id: P51572
gene_symbol: BCAP31
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  BCAP31 (also known as BAP31) is an abundant ER-resident integral membrane protein
  that functions as a chaperone and cargo receptor for ER quality control. It has
  three
  transmembrane domains with a cytosolic C-terminal coiled-coil domain containing
  a
  KKXX ER-retrieval motif. BCAP31 plays essential roles in (1) ER-to-Golgi transport
  of select membrane proteins, (2) ER-associated degradation (ERAD) by promoting
  retrotranslocation of misfolded proteins via interaction with Sec61 and Derlin-1,
  and (3) mitochondrial homeostasis via ER-mitochondria contact sites through interaction
  with Tom40 to facilitate import of Complex I components. Importantly, while BCAP31
  is cleaved by caspase-8 during apoptosis to generate a p20 fragment, this reflects
  its role as a SUBSTRATE of apoptosis machinery, not a direct participant in apoptosis
  initiation. The p20 cleavage product induces ER calcium release and mitochondrial
  fission as a consequence of apoptotic signaling. Loss-of-function mutations cause
  DDCH syndrome (deafness, dystonia, central hypomyelination).
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      BCAP31 is definitively an ER membrane protein with three transmembrane domains.
      This is well-established through multiple experimental approaches including
      biochemistry, immunofluorescence, and proteomics (PMID:9334338, PMID:18555783,
      PMID:31206022). The IBA annotation is well-supported by the phylogenetic evidence
      and consistent with all experimental data.
    action: ACCEPT
    reason: >-
      Core localization. BCAP31 is one of the most abundant ER membrane proteins
      (PMID:18555783). UniProt states it "Functions as a chaperone protein...Is
      one
      of the most abundant endoplasmic reticulum (ER) proteins."
    supported_by:
    - reference_id: PMID:9334338
      supporting_text: "We have identified a human Bcl-2-interacting protein, p28
        Bap31. It is a 28-kD (p28) polytopic integral protein of the endoplasmic reticulum"
    - reference_id: PMID:18555783
      supporting_text: "BAP31 is an endoplasmic reticulum protein-sorting factor that
        associates with newly synthesized integral membrane proteins"
    - reference_id: file:human/BCAP31/BCAP31-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      BCAP31 functions as a cargo receptor that promotes ER export of select membrane
      proteins. This is a core function supported by multiple studies showing BCAP31
      controls the fate of newly synthesized membrane proteins including their egress
      from the ER (PMID:18555783). The protein shuttles between ER and intermediate
      compartment/cis-Golgi (UniProt).
    action: ACCEPT
    reason: >-
      Core function. BCAP31 is described as an ER protein-sorting factor controlling
      egress of membrane proteins (PMID:18555783). The deep research confirms this
      as a primary function.
    supported_by:
    - reference_id: PMID:18555783
      supporting_text: "BAP31 is an endoplasmic reticulum protein-sorting factor that
        associates with newly synthesized integral membrane proteins and controls
        their fate (i.e., egress, retention, survival, or degradation)"
- term:
    id: GO:0070973
    label: protein localization to endoplasmic reticulum exit site
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      BCAP31 cycles between peripheral ER and a juxtanuclear ER quality control
      compartment
      related to ERAD, and functions in cargo selection for ER export. The IBA annotation
      is consistent with the broader role in ER-to-Golgi transport.
    action: ACCEPT
    reason: >-
      Consistent with core cargo receptor/ER export function. The deep research
      describes
      BCAP31 as cycling between peripheral ER and juxtanuclear ERQC compartment.
    supported_by:
    - reference_id: PMID:18555783
      supporting_text: "BAP31 is an endoplasmic reticulum protein-sorting factor that
        associates with newly synthesized integral membrane proteins and controls
        their fate (i.e., egress, retention, survival, or degradation)"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      InterPro-based annotation that BCAP31 localizes to ER. This is correct but
      more general than the ER membrane annotation. Acceptable as a broader CC term.
    action: ACCEPT
    reason: >-
      Correct general localization. The more specific ER membrane term is also present.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Automated annotation for ER membrane localization. Duplicates the IBA annotation
      but with different evidence - this is acceptable as IEA provides independent
      computational support.
    action: ACCEPT
    reason: >-
      Correct localization supported by multiple evidence types.
