id: O95816
gene_symbol: BAG2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'BAG2 (BAG family molecular chaperone regulator 2) is a cytosolic co-chaperone
  of the HSP70/HSC70 molecular chaperone system. Through its C-terminal BAG domain it
  binds the ATPase (nucleotide-binding) domain of HSP70/HSC70 and acts as a nucleotide-exchange
  factor (NEF), promoting ADP release and consequent release of bound client/substrate
  proteins, thereby regulating the HSP70 chaperone cycle. BAG2 is a major component of
  complexes containing the chaperone-associated E3 ubiquitin ligase CHIP (STUB1) and
  inhibits CHIP ligase activity by disrupting cooperation between CHIP and its E2 enzyme,
  so that BAG2 reduces ubiquitination of chaperone clients and shifts protein triage
  away from degradation toward folding/maturation and stabilization. In neurons, the
  BAG2/HSP70 complex is tethered to microtubules and captures misfolded, phosphorylated,
  detergent-insoluble tau, delivering it for ubiquitin-independent proteasomal degradation.
  BAG2 also binds and stabilizes specific clients (e.g., CFTR, PINK1, polyglutamine-expanded
  ataxin-3) by lowering their ubiquitination. Unlike BAG1, BAG2 lacks a ubiquitin-like
  domain. Its core roles are HSP70 nucleotide exchange, chaperone-assisted protein
  quality control, and negative regulation of CHIP-dependent client ubiquitination.'
alternative_products:
- name: '1'
  id: O95816-1
- name: '2'
  id: O95816-2
  sequence_note: VSP_056462
existing_annotations:
- term:
    id: GO:0000774
    label: adenyl-nucleotide exchange factor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: BAG2 is a nucleotide-exchange factor (NEF) for HSP70/HSC70, promoting ADP
      release via its BAG domain. This is the core molecular function and is well supported
      experimentally.
    action: ACCEPT
    reason: NEF activity toward HSP70/HSC70 is the defining, experimentally validated
      molecular function of BAG2 and is consistent with the phylogenetic inference.
    supported_by:
    - reference_id: file:human/BAG2/BAG2-uniprot.txt
      supporting_text: a nucleotide-exchange factor (NEF) promoting the release of ADP from
      reference_section_type: DATABASE_ENTRY
    - reference_id: PMID:24318877
      supporting_text: Proteins with Bcl2-associated anthanogene (BAG) domains act as nucleotide
        exchange factors (NEFs) for the molecular chaperone heat shock protein 70 (Hsp70).
      reference_section_type: ABSTRACT
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: BAG2 stabilizes specific chaperone clients (CFTR, PINK1, ataxin-3) by
      reducing their ubiquitination, so protein stabilization is a supported core process.
    action: ACCEPT
    reason: BAG2 lowers ubiquitination of clients such as PINK1 and pathogenic ataxin-3,
      stabilizing them, and stabilizes immature CFTR conformations. This is a well-supported
      outcome of BAG2 co-chaperone/CHIP-inhibitory activity.
    supported_by:
    - reference_id: PMID:24383081
      supporting_text: which directly binds with and stabilises PINK1 by decreasing its
        ubiquitination
      reference_section_type: ABSTRACT
    - reference_id: PMID:25006867
      supporting_text: stabilise pathogenic ataxin3-80Q by inhibiting its ubiquitination
      reference_section_type: ABSTRACT
- term:
    id: GO:0000774
    label: adenyl-nucleotide exchange factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: NEF activity for HSP70/HSC70 is the defining molecular function of BAG2,
      well supported experimentally and consistent with the InterPro/BAG-domain inference.
    action: ACCEPT
    reason: The BAG domain confers nucleotide-exchange activity on HSP70/HSC70; this IEA
      annotation agrees with direct biochemical evidence.
    supported_by:
    - reference_id: file:human/BAG2/BAG2-uniprot.txt
      supporting_text: a nucleotide-exchange factor (NEF) promoting the release of ADP from
      reference_section_type: DATABASE_ENTRY
    - reference_id: PMID:24318877
      supporting_text: Proteins with Bcl2-associated anthanogene (BAG) domains act as nucleotide
        exchange factors (NEFs) for the molecular chaperone heat shock protein 70 (Hsp70).
      reference_section_type: ABSTRACT
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: As an HSP70/HSC70 co-chaperone that regulates the chaperone cycle and can
      display intrinsic client-stabilizing activity, BAG2 participates in protein folding/refolding.
    action: ACCEPT
    reason: BAG2 modulates HSP70/HSC70 chaperone activity and contributes to chaperone-assisted
      folding/maturation of clients (e.g., CFTR), supporting the protein folding process.
    supported_by:
    - reference_id: PMID:16207813
      supporting_text: stimulates the chaperone-assisted maturation of CFTR
      reference_section_type: ABSTRACT
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: BAG2 binds the ATPase domain of HSP70/HSC70 chaperones; chaperone binding is
      a core molecular feature underlying its co-chaperone/NEF role.
