: GO:0030867
    label: rough endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Rough ER membrane is consistent with CCDC47 being a ribosome-associated
      translocon component.
    action: ACCEPT
    reason: CCDC47 is part of a ribosome-bound (rough ER) translocon assembly; the
      rough ER membrane localization is appropriate.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: Rough endoplasmic reticulum membrane
      reference_section_type: OTHER
- term:
    id: GO:0032469
    label: endoplasmic reticulum calcium ion homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: ER calcium homeostasis is supported by patient-cell data showing reduced
      ER calcium stores, but is secondary to the biogenesis scaffold function.
    action: KEEP_AS_NON_CORE
    reason: Loss-of-function patient cells show decreased ER Ca2+ storage and impaired
      Ca2+ signaling, supporting a role in ER calcium homeostasis; retain as a non-core
      contextual function.
    supported_by:
    - reference_id: PMID:30401460
      supporting_text: In vitro cellular experiments showed decreased total ER Ca2+
        storage, impaired Ca2+ signaling mediated by the IP3R Ca2+ release channel,
        and reduced ER Ca2+ refilling via store-operated Ca2+ entry.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21903422
  qualifier: enables
  review:
    summary: Generic protein binding from an innate-immunity interaction network is
      uninformative for CCDC47 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome does not capture
      a physiologically interpretable CCDC47 function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Generic protein binding from a neurodegenerative-disease interactome map
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding does not identify a specific CCDC47 molecular
      function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814900
  qualifier: enables
  review:
    summary: The meaningful interaction underlying this annotation is the obligate
      CCDC47-Asterix (WDR83OS) PAT complex, which is captured by the complex/chaperone
      terms; bare protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific WDR83OS/Asterix interaction is better represented by the PAT
      complex (protein folding chaperone complex / multi-pass translocon complex) and
      chaperone annotations than by generic protein binding.
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: CCDC47 and Asterix form an obligate complex because knockdown
        or knockout of either protein results in substantial loss of the other
      reference_section_type: RESULTS
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Generic protein binding from the OpenCell endogenous-tagging interactome/localization
      cartography is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding does not capture a specific CCDC47 function.
- term:
    id: GO:0005791
    label: rough endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Rough ER localization is consistent with CCDC47 being a ribosome-associated
      translocon factor.
    action: ACCEPT
    reason: Consistent with the membrane-protein-biogenesis role at the ribosome-Sec61
      channel of the rough ER.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: Rough endoplasmic reticulum membrane
      reference_section_type: OTHER
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence-based ER annotation is consistent with the established
      ER residence of CCDC47.
    action: ACCEPT
    reason: Direct localization evidence supports ER residence, the core compartment
      for CCDC47.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: OTHER
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:32814900
  qualifier: located_in
  review:
    summary: Direct evidence places CCDC47 in the ER membrane as a single-pass component
      of the PAT complex.
    action: ACCEPT
    reason: The PAT-complex study directly demonstrates CCDC47 as an ER membrane protein;
      this is the correct specific localization.
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: CCDC47 is an ER-resident single-pass membrane protein with a
        well-conserved cytosolic domain
      reference_section_type: RESULTS
- term:
    id: GO:0045048
    label: protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:32814900
  qualifier: involved_in
  review:
    summary: CCDC47 promotes biogenesis of multi-spanning membrane proteins as part
      of the PAT complex; the more specific multi-pass insertion term better captures
      this.
    action: MODIFY
    reason: The general ER protein-insertion term is correct but imprecise; CCDC47
      acts specifically in multi-pass (polytopic) membrane protein insertion/biogenesis.
    proposed_replacement_terms:
    - id: GO:0160063
      label: multi-pass transmembrane protein insertion into ER membrane
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: Cells that lack either subunit of the PAT complex show reduced
        biogenesis of
      reference_section_type: ABSTRACT
    - reference_id: PMID:32814900
      supporting_text: Thus, the PAT complex is an intramembrane chaperone that protects
        TMDs during assembly to minimize misfolding of multi-spanning membrane proteins
        and maintain cellular protein homeostasis.
      reference_section_type: ABSTRACT
- term:
    id: GO:0101031
    label: protein folding chaperone complex
  evidence_type: IPI
  original_reference_id: PMID:32814900
  qualifier: part_of
  review:
    summary: CCDC47 is part of the PAT intramembrane chaperone complex, captured well
      by this term.
    action: ACCEPT
    reason: The obligate CCDC47-Asterix PAT complex functions as an intramembrane chaperone;
      this complex annotation is directly supported.