- term:
    id: GO:0006886
    label: intracellular protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      InterPro-based annotation for protein transport. This is a broader parent
      term
      of the more specific ER-to-Golgi transport annotation. Acceptable as a general
      process annotation.
    action: ACCEPT
    reason: >-
      Correct general process. BCAP31 is a cargo receptor for membrane protein transport.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      This annotation derives from the UniProt "Apoptosis" keyword. However, BCAP31
      is a SUBSTRATE of caspase-8, not an active participant in apoptosis. Being
      cleaved
      during apoptosis does not make a protein "involved in" apoptotic process.
      The p20
      cleavage product does induce downstream effects (ER Ca2+ release, mitochondrial
      fission), but this is a CONSEQUENCE of apoptotic signaling, not a core function.
      This is analogous to other caspase substrates like AIMP1 that are over-annotated
      to apoptosis simply because they are cleaved.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      BCAP31 is a caspase-8 substrate cleaved during apoptosis (PMID:9334338), not
      an active regulator of apoptosis. The core functions are ER quality control,
      cargo transport, and mitochondrial homeostasis. Being a target of caspases
      does
      not constitute involvement in apoptotic process - this conflates being affected
      BY apoptosis with causing or regulating apoptosis.
    supported_by:
    - reference_id: PMID:9334338
      supporting_text: "In the absence (but not presence) of elevated Bcl-2 levels,
        apoptotic signaling by adenovirus E1A oncoproteins promote cleavage of p28
        at the two caspase recognition sites. Purified caspase-8 (FLICE/MACH/Mch5)
        and caspase-1(ICE), but not caspase-3 (CPP32/apopain/ Yama), efficiently catalyze
        this reaction in vitro."
    - reference_id: PMID:21183955
      supporting_text: "Here, we show that the mitochondrial fission protein Fission
        1 homologue (Fis1) conveys an apoptosis signal from the mitochondria to the
        ER by interacting with Bap31 at the ER and facilitating its cleavage into
        the pro-apoptotic p20Bap31"
- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      Keyword-based annotation for protein transport. Correct but general - BCAP31
      specifically functions in ER-to-Golgi transport and ERAD.
    action: ACCEPT
    reason: >-
      Correct general process annotation consistent with core cargo receptor function.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Very general CC term. BCAP31 is a multi-pass membrane protein, so this is
      technically
      correct but uninformative given more specific annotations.
    action: ACCEPT
    reason: >-
      Technically correct though very general. More specific ER membrane annotation
      is also present.
- term:
    id: GO:0016192
    label: vesicle-mediated transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      General term for vesicle transport. Consistent with BCAP31's role in ER-to-Golgi
      trafficking, though the more specific term is also annotated.
    action: ACCEPT
    reason: >-
      Correct general process consistent with cargo receptor function.
- term:
    id: GO:0033116
    label: endoplasmic reticulum-Golgi intermediate compartment membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      BCAP31 cycles between ER and ERGIC/cis-Golgi. UniProt states it "May shuttle
      between the ER and the intermediate compartment/cis-Golgi complex."
    action: ACCEPT
    reason: >-
      Consistent with the itinerant nature of BCAP31 cycling between ER and ERGIC.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15024066
  review:
    summary: >-
      Interaction with HACD2 (protein tyrosine phosphatase-like B) shown by yeast
      two-hybrid. While the interaction is real, "protein binding" is uninformative.
      BCAP31 regulates turnover of HACD2, consistent with its ERAD function.
    action: REMOVE
    reason: >-
      Generic "protein binding" is not informative. The specific interaction with
      HACD2 relates to BCAP31's ERAD function but "protein binding" does not capture
      this biological context.
    supported_by:
    - reference_id: PMID:15024066
      supporting_text: The yeast split-ubiquitin membrane protein two-hybrid 
        screen identifies BAP31 as a regulator of the turnover of endoplasmic 
        reticulum-associated protein tyrosine phosphatase-like B.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17500595
  review:
    summary: >-
      High-throughput screen showing BCAP31 as a huntingtin interactor. Generic
      protein binding annotation from large-scale study.