    action: ACCEPT
    reason: Direct binding of BAG2 to the HSP/HSC70 ATPase domain is well established and
      is the basis of its NEF activity.
    supported_by:
    - reference_id: file:human/BAG2/BAG2-uniprot.txt
      supporting_text: Binds to the ATPase domain of HSP/HSC70 chaperones
      reference_section_type: DATABASE_ENTRY
    - reference_id: PMID:9873016
      supporting_text: bind with high affinity (KD congruent with 1-10
      reference_section_type: ABSTRACT
- term:
    id: GO:0051247
    label: positive regulation of protein metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: This is an over-broad parent process term. BAG2's effects on protein metabolism
      are better captured by specific terms (protein stabilization, protein folding,
      negative regulation of ubiquitination).
    action: MARK_AS_OVER_ANNOTATED
    reason: positive regulation of protein metabolic process is too general to convey BAG2
      function and duplicates more specific accepted terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18457437
  qualifier: enables
  review:
    summary: Generic high-throughput interactome/affinity-purification protein-binding
      annotation (EBNA5 TAP-MS); uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a proteomic screen does not identify a physiologically
      interpretable BAG2 molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22365833
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a spliceosome interaction-mapping
      study; uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22810586
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a tumour-virus host network
      perturbation screen; uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24510904
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from an LRRK2 interactor screen;
      uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24981860
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a chromatin protein-interaction
      study; uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: From a quantitative chaperone interaction network; the relevant BAG2 biology
      (HSP70 co-chaperone binding) is captured by specific chaperone-binding terms, so
      bare protein binding is uninformative here.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is too general; chaperone-network membership is better
      represented by protein-folding chaperone binding/complex terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25852190
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a TRAIL apoptosis kinase-network
      study; uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25959826
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a neurodegenerative-disease
      interaction proteomics study; uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a quantitative interactome study;
      uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29513927
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a ROCO-protein interaction-network
      study; uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29568061
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a MAC-tag AP-MS/BioID mapping study;
      uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a histone crosslinking-MS study;
      uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from an EGFR-network rewiring study;
      uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from the binary interactome reference map;
      uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a neurodegenerative-disease interactome
      study; uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a dual proteome-scale network study;
      uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35167623
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a DNAJB1-PRKACA signaling study;
      uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35266954
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a TRIM1/LRRK2 study; uninformative
      for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from the OpenCell endogenous-tagging
      study; uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37045861
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a RAF1-BRAF interactome study;
      uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a multimodal cell-map study;
      uninformative for BAG2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome is not informative.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22365833
  qualifier: enables
  review:
    summary: BAG2 self-association (homodimer) is a real biochemical property, but this
      particular annotation derives from a high-throughput spliceosome interaction map.
    action: KEEP_AS_NON_CORE
    reason: BAG2 forms homodimers, so identical protein binding is plausible, but the
      supporting study is a generic interactome screen; retain as non-core.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: BAG2 homodimerization is consistent with biochemistry; annotation from a
      chaperone interaction-network screen.
    action: KEEP_AS_NON_CORE
    reason: Self-association is a genuine BAG2 property; retain as non-core given the
      high-throughput source.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: BAG2 homodimerization is consistent with biochemistry; annotation from the
      proteome-scale interactome map.
    action: KEEP_AS_NON_CORE
    reason: Self-association is a genuine BAG2 property; retain as non-core given the
      high-throughput source.
- term:
    id: GO:0005874
    label: microtubule
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: colocalizes_with
  review:
    summary: The BAG2/HSP70 complex is tethered to the microtubule in neurons; microtubule
      colocalization is supported but is a context-specific (neuronal) localization.
    action: KEEP_AS_NON_CORE
    reason: Microtubule tethering is demonstrated for the tau-triage function but is a
      neuronal-context localization rather than the universal BAG2 site of action.
    supported_by:
    - reference_id: PMID:19228967
      supporting_text: The BAG2/Hsp70 complex is tethered to the microtubule
      reference_section_type: ABSTRACT
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Neuronal compartment localization inferred from the tau-triage microtubule
      work; context-specific.
    action: KEEP_AS_NON_CORE
    reason: Axonal localization is a neuronal-context inference, not a core universal
      localization of BAG2.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Neuronal compartment localization inferred from the tau-triage microtubule
      work; context-specific.
    action: KEEP_AS_NON_CORE
    reason: Dendritic localization is a neuronal-context inference, not a core universal
      localization of BAG2.