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: Here we identify the PAT complex, an abundant obligate heterodimer
        of the widely conserved ER-resident membrane proteins CCDC47 and Asterix.
      reference_section_type: ABSTRACT
    - reference_id: PMID:32814900
      supporting_text: Thus, the PAT complex is an intramembrane chaperone that protects
        TMDs during assembly to minimize misfolding of multi-spanning membrane proteins
        and maintain cellular protein homeostasis.
      reference_section_type: ABSTRACT
- term:
    id: GO:0160064
    label: multi-pass translocon complex
  evidence_type: IPI
  original_reference_id: PMID:36261522
  qualifier: part_of
  review:
    summary: CCDC47 (within the PAT subcomplex) is a component of the multi-pass translocon;
      this is the most specific and accurate complex term.
    action: ACCEPT
    reason: The multi-pass translocon study directly establishes the PAT complex (CCDC47/Asterix)
      as one of three accessory subcomplexes of the MPT.
    supported_by:
    - reference_id: PMID:36261522
      supporting_text: 'This ''multipass translocon'' is distinguished by three components
        that selectively bind the ribosome-Sec61 complex during multipass protein synthesis:
        the GET- and EMC-like (GEL), protein associated with translocon (PAT) and back
        of Sec61 (BOS) complexes.'
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:25009997
  qualifier: located_in
  review:
    summary: Experimental evidence supports ER membrane localization of CCDC47/calumin.
    action: ACCEPT
    reason: Consistent with established ER membrane residence.
    supported_by:
    - reference_id: PMID:25009997
      supporting_text: Calumin is an endoplasmic reticulum (ER)-transmembrane protein
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:30401460
  qualifier: located_in
  review:
    summary: Experimental evidence supports ER membrane localization of CCDC47/calumin.
    action: ACCEPT
    reason: Consistent with established ER membrane residence; this is the core compartment.
    supported_by:
    - reference_id: PMID:30401460
      supporting_text: bi-allelic variants in CCDC47 that encodes the Ca2+-binding
        ER transmembrane protein CCDC47
      reference_section_type: ABSTRACT
- term:
    id: GO:0030867
    label: rough endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Orthology-based rough ER membrane localization is consistent with the
      ribosome-associated translocon role.
    action: ACCEPT
    reason: Consistent with experimental ER membrane localization and ribosome association.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: Rough endoplasmic reticulum membrane
      reference_section_type: OTHER
- term:
    id: GO:0160063
    label: multi-pass transmembrane protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:36261522
  qualifier: involved_in
  review:
    summary: This is the most precise core biological process for CCDC47 - facilitating
      insertion/biogenesis of multi-pass membrane proteins via the multi-pass translocon.
    action: ACCEPT
    reason: Directly supported by reconstitution and depletion studies showing the
      multi-pass translocon components (including CCDC47/PAT) are required for multi-pass
      protein topogenesis and stability.
    supported_by:
    - reference_id: PMID:36261522
      supporting_text: Reconstitution studies demonstrate a role for multipass translocon
        components in protein topogenesis, and cells lacking these components show
        reduced multipass protein stability.
      reference_section_type: ABSTRACT
- term:
    id: GO:0160064
    label: multi-pass translocon complex
  evidence_type: IDA
  original_reference_id: PMID:36261522
  qualifier: part_of
  review:
    summary: Direct structural/biochemical evidence places CCDC47 (PAT subcomplex)
      in the multi-pass translocon.
    action: ACCEPT
    reason: The most specific and accurate complex localization for CCDC47, directly
      demonstrated.
    supported_by:
    - reference_id: PMID:36261522
      supporting_text: 'This ''multipass translocon'' is distinguished by three components
        that selectively bind the ribosome-Sec61 complex during multipass protein synthesis:
        the GET- and EMC-like (GEL), protein associated with translocon (PAT) and back
        of Sec61 (BOS) complexes.'