    action: REMOVE
    reason: >-
      Generic "protein binding" from HTP study is not informative about molecular
      function.
    supported_by:
    - reference_id: PMID:17500595
      supporting_text: Huntingtin interacting proteins are genetic modifiers of 
        neurodegeneration.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18555783
  review:
    summary: >-
      Interaction with CFTR, Sec61beta, TRAM, and Derlin-1 shown in this landmark
      Cell paper. These interactions are functionally important for ERAD. However,
      "protein binding" does not capture the biological significance.
    action: REMOVE
    reason: >-
      Generic term. The specific interactions with Sec61, TRAM, and Derlin-1 support
      the ERAD function annotations which are more informative.
    supported_by:
    - reference_id: PMID:18555783
      supporting_text: "we show that a part of the BAP31 population interacts with
        two components of the Sec61 preprotein translocon, Sec61beta and TRAM. BAP31
        associates with the N terminus of one of its newly synthesized client proteins,
        the DeltaF508 mutant of CFTR"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21183955
  review:
    summary: >-
      Interaction with Fis1 and caspase-8 at the ER-mitochondria interface. While
      real interactions, "protein binding" is uninformative.
    action: REMOVE
    reason: >-
      Generic term does not capture the biological context of ER-mitochondria contacts.
    supported_by:
    - reference_id: PMID:21183955
      supporting_text: Fis1 and Bap31 bridge the mitochondria-ER interface to 
        establish a platform for apoptosis induction.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25854864
  review:
    summary: >-
      Interaction with RSV SH protein. Host-virus interaction.
    action: REMOVE
    reason: >-
      Generic protein binding. The interaction with viral protein is tangential
      to
      core function.
    supported_by:
    - reference_id: PMID:25854864
      supporting_text: Interaction between human BAP31 and respiratory syncytial
        virus small hydrophobic (SH) protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  review:
    summary: >-
      Large-scale crosslinking mass spectrometry study.
    action: REMOVE
    reason: >-
      Generic term from HTP study is not informative.
    supported_by:
    - reference_id: PMID:30021884
      supporting_text: Epub 2018 Jul 18. Histone Interaction Landscapes 
        Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      Binary interactome mapping study.
    action: REMOVE
    reason: >-
      Generic term from HTP study is not informative.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: Apr 8. A reference map of the human binary protein 
        interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      Interactome mapping in neurodegenerative disease context.
    action: REMOVE
    reason: >-
      Generic term from HTP study is not informative.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of 
        Neurodegenerative Disease Proteins and Uncovers Widespread Protein 
        Aggregation in Affected Brains.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      Dual proteome-scale network study.
    action: REMOVE
    reason: >-
      Generic term from HTP study is not informative.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
        cell-specific remodeling of the human interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: >-
      OpenCell endogenous tagging study.
    action: REMOVE
    reason: >-
      Generic term from HTP study is not informative.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: '2022 Mar 11. OpenCell: Endogenous tagging for the cartography
        of human cellular organization.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36012204
  review:
    summary: >-
      CFTR interactome study using proximity labeling.
    action: REMOVE
    reason: >-
      Generic term from HTP study. CFTR interaction is covered by ERAD annotations.
    supported_by:
    - reference_id: PMID:36012204
      supporting_text: Differential CFTR-Interactome Proximity Labeling 
        Procedures Identify Enrichment in Multiple SLC Transporters.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9334338
  review:
    summary: >-
      Landmark paper identifying BCAP31 interactions with Bcl-2, Bcl-XL, and procaspase-8.
      Important interactions but "protein binding" is uninformative.
    action: REMOVE
    reason: >-
      Generic term. The interactions with BCL2 family and caspase-8 are biologically
      significant but relate to BCAP31 being a substrate, not its core function.
    supported_by:
    - reference_id: PMID:9334338
      supporting_text: "In cotransfected 293T cells, p28 is part of a complex that
        includes Bcl-2/Bcl-XL and procaspase-8 (pro-FLICE)"
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara transfer from mouse. BCAP31 cycles through ERGIC and may reach
      cis-Golgi. Acceptable localization.
    action: ACCEPT
    reason: >-
      Consistent with BCAP31's itinerant behavior cycling between ER and Golgi compartments.
