BCAP31 (also known as BAP31) is an abundant ER-resident integral membrane protein that functions as a translocon-associated protein translocation chaperone 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) quality control of newly synthesized membrane proteins (controlling their egress, retention, and degradation), (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).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | 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. 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." Supporting Evidence: PMID:9334338 We have identified a human Bcl-2-interacting protein, p28 Bap31. It is a 28-kD (p28) polytopic integral protein of the endoplasmic reticulum PMID:18555783 BAP31 is an endoplasmic reticulum protein-sorting factor that associates with newly synthesized integral membrane proteins file:human/BCAP31/BCAP31-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Per geneontology/go-annotation#6385, GO curators flag this IBA as an over-propagation from PANTHER node PTN000294723. BCAP31 acts upstream of the ER exit site as a translocon-associated quality-control chaperone, not as a dedicated cargo receptor that mediates ER-to-Golgi vesicular transport. Its effect on ER export of select membrane proteins (e.g. MHC class I) is an indirect downstream consequence of its chaperone/QC role: it engages clients at the earliest folding steps, knockdown only delays rather than abolishes export, and its C-terminal KKXX motif is a COPI retrieval signal rather than an anterograde export signal. Reason: Over-annotation flagged by GO curators in geneontology/go-annotation#6385. BCAP31's well-supported molecular role is protein translocation chaperone activity (GO:0140388) associated with the Sec61 translocon; ER-to-Golgi vesicle-mediated transport is at most an indirect downstream effect, so the IBA involved_in over-states a direct mechanistic role. Curator M. Feuermann is re-annotating the PANTHER family with corrected terms. Supporting Evidence: PMID:18555783 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) |
| GO:0070973 protein localization to endoplasmic reticulum exit site | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Per geneontology/go-annotation#6385, this IBA is an over-propagation from PANTHER node PTN000294723 (it is asserted on the S. pombe ortholog SPAC9E9.04 and propagated across the family). BCAP31 acts as a translocon-associated chaperone upstream of the ER exit site; actively localizing proteins to ER exit sites is not a directly supported function. Reason: Over-propagated IBA flagged in geneontology/go-annotation#6385. BCAP31's core role is ER quality control / protein translocation chaperone activity at the Sec61 translocon, not delivery of cargo to ER exit sites. Supporting Evidence: PMID:18555783 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) |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000002 | ACCEPT | 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. Reason: Correct general localization. The more specific ER membrane term is also present. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation for ER membrane localization. Duplicates the IBA annotation but with different evidence - this is acceptable as IEA provides independent computational support. Reason: Correct localization supported by multiple evidence types. |
| GO:0006886 intracellular protein transport | IEA GO_REF:0000002 | ACCEPT | 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. Reason: Correct general process. BCAP31 is a protein translocation chaperone for membrane proteins. |
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:9334338 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. PMID:21183955 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 |
| GO:0015031 protein transport | IEA GO_REF:0000043 | ACCEPT | Summary: Keyword-based annotation for protein transport. Correct but general - BCAP31 specifically functions in ER-to-Golgi transport and ERAD. Reason: Correct general process annotation consistent with core protein translocation chaperone function. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Very general CC term. BCAP31 is a multi-pass membrane protein, so this is technically correct but uninformative given more specific annotations. Reason: Technically correct though very general. More specific ER membrane annotation is also present. |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: Broad vesicle-mediated transport term. BCAP31's core function is translocon-associated retrotranslocation via Sec61/Derlin-1, which is a channel-mediated protein translocation process, not vesicle-mediated transport. This annotation shares the same over-annotation basis as its child GO:0006888 (ER-to-Golgi vesicle-mediated transport). Reason: Accepting the parent while marking child GO:0006888 MARK_AS_OVER_ANNOTATED for the same reason would be logically inconsistent. Retrotranslocation via Sec61/Derlin-1 is a channel-mediated process distinct from vesicle-mediated transport. The IEA provenance (GO_REF:0000043, UniProtKB keyword mapping) does not override the biological reasoning established in the GO:0006888 review. |
| GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane | IEA GO_REF:0000044 | ACCEPT | Summary: BCAP31 cycles between ER and ERGIC/cis-Golgi. UniProt states it "May shuttle between the ER and the intermediate compartment/cis-Golgi complex." Reason: Consistent with the itinerant nature of BCAP31 cycling between ER and ERGIC. |
| GO:0005515 protein binding | IPI PMID:15024066 The yeast split-ubiquitin membrane protein two-hybrid screen... | REMOVE | 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. 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. Supporting Evidence: PMID:15024066 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. |
| GO:0005515 protein binding | IPI PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neu... | REMOVE | Summary: High-throughput screen showing BCAP31 as a huntingtin interactor. Generic protein binding annotation from large-scale study. Reason: Generic "protein binding" from HTP study is not informative about molecular function. Supporting Evidence: PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neurodegeneration. |
| GO:0005515 protein binding | IPI PMID:18555783 BAP31 interacts with Sec61 translocons and promotes retrotra... | REMOVE | 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. Reason: Generic term. The specific interactions with Sec61, TRAM, and Derlin-1 support the ERAD function annotations which are more informative. Supporting Evidence: PMID:18555783 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 |
| GO:0005515 protein binding | IPI PMID:21183955 Fis1 and Bap31 bridge the mitochondria-ER interface to estab... | REMOVE | Summary: Interaction with Fis1 and caspase-8 at the ER-mitochondria interface. While real interactions, "protein binding" is uninformative. Reason: Generic term does not capture the biological context of ER-mitochondria contacts. Supporting Evidence: PMID:21183955 Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. |
| GO:0005515 protein binding | IPI PMID:25854864 Interaction between human BAP31 and respiratory syncytial vi... | REMOVE | Summary: Interaction with RSV SH protein. Host-virus interaction. Reason: Generic protein binding. The interaction with viral protein is tangential to core function. Supporting Evidence: PMID:25854864 Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein. |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | REMOVE | Summary: Large-scale crosslinking mass spectrometry study. Reason: Generic term from HTP study is not informative. Supporting Evidence: PMID:30021884 Epub 2018 Jul 18. Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome | REMOVE | Summary: Binary interactome mapping study. Reason: Generic term from HTP study is not informative. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Interactome mapping in neurodegenerative disease context. Reason: Generic term from HTP study is not informative. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Dual proteome-scale network study. Reason: Generic term from HTP study is not informative. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: OpenCell endogenous tagging study. Reason: Generic term from HTP study is not informative. Supporting Evidence: PMID:35271311 2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization. |
| GO:0005515 protein binding | IPI PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures ... | REMOVE | Summary: CFTR interactome study using proximity labeling. Reason: Generic term from HTP study. CFTR interaction is covered by ERAD annotations. Supporting Evidence: PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters. |
| GO:0005515 protein binding | IPI PMID:9334338 p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated prote... | REMOVE | Summary: Landmark paper identifying BCAP31 interactions with Bcl-2, Bcl-XL, and procaspase-8. Important interactions but "protein binding" is uninformative. 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. Supporting Evidence: PMID:9334338 In cotransfected 293T cells, p28 is part of a complex that includes Bcl-2/Bcl-XL and procaspase-8 (pro-FLICE) |
| GO:0000139 Golgi membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse. BCAP31 cycles through ERGIC and may reach cis-Golgi. Acceptable localization. Reason: Consistent with BCAP31's itinerant behavior cycling between ER and Golgi compartments. |
| GO:0007283 spermatogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. 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. |