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32820719
  qualifier: enables
  review:
    summary: The meaningful interactions underlying this annotation are CCDC47's associations
      within the Sec61/MPT translocon; bare protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific translocon interactions are captured by the multi-pass translocon
      complex annotation; generic protein binding adds nothing.
    supported_by:
    - reference_id: PMID:32820719
      supporting_text: 'Here we describe a ~ 360 kDa ribosome-associated complex comprising
        the core Sec61 channel and five accessory factors: TMCO1, CCDC47 and the Nicalin-TMEM147-NOMO
        complex.'
      reference_section_type: ABSTRACT
- term:
    id: GO:0043022
    label: ribosome binding
  evidence_type: IDA
  original_reference_id: PMID:32820719
  qualifier: enables
  review:
    summary: CCDC47 is part of a ribosome-associated translocon assembly, supporting
      a ribosome-binding molecular function.
    action: ACCEPT
    reason: Cryo-EM and biochemistry place CCDC47 within a ribosome-associated Sec61
      translocon complex; ribosome binding is supported and relevant to co-translational
      multi-pass biogenesis.
    supported_by:
    - reference_id: PMID:32820719
      supporting_text: 'Here we describe a ~ 360 kDa ribosome-associated complex comprising
        the core Sec61 channel and five accessory factors: TMCO1, CCDC47 and the Nicalin-TMEM147-NOMO
        complex.'
      reference_section_type: ABSTRACT
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:32814900
  qualifier: enables
  review:
    summary: As part of the PAT intramembrane chaperone, CCDC47 contributes chaperone
      activity that protects nascent transmembrane domains during multi-pass biogenesis.
    action: ACCEPT
    reason: The PAT complex is directly described as an intramembrane chaperone; CCDC47
      is its scaffold/occluder subunit. Note Asterix is the substrate-contacting subunit,
      but the chaperone-function annotation at the protein level is appropriate.
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: Thus, the PAT complex is an intramembrane chaperone that protects
        TMDs during assembly to minimize misfolding of multi-spanning membrane proteins
        and maintain cellular protein homeostasis.
      reference_section_type: ABSTRACT
- term:
    id: GO:0032469
    label: endoplasmic reticulum calcium ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:30401460
  qualifier: involved_in
  review:
    summary: Patient-cell loss-of-function data directly support a role for CCDC47
      in ER calcium homeostasis, but this is a secondary/contextual function.
    action: KEEP_AS_NON_CORE
    reason: Reduced ER Ca2+ storage and impaired Ca2+ signaling in CCDC47-deficient
      cells support this process; retain as non-core relative to the membrane-biogenesis
      scaffold role.
    supported_by:
    - reference_id: PMID:30401460
      supporting_text: In vitro cellular experiments showed decreased total ER Ca2+
        storage, impaired Ca2+ signaling mediated by the IP3R Ca2+ release channel,
        and reduced ER Ca2+ refilling via store-operated Ca2+ entry.
      reference_section_type: ABSTRACT
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:25009997
  qualifier: involved_in
  review:
    summary: Calumin co-IPs with ERAD machinery and its knockdown reduces ERAD efficiency,
      supporting involvement in ER-associated degradation as a secondary function.
    action: KEEP_AS_NON_CORE
    reason: Experimental knockdown data link CCDC47/calumin to ERAD efficiency, but
      this is a contextual ER proteostasis role distinct from its core multi-pass biogenesis
      scaffold function.
    supported_by:
    - reference_id: PMID:25009997
      supporting_text: calumin knockdown in HEK 293 cells resulted in ERAD being less
        efficient, as demonstrated by attenuation in both degradations of a misfolded
        α1-antitrypsin variant and the ER-to-cytosol dislocation of cholera toxin A1
        subunit.
      reference_section_type: ABSTRACT
- term:
    id: GO:0001649
    label: osteoblast differentiation
  evidence_type: HDA
  original_reference_id: PMID:16210410
  qualifier: involved_in
  review:
    summary: This annotation derives from detection of CCDC47 in a differential membrane-proteomics
      dataset of an MSC line during osteoblast differentiation, not from functional
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: Presence in a high-throughput differential proteomics profile is not evidence
      that CCDC47 functions in osteoblast differentiation.