- term:
    id: GO:0007283
    label: spermatogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl transfer from mouse. There is some evidence for BCAP31 involvement
      in spermatogenesis but this appears to be a tissue-specific developmental
      role
      rather than core function.
    action: KEEP_AS_NON_CORE
    reason: >-
      BCAP31 is expressed broadly including in testis, and ER function is important
      in spermatogenesis. However, this is a downstream developmental consequence
      rather than core molecular function.
- term:
    id: GO:0030136
    label: clathrin-coated vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl transfer from rat. Some evidence for BCAP31 in clathrin-coated vesicles
      but this is not well-established for human.
    action: UNDECIDED
    reason: >-
      Limited evidence for this specific localization in human. May reflect detection
      during trafficking.
- term:
    id: GO:0032580
    label: Golgi cisterna membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      More specific Golgi localization transferred from rat.
    action: ACCEPT
    reason: >-
      Consistent with BCAP31 cycling through ER-Golgi trafficking pathway.
- term:
    id: GO:0042288
    label: MHC class I protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      BCAP31 is known to promote ER export and quality control of MHC class I molecules.
      This is a specific and informative MF annotation.
    action: ACCEPT
    reason: >-
      The deep research confirms BCAP31 "enhances ER export and quality control
      of
      human MHC I" (The Journal of Immunology, 2006). This is a meaningful cargo-specific
      binding function.
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      General MF term. BCAP31 does form large complexes but this is not very informative.
    action: ACCEPT
    reason: >-
      Technically correct - BCAP31 is part of large protein complexes at the ER
      membrane.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      HPA immunofluorescence-based annotation for ER localization.
    action: ACCEPT
    reason: >-
      Experimental confirmation of ER localization.
- term:
    id: GO:0098553
    label: lumenal side of endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8951499
  review:
    summary: >-
      Reactome annotation relating to MHC class I peptide loading. BCAP31 has a
      short
      lumenal N-terminus but most of the protein is cytosolic. This specific localization
      relates to its role in peptide loading complex.
    action: ACCEPT
    reason: >-
      Part of BCAP31's topology includes lumenal-facing domains involved in cargo
      recognition for MHC class I trafficking.
- term:
    id: GO:0098553
    label: lumenal side of endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983138
  review:
    summary: >-
      Reactome annotation for MHC transport. Duplicate evidence for same localization.
    action: ACCEPT
    reason: >-
      Consistent with MHC class I trafficking role.
- term:
    id: GO:0098553
    label: lumenal side of endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983142
  review:
    summary: >-
      Peptide loading complex formation in Reactome.
    action: ACCEPT
    reason: >-
      Consistent with BCAP31's role in MHC class I quality control.
- term:
    id: GO:0098553
    label: lumenal side of endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983161
  review:
    summary: >-
      Dissociation of peptide loading complex annotation.
    action: ACCEPT
    reason: >-
      Consistent with MHC class I trafficking role.
- term:
    id: GO:1904294
    label: positive regulation of ERAD pathway
  evidence_type: IGI
  original_reference_id: PMID:18555783
  review:
    summary: >-
      This is a core function of BCAP31. The Cell paper shows BCAP31 promotes
      retrotranslocation and degradation of misfolded CFTR via interaction with
      Derlin-1 complex.
    action: ACCEPT
    reason: >-
      Core function. BCAP31 "promotes retrotranslocation of CFTRDeltaF508 via the
      derlin-1 complex" (PMID:18555783). This is one of the primary molecular functions.
    supported_by:
    - reference_id: PMID:18555783
      supporting_text: "BAP31 associates with the N terminus of one of its newly synthesized
        client proteins, the DeltaF508 mutant of CFTR, and promotes its retrotranslocation
        from the ER and degradation by the cytoplasmic 26S proteasome system. Depletion
        of BAP31 reduces the proteasomal degradation of DeltaF508"
- term:
    id: GO:2000060
    label: positive regulation of ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:18555783
  review:
    summary: >-
      BCAP31 promotes degradation of misfolded ER proteins via the proteasome. This
      is part of its ERAD function.