| GO:0030136 clathrin-coated vesicle | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl transfer from rat. No affirmative evidence for clathrin-coated vesicle localization of BCAP31 in human or rat literature. BCAP31 cycles between the ER and cis-Golgi via COPI/COPII machinery, which is mechanistically distinct from the clathrin pathway (post-Golgi/endocytic). Reason: The IEA Ensembl transfer from rat has no human-specific support, and there is no affirmative literature evidence — including in the deep research and gene notes for BCAP31 — for association with clathrin-coated vesicles. BCAP31's trafficking is COPI/COPII-mediated between the ER and cis-Golgi, mechanistically distinct from the clathrin pathway, so the annotation is unlikely to be correct rather than merely over-annotated. |
| GO:0032580 Golgi cisterna membrane | IEA GO_REF:0000107 | ACCEPT | Summary: More specific Golgi localization transferred from rat. Reason: Consistent with BCAP31 cycling through ER-Golgi trafficking pathway. |
| GO:0042288 MHC class I protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: BCAP31 is known to promote ER export and quality control of MHC class I molecules. This is a specific and informative MF annotation. 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. |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | ACCEPT | Summary: General MF term. BCAP31 does form large complexes but this is not very informative. Reason: Technically correct - BCAP31 is part of large protein complexes at the ER membrane. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence-based annotation for ER localization. Reason: Experimental confirmation of ER localization. |
| GO:0098553 lumenal side of endoplasmic reticulum membrane | TAS Reactome:R-HSA-8951499 | ACCEPT | 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. Reason: Part of BCAP31's topology includes lumenal-facing domains involved in cargo recognition for MHC class I trafficking. |
| GO:0098553 lumenal side of endoplasmic reticulum membrane | TAS Reactome:R-HSA-983138 | ACCEPT | Summary: Reactome annotation for MHC transport. Duplicate evidence for same localization. Reason: Consistent with MHC class I trafficking role. |
| GO:0098553 lumenal side of endoplasmic reticulum membrane | TAS Reactome:R-HSA-983142 | ACCEPT | Summary: Peptide loading complex formation in Reactome. Reason: Consistent with BCAP31's role in MHC class I quality control. |
| GO:0098553 lumenal side of endoplasmic reticulum membrane | TAS Reactome:R-HSA-983161 | ACCEPT | Summary: Dissociation of peptide loading complex annotation. Reason: Consistent with MHC class I trafficking role. |
| GO:1904294 positive regulation of ERAD pathway | IGI PMID:18555783 BAP31 interacts with Sec61 translocons and promotes retrotra... | ACCEPT | 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. Reason: Core function. BCAP31 "promotes retrotranslocation of CFTRDeltaF508 via the derlin-1 complex" (PMID:18555783). This is one of the primary molecular functions. Supporting Evidence: PMID:18555783 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 |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | IDA PMID:18555783 BAP31 interacts with Sec61 translocons and promotes retrotra... | ACCEPT | Summary: BCAP31 promotes degradation of misfolded ER proteins via the proteasome. This is part of its ERAD function. Reason: Core function. BCAP31 promotes proteasomal degradation of ERAD substrates. Supporting Evidence: PMID:18555783 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 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9837136 | ACCEPT | Summary: Reactome annotation for RSV SH binding to BCAP31 at ER membrane. Reason: Confirms ER membrane localization through additional pathway curation. |
| GO:0005515 protein binding | IPI PMID:31206022 BAP31 regulates mitochondrial function via interaction with ... | REMOVE | 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. Reason: Generic term. The important Tom40 interaction is better captured by the MAM and mitochondria-related process annotations. Supporting Evidence: PMID:31206022 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 |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:31206022 BAP31 regulates mitochondrial function via interaction with ... | ACCEPT | Summary: BCAP31 responds to ER stress by delocalizing from ER-mitochondria contact sites and binding BCL2. This is an important regulatory function. 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). Supporting Evidence: PMID:31206022 the BAP31-Tom40 ER-mitochondria bridging complex...plays a role as a previously unidentified stress sensor |