    supported_by:
    - reference_id: PMID:16210410
      supporting_text: we used MS to characterize changes in expression of membrane
        protein markers before and after short-term induction of osteoblast (OB) differentiation
      reference_section_type: ABSTRACT
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:16210410
  qualifier: located_in
  review:
    summary: Generic membrane localization is subsumed by the specific ER membrane
      annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: The bare membrane term is uninformative given direct, specific ER membrane
      localization evidence.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: Generic membrane localization from an NK-cell membrane-proteome dataset
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by the specific ER membrane localization; bare membrane adds nothing.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    summary: This annotation comes from a high-throughput mRNA interactome-capture
      atlas; there is no specific evidence of a physiological RNA-binding function
      for CCDC47.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput crosslinking capture does not establish a meaningful RNA-binding
      molecular function for an ER membrane translocon scaffold.
    supported_by:
    - reference_id: PMID:22658674
      supporting_text: 'Employing two complementary protocols for covalent UV crosslinking
        of RBPs to RNA, we describe a systematic, unbiased, and comprehensive approach,
        termed "interactome capture," to define the mRNA interactome of proliferating
        human HeLa cells.'
      reference_section_type: ABSTRACT
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- 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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16210410
  title: Differential expression profiling of membrane proteins by quantitative proteomics
    in a human mesenchymal stem cell line undergoing osteoblast differentiation.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:21903422
  title: Mapping a dynamic innate immunity protein interaction network regulating
    type I interferon production.
  findings: []
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
- id: PMID:25009997
  title: Contribution of calumin to embryogenesis through participation in the endoplasmic
    reticulum-associated degradation activity.
  findings:
  - statement: Calumin co-IPs with ERAD machinery and its knockdown reduces ERAD efficiency.
    supporting_text: calumin knockdown in HEK 293 cells resulted in ERAD being less
      efficient, as demonstrated by attenuation in both degradations of a misfolded
      α1-antitrypsin variant and the ER-to-cytosol dislocation of cholera toxin A1
      subunit.
    reference_section_type: ABSTRACT
- id: PMID:30401460
  title: Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair,
    Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay.
  findings:
  - statement: CCDC47/calumin binds Ca2+ with low affinity and high capacity; biallelic
      loss causes a multisystem disorder with impaired ER calcium homeostasis.
    supporting_text: In vitro cellular experiments showed decreased total ER Ca2+ storage,
      impaired Ca2+ signaling mediated by the IP3R Ca2+ release channel, and reduced
      ER Ca2+ refilling via store-operated Ca2+ entry.
    reference_section_type: ABSTRACT
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:32814900
  title: An intramembrane chaperone complex facilitates membrane protein biogenesis.
  findings:
  - statement: CCDC47 and Asterix (WDR83OS) form the obligate PAT intramembrane chaperone
      complex that protects nascent TMDs during multi-pass membrane protein biogenesis.
    supporting_text: Here we identify the PAT complex, an abundant obligate heterodimer
      of the widely conserved ER-resident membrane proteins CCDC47 and Asterix.
    reference_section_type: ABSTRACT
  - statement: Asterix is the substrate-contacting subunit; CCDC47 is the scaffold
      required for Asterix stability.
    supporting_text: Asterix is the substrate- interacting subunit of the PAT complex,
      while CCDC47 is needed for Asterix stability.
    reference_section_type: RESULTS
- id: PMID:32820719
  title: An ER translocon for multi-pass membrane protein biogenesis.
  findings:
  - statement: CCDC47 is a component of a ribosome-associated Sec61 multi-pass translocon
      assembly.
    supporting_text: 'Here we describe a ~ 360 kDa ribosome-associated complex comprising
      the core Sec61 channel and five accessory factors: TMCO1, CCDC47 and the Nicalin-TMEM147-NOMO
      complex.'
    reference_section_type: ABSTRACT
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:36261522
  title: Substrate-driven assembly of a translocon for multipass membrane proteins.
  findings:
  - statement: The PAT complex (CCDC47/Asterix) is one of three accessory subcomplexes
      of the substrate-recruited multi-pass translocon required for multi-pass protein
      topogenesis.