    action: ACCEPT
    reason: >-
      Core function. BCAP31 promotes proteasomal degradation of ERAD substrates.
    supported_by:
    - reference_id: PMID:18555783
      supporting_text: "BAP31 associates with the N terminus of one of its newly synthesized
        client proteins, the DeltaF508 mutant of CFTR, and promotes its retrotranslocation
        from the ER and degradation by the cytoplasmic 26S proteasome system"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9837136
  review:
    summary: >-
      Reactome annotation for RSV SH binding to BCAP31 at ER membrane.
    action: ACCEPT
    reason: >-
      Confirms ER membrane localization through additional pathway curation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31206022
  review:
    summary: >-
      This Science Advances paper shows important interactions with Tom40, NDUFS4,
      NDUFB11, VDAC1, and BCL2 at ER-mitochondria contact sites. However, "protein
      binding" is uninformative.
    action: REMOVE
    reason: >-
      Generic term. The important Tom40 interaction is better captured by the MAM
      and mitochondria-related process annotations.
    supported_by:
    - reference_id: PMID:31206022
      supporting_text: "BAP31 interacts with mitochondria-localized proteins, including
        Tom40, to stimulate the translocation of NDUFS4, the component of complex
        I from the cytosol to the mitochondria"
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:31206022
  review:
    summary: >-
      BCAP31 responds to ER stress by delocalizing from ER-mitochondria contact
      sites
      and binding BCL2. This is an important regulatory function.
    action: ACCEPT
    reason: >-
      BCAP31 functions as a stress sensor at ER-mitochondria contact sites. "In
      response
      to ER stress, delocalizes from the ER-mitochondria contact sites and binds
      BCL2"
      (UniProt, PMID:31206022).
    supported_by:
    - reference_id: PMID:31206022
      supporting_text: "the BAP31-Tom40 ER-mitochondria bridging complex...plays a
        role as a previously unidentified stress sensor"
- term:
    id: GO:0044233
    label: mitochondria-associated endoplasmic reticulum membrane contact site
  evidence_type: IDA
  original_reference_id: PMID:31206022
  review:
    summary: >-
      BCAP31 localizes to MAM/MERCs through interaction with mitochondrial Tom40.
      This is important for its role in mitochondrial homeostasis.
    action: ACCEPT
    reason: >-
      Core localization for mitochondrial function. "Associates with the mitochondria-associated
      endoplasmic reticulum membrane via interaction with TOMM40" (UniProt).
    supported_by:
    - reference_id: PMID:31206022
      supporting_text: "the ER membrane protein, BAP31, acts as a key factor in mitochondrial
        homeostasis...by forming an ER-mitochondria bridging protein complex"
- term:
    id: GO:0070585
    label: protein localization to mitochondrion
  evidence_type: IGI
  original_reference_id: PMID:31206022
  review:
    summary: >-
      BCAP31 facilitates import of NDUFS4 and other Complex I components into
      mitochondria via interaction with Tom40.
    action: ACCEPT
    reason: >-
      Important function at ER-mitochondria interface. BCAP31 "stimulate[s] the
      translocation of NDUFS4...from the cytosol to the mitochondria."
    supported_by:
    - reference_id: PMID:31206022
      supporting_text: "Within this complex, BAP31 interacts with mitochondria-localized
        proteins, including Tom40, to stimulate the translocation of NDUFS4, the component
        of complex I from the cytosol to the mitochondria"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:24454821
  review:
    summary: >-
      Experimental demonstration of ER localization.
    action: ACCEPT
    reason: >-
      Confirms core ER localization.
    supported_by:
    - reference_id: PMID:24454821
      supporting_text: eCollection 2014. Transmembrane and coiled-coil domain 
        family 1 is a novel protein of the endoplasmic reticulum.
- term:
    id: GO:0097038
    label: perinuclear endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:25854864
  review:
    summary: >-
      BCAP31 localizes to perinuclear ER in addition to peripheral ER. Consistent
      with its cycling between compartments.
    action: ACCEPT
    reason: >-
      BCAP31 cycles between peripheral ER and juxtanuclear ERQC compartment. This
      annotation captures part of that distribution.
    supported_by:
    - reference_id: PMID:25854864
      supporting_text: Interaction between human BAP31 and respiratory syncytial
        virus small hydrophobic (SH) protein.