| GO:0044233 mitochondria-associated endoplasmic reticulum membrane contact site | IDA PMID:31206022 BAP31 regulates mitochondrial function via interaction with ... | ACCEPT | Summary: BCAP31 localizes to MAM/MERCs through interaction with mitochondrial Tom40. This is important for its role in mitochondrial homeostasis. Reason: Core localization for mitochondrial function. "Associates with the mitochondria-associated endoplasmic reticulum membrane via interaction with TOMM40" (UniProt). Supporting Evidence: PMID:31206022 the ER membrane protein, BAP31, acts as a key factor in mitochondrial homeostasis...by forming an ER-mitochondria bridging protein complex |
| GO:0070585 protein localization to mitochondrion | IGI PMID:31206022 BAP31 regulates mitochondrial function via interaction with ... | ACCEPT | Summary: BCAP31 facilitates import of NDUFS4 and other Complex I components into mitochondria via interaction with Tom40. Reason: Important function at ER-mitochondria interface. BCAP31 "stimulate[s] the translocation of NDUFS4...from the cytosol to the mitochondria." Supporting Evidence: PMID:31206022 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 |
| GO:0005783 endoplasmic reticulum | IDA PMID:24454821 Transmembrane and coiled-coil domain family 1 is a novel pro... | ACCEPT | Summary: Experimental demonstration of ER localization. Reason: Confirms core ER localization. Supporting Evidence: PMID:24454821 eCollection 2014. Transmembrane and coiled-coil domain family 1 is a novel protein of the endoplasmic reticulum. |
| GO:0097038 perinuclear endoplasmic reticulum | IDA PMID:25854864 Interaction between human BAP31 and respiratory syncytial vi... | ACCEPT | Summary: BCAP31 localizes to perinuclear ER in addition to peripheral ER. Consistent with its cycling between compartments. Reason: BCAP31 cycles between peripheral ER and juxtanuclear ERQC compartment. This annotation captures part of that distribution. Supporting Evidence: PMID:25854864 Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein. |
| GO:1904154 positive regulation of retrograde protein transport, ER to cytosol | IDA PMID:18555783 BAP31 interacts with Sec61 translocons and promotes retrotra... | ACCEPT | Summary: BCAP31 promotes retrotranslocation of misfolded proteins from ER to cytosol for proteasomal degradation. Core ERAD function. Reason: Core function. BCAP31 "promotes retrotranslocation of CFTRDeltaF508" (PMID:18555783). Supporting Evidence: PMID:18555783 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 |
| GO:0005783 endoplasmic reticulum | IDA PMID:18555783 BAP31 interacts with Sec61 translocons and promotes retrotra... | ACCEPT | Summary: ER localization from the ERAD study. Reason: Core localization confirmed in landmark ERAD paper. Supporting Evidence: PMID:18555783 BAP31 interacts with Sec61 translocons and promotes retrotranslocation of CFTRDeltaF508 via the derlin-1 complex. |
| GO:0005783 endoplasmic reticulum | IDA PMID:19401338 Role of syntaxin 18 in the organization of endoplasmic retic... | ACCEPT | Summary: ER localization from syntaxin 18 organization study. Reason: Consistent ER localization evidence. Supporting Evidence: PMID:19401338 Apr 28. Role of syntaxin 18 in the organization of endoplasmic reticulum subdomains. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells | ACCEPT | Summary: High-throughput membrane proteomics of NK cells. Very general annotation. Reason: Technically correct though uninformative. BCAP31 is a membrane protein. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-351894 | KEEP AS NON CORE | 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. 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. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-351894 | ACCEPT | Summary: Reactome annotation for caspase cleavage context - BCAP31 at ER membrane. Reason: Core localization. |
| GO:0005811 lipid droplet | IDA PMID:14741744 Identification of major proteins in the lipid droplet-enrich... | KEEP AS NON CORE | Summary: BCAP31 identified in lipid droplet-enriched fraction from hepatocytes. May reflect ER contact sites with lipid droplets. 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. Supporting Evidence: PMID:14741744 Identification of major proteins in the lipid droplet-enriched fraction isolated from the human hepatocyte cell line HuH7. |
| GO:2001244 positive regulation of intrinsic apoptotic signaling pathway | IMP PMID:21183955 Fis1 and Bap31 bridge the mitochondria-ER interface to estab... | MARK AS OVER ANNOTATED | 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. 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." Supporting Evidence: PMID:21183955 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 PMID:9334338 The resulting NH2-terminal p20 fragment induces apoptosis when expressed ectopically in otherwise normal cells |
| GO:0005783 endoplasmic reticulum | IDA PMID:21183955 Fis1 and Bap31 bridge the mitochondria-ER interface to estab... | ACCEPT | Summary: ER localization from the Fis1-Bap31 apoptosis study. Reason: Core localization. Supporting Evidence: PMID:21183955 Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. |