    supporting_text: Reconstitution studies demonstrate a role for multipass translocon
      components in protein topogenesis, and cells lacking these components show reduced
      multipass protein stability.
    reference_section_type: ABSTRACT
- id: file:human/CCDC47/CCDC47-uniprot.txt
  title: CCDC47 UniProtKB record (Q96A33)
  findings: []
- id: file:human/CCDC47/CCDC47-notes.md
  title: Manual CCDC47 curation notes
  findings: []
core_functions:
- description: CCDC47 is the scaffold subunit of the PAT intramembrane chaperone complex
    (an obligate heterodimer with WDR83OS/Asterix), a component of the ribosome-associated
    multi-pass translocon that promotes biogenesis of multi-pass (polytopic) membrane
    proteins downstream of Sec61. CCDC47 occludes the Sec61 lateral gate and stabilizes
    Asterix, which shields hydrophilic transmembrane segments of nascent clients until
    they fold.
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
  - id: GO:0160063
    label: multi-pass transmembrane protein insertion into ER membrane
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:0160064
    label: multi-pass translocon complex
  supported_by:
  - reference_id: PMID:32814900
    supporting_text: Here we identify the PAT complex, an abundant obligate heterodimer
      of the widely conserved ER-resident membrane proteins CCDC47 and Asterix.
    reference_section_type: ABSTRACT
  - reference_id: PMID:32814900
    supporting_text: Thus, the PAT complex is an intramembrane chaperone that protects
      TMDs during assembly to minimize misfolding of multi-spanning membrane proteins
      and maintain cellular protein homeostasis.
    reference_section_type: ABSTRACT
  - reference_id: PMID:36261522
    supporting_text: Reconstitution studies demonstrate a role for multipass translocon
      components in protein topogenesis, and cells lacking these components show reduced
      multipass protein stability.
    reference_section_type: ABSTRACT
- description: CCDC47/calumin contributes to ER calcium homeostasis as a low-affinity,
    high-capacity Ca2+-binding ER membrane protein; loss of function reduces ER calcium
    stores and impairs ER calcium signaling.
  molecular_function:
    id: GO:0005509
    label: calcium ion binding
  directly_involved_in:
  - id: GO:0032469
    label: endoplasmic reticulum calcium ion homeostasis
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:30401460
    supporting_text: CCDC47, also known as calumin, has been shown to bind Ca2+ with
      low affinity and high capacity.
    reference_section_type: ABSTRACT
  - reference_id: PMID:30401460
    supporting_text: In vitro cellular experiments showed decreased total ER Ca2+ storage,
      impaired Ca2+ signaling mediated by the IP3R Ca2+ release channel, and reduced
      ER Ca2+ refilling via store-operated Ca2+ entry.
    reference_section_type: ABSTRACT
proposed_new_terms: []
suggested_questions:
- question: Does CCDC47 contribute catalytically/mechanistically to multi-pass biogenesis
    beyond stabilizing Asterix and occluding the Sec61 lateral gate, or is its role
    purely structural/scaffolding?
- question: Is the ER calcium homeostasis phenotype of CCDC47 deficiency a direct consequence
    of its Ca2+-binding capacity, or an indirect result of impaired biogenesis of
    calcium-handling membrane proteins?
suggested_experiments:
- hypothesis: CCDC47 is required specifically for biogenesis of a defined set of multi-pass
    membrane proteins (GPCRs, channels, transporters) but not single-pass or tail-anchored
    proteins.
  description: Perform proteome-wide and targeted membrane-protein stability/surface-expression
    assays (e.g., dual-color ratiometric reporters) in CCDC47-knockout versus rescued
    cells across diverse client topologies.
  experiment_type: cell-based membrane protein biogenesis assay
- hypothesis: The ER calcium defect in CCDC47-deficient cells is secondary to mislocalization/instability
    of calcium-handling multi-pass channels rather than to direct loss of CCDC47 Ca2+
    buffering.
  description: Quantify ER calcium stores and IP3R/SOCE-mediated signaling in CCDC47-null
    cells rescued with wild-type CCDC47 versus a Ca2+-binding-deficient mutant, and
    measure abundance/localization of key ER calcium channels.
  experiment_type: calcium imaging with structure-function rescue