- term:
    id: GO:1904154
    label: positive regulation of retrograde protein transport, ER to cytosol
  evidence_type: IDA
  original_reference_id: PMID:18555783
  review:
    summary: >-
      BCAP31 promotes retrotranslocation of misfolded proteins from ER to cytosol
      for proteasomal degradation. Core ERAD function.
    action: ACCEPT
    reason: >-
      Core function. BCAP31 "promotes retrotranslocation of CFTRDeltaF508" (PMID:18555783).
    supported_by:
    - reference_id: PMID:18555783
      supporting_text: "BAP31 associates with the N terminus of one of its newly synthesized
        client proteins, the DeltaF508 mutant of CFTR, and promotes its retrotranslocation
        from the ER"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:18555783
  review:
    summary: >-
      ER localization from the ERAD study.
    action: ACCEPT
    reason: >-
      Core localization confirmed in landmark ERAD paper.
    supported_by:
    - reference_id: PMID:18555783
      supporting_text: BAP31 interacts with Sec61 translocons and promotes 
        retrotranslocation of CFTRDeltaF508 via the derlin-1 complex.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:19401338
  review:
    summary: >-
      ER localization from syntaxin 18 organization study.
    action: ACCEPT
    reason: >-
      Consistent ER localization evidence.
    supported_by:
    - reference_id: PMID:19401338
      supporting_text: Apr 28. Role of syntaxin 18 in the organization of 
        endoplasmic reticulum subdomains.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: >-
      High-throughput membrane proteomics of NK cells. Very general annotation.
    action: ACCEPT
    reason: >-
      Technically correct though uninformative. BCAP31 is a membrane protein.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: Defining the membrane proteome of NK cells.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-351894
  review:
    summary: >-
      This Reactome annotation is for "Caspase mediated cleavage of BAP31". The
      cytosolic annotation likely refers to the cytosolic domain of BCAP31 or the
      released p20 fragment after caspase cleavage.
    action: KEEP_AS_NON_CORE
    reason: >-
      The C-terminal cytosolic domain of BCAP31 faces the cytosol, and the p20
      cleavage product may be released to cytosol. This relates to apoptotic
      cleavage rather than core function.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-351894
  review:
    summary: >-
      Reactome annotation for caspase cleavage context - BCAP31 at ER membrane.
    action: ACCEPT
    reason: >-
      Core localization.
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:14741744
  review:
    summary: >-
      BCAP31 identified in lipid droplet-enriched fraction from hepatocytes. May
      reflect ER contact sites with lipid droplets.
    action: KEEP_AS_NON_CORE
    reason: >-
      BCAP31 may associate with lipid droplets via ER contact sites, but this is
      not a primary localization. The ER is the main site of function.
    supported_by:
    - reference_id: PMID:14741744
      supporting_text: Identification of major proteins in the lipid 
        droplet-enriched fraction isolated from the human hepatocyte cell line 
        HuH7.
- term:
    id: GO:2001244
    label: positive regulation of intrinsic apoptotic signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:21183955
  review:
    summary: >-
      This paper shows that the Fis1-Bap31 complex facilitates caspase-8 cleavage
      of BCAP31 to p20, which triggers ER calcium release and mitochondrial apoptotic
      signaling. However, BCAP31 is being CLEAVED (as a substrate) to generate p20.
      The p20 product induces apoptosis, but intact BCAP31 is not an active positive
      regulator - it is a substrate that when cleaved releases a pro-apoptotic fragment.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This annotation conflates being a caspase substrate with being a positive
      regulator
      of apoptosis. BCAP31 is cleaved BY caspase-8 at the Fis1-Bap31 platform; the
      resulting p20 fragment induces apoptotic signaling. The intact protein's role
      is in ER quality control and mitochondrial homeostasis, not promoting apoptosis.