| GO:0005886 plasma membrane | IDA PMID:8706661 Molecular cloning and characterization of a transmembrane su... | MARK AS OVER ANNOTATED | Summary: Early paper identifying BCAP31 as a transmembrane surface antigen detected with mAb 6C6 on human breast cancer cells. The protein was initially characterized as a cell surface protein but subsequent work has firmly established BCAP31 as an ER-resident integral membrane protein with a KKXX ER-retrieval motif. The notes for this gene explicitly flag this divergence: "the original surface-antigen study supports antibody-accessible surface expression... but later work establishes ER/ERGIC residency as the primary biology." Reason: Term is not entirely wrong - the original mAb 6C6 study (PMID:8706661) does detect surface expression - but it represents an over-annotation: BCAP31's core localization is the ER membrane, and any plasma membrane signal likely reflects trafficking intermediates, overexpression artifacts, or transient surface exposure of cargo-bound complexes rather than a steady-state plasma membrane pool. The KKXX ER-retrieval motif and downstream literature strongly support ER residency as the functional localization. Supporting Evidence: PMID:9334338 It is a 28-kD (p28) polytopic integral protein of the endoplasmic reticulum whose COOH-terminal cytosolic region contains overlapping predicted leucine zipper and weak death effector homology domains PMID:8706661 transfection into cell lines that do not react with the 6C6 mAb, which resulted in the expression of a 28-kDa surface protein that was recognized by the antibody. |
| GO:0140597 protein carrier chaperone | NAS | NEW | Summary: Broader carrier chaperone term. GO:0140388 (protein translocation chaperone activity) is the curator-recommended primary MF for BCAP31 per geneontology/go-annotation#6385; GO:0140597 is retained as a secondary annotation capturing the general client-escorting and fate-decision role (egress, retention, or degradation) that encompasses but is not limited to the translocation-specific GO:0140388 activity. Reason: GO:0140597 (protein carrier chaperone) is the parent term of GO:0140388 and captures the broader aspect of BCAP31 function: associating with newly synthesized integral membrane proteins and directing their fate across all outcomes (folding, retention, ERAD, or export). Retained as secondary alongside the more specific curator-recommended GO:0140388. Supporting Evidence: PMID:18555783 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) |
| GO:0036503 ERAD pathway | IGI PMID:18555783 BAP31 interacts with Sec61 translocons and promotes retrotra... | NEW | Summary: NEW annotation capturing BCAP31's direct participation in ER-associated degradation. The Sec61/Derlin-1 study showed BCAP31 binds a misfolded ERAD substrate (CFTRDeltaF508) and promotes its retrotranslocation and proteasomal degradation. Reason: The PN suggestion to add ERAD pathway stands up biologically. BCAP31 is not just an upstream ER-stress factor; it directly facilitates substrate retrotranslocation within the ERAD machinery. This direct pathway term is more appropriate than representing the function only with positive-regulation child terms. Supporting Evidence: PMID:18555783 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 |
| GO:0140388 protein translocation chaperone activity | IDA PMID:18555783 BAP31 interacts with Sec61 translocons and promotes retrotra... | NEW | Summary: NEW annotation capturing BCAP31's core molecular function. Per geneontology/go-annotation#6385, GO curator M. Feuermann identifies protein translocation chaperone activity as the correct molecular function for this PANTHER family (PTN000294723). BCAP31 associates with the Sec61 translocon and with newly synthesized integral membrane proteins, chaperoning them through folding/retention and, for misfolded clients, retrotranslocation for degradation. Reason: Replaces the over-stated cargo-receptor / ER-to-Golgi-transport framing (see GO:0006888, marked over-annotated). GO:0140388 is the molecular function recommended by GO curators in geneontology/go-annotation#6385 and is supported by the Sec61/Derlin-1 translocon-association data in PMID:18555783. Supporting Evidence: PMID:18555783 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) |
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Download this section (compressed HTML)Q: 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?
Q: Does the ER-mitochondria bridging function via Tom40 represent an evolutionarily conserved role or a specialized function in certain cell types?
Experiment: Structure-function analysis separating the ERAD and ER-to-Golgi transport functions to determine which is critical for DDCH syndrome pathogenesis.
Experiment: Proximity labeling to comprehensively identify BCAP31 cargo proteins beyond MHC class I and CFTR.
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