      The paper shows "Fis1 conveys an apoptosis signal...by facilitating [BCAP31's]
      cleavage into the pro-apoptotic p20Bap31."
    supported_by:
    - reference_id: PMID:21183955
      supporting_text: "Here, we show that the mitochondrial fission protein Fission
        1 homologue (Fis1) conveys an apoptosis signal from the mitochondria to the
        ER by interacting with Bap31 at the ER and facilitating its cleavage into
        the pro-apoptotic p20Bap31"
    - reference_id: PMID:9334338
      supporting_text: "The resulting NH2-terminal p20 fragment induces apoptosis
        when expressed ectopically in otherwise normal cells"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:21183955
  review:
    summary: >-
      ER localization from the Fis1-Bap31 apoptosis study.
    action: ACCEPT
    reason: >-
      Core localization.
    supported_by:
    - reference_id: PMID:21183955
      supporting_text: Fis1 and Bap31 bridge the mitochondria-ER interface to 
        establish a platform for apoptosis induction.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:8706661
  review:
    summary: >-
      Early paper identifying BCAP31 as a transmembrane surface antigen. The protein
      was initially characterized as a cell surface protein but is now known to
      primarily localize to ER.
    action: UNDECIDED
    reason: >-
      While BCAP31 was initially identified as a surface antigen, it is now well-established
      as an ER-resident protein. Some surface expression may occur but ER is the
      primary functional site. The early characterization may have detected trafficking
      intermediates or overexpression artifacts.
    supported_by:
    - reference_id: PMID:8706661
      supporting_text: Molecular cloning and characterization of a transmembrane
        surface antigen in human cells.
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:18555783
      supporting_text: "BAP31 associates with the N terminus of one of its newly synthesized
        client proteins, the DeltaF508 mutant of CFTR, and promotes its retrotranslocation
        from the ER and degradation by the cytoplasmic 26S proteasome system"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping
  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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:9334338
  title: p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the 
    endoplasmic reticulum
  findings:
  - statement: BCAP31 identified as ER membrane protein that associates with 
      BCL2, BCL-XL, and procaspase-8
  - statement: Contains caspase cleavage sites flanking coiled-coil domain
  - statement: p20 cleavage fragment induces apoptosis when expressed
- id: PMID:18555783
  title: BAP31 interacts with Sec61 translocons and promotes retrotranslocation 
    of CFTRDeltaF508 via the derlin-1 complex
  findings:
  - statement: BCAP31 interacts with Sec61beta and TRAM at the translocon
  - statement: Promotes retrotranslocation and proteasomal degradation of 
      misfolded CFTR
  - statement: Associates with Derlin-1 complex for ERAD
- id: PMID:21183955
  title: Fis1 and Bap31 bridge the mitochondria-ER interface to establish a 
    platform for apoptosis induction
  findings:
  - statement: Fis1-Bap31 complex forms ER-mitochondria bridging platform
  - statement: Caspase-8 recruited to this platform and cleaves BCAP31 to p20
  - statement: p20 fragment triggers ER calcium release and mitochondrial 
      apoptosis
- id: PMID:31206022
  title: BAP31 regulates mitochondrial function via interaction with Tom40 
    within ER-mitochondria contact sites
  findings:
  - statement: BCAP31 forms complex with Tom40 at ER-mitochondria contact sites
  - statement: Stimulates translocation of NDUFS4 and NDUFB11 to mitochondria 
      for Complex I assembly
  - statement: Loss of BCAP31 impairs mitochondrial function and oxygen 
      consumption
  - statement: BCAP31-Tom40 complex acts as ER stress sensor
- id: PMID:14741744
  title: Identification of major proteins in the lipid droplet-enriched fraction
    isolated from the human hepatocyte cell line HuH7.
  findings: []
- id: PMID:15024066
  title: The yeast split-ubiquitin membrane protein two-hybrid screen identifies
    BAP31 as a regulator of the turnover of endoplasmic reticulum-associated 
    protein tyrosine phosphatase-like B.
  findings: []
- id: PMID:17500595
  title: Huntingtin interacting proteins are genetic modifiers of 
    neurodegeneration
  findings: []
- id: PMID:19401338
  title: Role of syntaxin 18 in the organization of endoplasmic reticulum 
    subdomains
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells
  findings: []
- id: PMID:24454821
  title: Transmembrane and coiled-coil domain family 1 is a novel protein of the
    endoplasmic reticulum.
  findings: []
- id: PMID:25854864
  title: Interaction between human BAP31 and respiratory syncytial virus small 
    hydrophobic (SH) protein
  findings: []
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass 
    Spectrometry
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
    Proteins
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the 
    human interactome
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization'
  findings: []
- id: PMID:36012204
  title: Differential CFTR-Interactome Proximity Labeling Procedures
  findings: []
- id: PMID:8706661
  title: Molecular cloning and characterization of a transmembrane surface 
    antigen in human cells
  findings: []
- id: Reactome:R-HSA-351894
  title: Caspase mediated cleavage of BAP31
  findings: []
- id: Reactome:R-HSA-8951499
  title: Loading of antigenic peptides on to class I MHC
  findings: []
- id: Reactome:R-HSA-983138
  title: Transport of MHC heterotrimer to ER exit site
  findings: []
- id: Reactome:R-HSA-983142
  title: Formation of peptide loading complex (PLC)
  findings: []
- id: Reactome:R-HSA-983161
  title: Dissociation of the Antigenic peptide:MHC:B2M peptide loading complex
  findings: []
- id: Reactome:R-HSA-9837136
  title: SH binds to BCAP31
  findings: []
- id: file:human/BCAP31/BCAP31-deep-research-falcon.md
  title: Deep research report on BCAP31
  findings: []
core_functions:
- molecular_function:
    id: GO:0140597
    label: protein carrier chaperone
  description: >-
    BCAP31 functions as a cargo receptor for selective ER-to-Golgi transport of
    membrane proteins including MHC class I molecules and tetraspanins.
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
  supported_by:
  - reference_id: PMID:18555783
    supporting_text: "BAP31 is an endoplasmic reticulum protein-sorting factor that
      associates with newly synthesized integral membrane proteins and controls their
      fate (i.e., egress, retention, survival, or degradation)"
- molecular_function:
    id: GO:0140597
    label: protein carrier chaperone
  description: >-
    BCAP31 promotes ERAD by interacting with the Sec61 translocon, TRAM, and Derlin-1
    complex to facilitate retrotranslocation and proteasomal degradation of misfolded
    ER membrane proteins like CFTR-deltaF508.
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:1904294
    label: positive regulation of ERAD pathway
  supported_by:
  - reference_id: PMID:18555783
    supporting_text: "BAP31 associates with the N terminus of one of its newly synthesized
      client proteins, the DeltaF508 mutant of CFTR, and promotes its retrotranslocation
      from the ER and degradation by the cytoplasmic 26S proteasome system"
- molecular_function:
    id: GO:0044877
    label: protein-containing complex binding
  description: >-
    BCAP31 forms a bridging complex with Tom40 at ER-mitochondria contact sites
    (MAMs) to facilitate import of mitochondrial Complex I components (NDUFS4, NDUFB11),
    maintaining mitochondrial respiratory function.
  locations:
  - id: GO:0044233
    label: mitochondria-associated endoplasmic reticulum membrane contact site
  directly_involved_in:
  - id: GO:0070585
    label: protein localization to mitochondrion
  supported_by:
  - reference_id: PMID:31206022
    supporting_text: "Within this complex, BAP31 interacts with mitochondria-localized
      proteins, including Tom40, to stimulate the translocation of NDUFS4, the component
      of complex I from the cytosol to the mitochondria"
proposed_new_terms: []
suggested_questions:
- question: >-
    What is the relative contribution of BCAP31's ERAD function vs. its ER-to-Golgi
    transport function in neural development, given that BCAP31 mutations cause
    DDCH syndrome with hypomyelination?
- question: >-
    Does the ER-mitochondria bridging function via Tom40 represent an evolutionarily
    conserved role or a specialized function in certain cell types?
suggested_experiments:
- description: >-
    Structure-function analysis separating the ERAD and ER-to-Golgi transport
    functions to determine which is critical for DDCH syndrome pathogenesis.
- description: >-
    Proximity labeling to comprehensively identify BCAP31 cargo proteins beyond
    MHC class I and CFTR.