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: BAG2 binds the HSP70/HSC70 chaperone ATPase domain; heat shock protein binding
      is a core molecular feature.
    action: ACCEPT
    reason: Direct binding of BAG2 to HSP/HSC70 is well established and underlies its
      co-chaperone/NEF activity.
    supported_by:
    - reference_id: file:human/BAG2/BAG2-uniprot.txt
      supporting_text: Binds to the ATPase domain of HSP/HSC70 chaperones
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0031397
    label: negative regulation of protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: BAG2 inhibits CHIP-mediated ubiquitination of chaperone clients; negative
      regulation of protein ubiquitination is a core process.
    action: ACCEPT
    reason: BAG2 abrogates CHIP/E2 cooperation and decreases ubiquitination of clients
      such as CFTR, PINK1, and ataxin-3.
    supported_by:
    - reference_id: PMID:16207813
      supporting_text: BAG-2 inhibits the ubiquitin ligase activity of CHIP by abrogating
        the CHIP/E2 cooperation
      reference_section_type: ABSTRACT
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: BAG2 binds and inhibits the E3 ubiquitin ligase CHIP (STUB1); ubiquitin protein
      ligase binding is supported and mechanistically central.
    action: ACCEPT
    reason: BAG2 is a main component of CHIP complexes and binds CHIP to inhibit its ligase
      activity.
    supported_by:
    - reference_id: PMID:16207813
      supporting_text: We identified the Hsc70 cochaperone
      reference_section_type: ABSTRACT
- term:
    id: GO:0048156
    label: tau protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: BAG2 (via the BAG2/HSP70 complex) captures misfolded/insoluble tau; tau binding
      is supported in the neuronal protein-triage context.
    action: KEEP_AS_NON_CORE
    reason: Tau binding/capture is well documented but is a client-specific, neuronal-context
      activity rather than the universal BAG2 molecular function.
    supported_by:
    - reference_id: PMID:19228967
      supporting_text: this complex can capture and deliver Tau to the
      reference_section_type: ABSTRACT
- term:
    id: GO:1901588
    label: dendritic microtubule
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: colocalizes_with
  review:
    summary: Neuronal dendritic-microtubule colocalization inferred from the tau-triage
      microtubule work; context-specific.
    action: KEEP_AS_NON_CORE
    reason: Highly specific neuronal localization inference; retain as non-core.
- term:
    id: GO:1901800
    label: positive regulation of proteasomal protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: In neurons BAG2/HSP70 delivers tau to the proteasome for ubiquitin-independent
      degradation, promoting proteasomal catabolism of this client.
    action: KEEP_AS_NON_CORE
    reason: Supported by the tau-triage mechanism (ubiquitin-independent proteasomal
      degradation), but it is a client/context-specific role rather than a general one.
    supported_by:
    - reference_id: PMID:19228967
      supporting_text: deliver Tau to the
      reference_section_type: ABSTRACT
- term:
    id: GO:0048156
    label: tau protein binding
  evidence_type: NAS
  original_reference_id: PMID:28386764
  qualifier: enables
  review:
    summary: Review-based assertion of BAG2-tau binding; consistent with the primary
      tau-triage data but context-specific (neuronal).
    action: KEEP_AS_NON_CORE
    reason: Tau binding is real but client/context-specific; retain as non-core.
- term:
    id: GO:0005874
    label: microtubule
  evidence_type: ISS
  original_reference_id: PMID:19228967
  qualifier: colocalizes_with
  review:
    summary: BAG2 associates with microtubules (even without tau) in the neuronal tau-triage
      work; supported but context-specific.
    action: KEEP_AS_NON_CORE
    reason: Microtubule association is demonstrated but is a neuronal-context localization.
    supported_by:
    - reference_id: PMID:19228967
      supporting_text: The BAG2/Hsp70 complex is tethered to the microtubule
      reference_section_type: ABSTRACT
- term:
    id: GO:0030424
    label: axon
  evidence_type: ISS
  original_reference_id: PMID:19228967
  qualifier: located_in
  review:
    summary: Neuronal axonal localization inferred from the tau-triage study; context-specific.
    action: KEEP_AS_NON_CORE
    reason: Axonal localization is a neuronal-context inference, not a core localization.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: ISS
  original_reference_id: PMID:19228967
  qualifier: located_in
  review:
    summary: Neuronal dendritic localization inferred from the tau-triage study;
      context-specific.
    action: KEEP_AS_NON_CORE
    reason: Dendritic localization is a neuronal-context inference, not a core localization.
- term:
    id: GO:0031397
    label: negative regulation of protein ubiquitination
  evidence_type: ISS
  original_reference_id: PMID:19228967
  qualifier: involved_in
  review:
    summary: By inhibiting CHIP, BAG2 directs the HSP70-tau complex away from ubiquitination;
      negative regulation of protein ubiquitination is core.
    action: ACCEPT
    reason: Consistent with BAG2's established CHIP-inhibitory, anti-ubiquitination role.
    supported_by:
    - reference_id: PMID:19228967
      supporting_text: BAG2 directs the Hsp70-Tau complex away from ubiquitination
      reference_section_type: DISCUSSION
- term:
    id: GO:0031397
    label: negative regulation of protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:24383081
  qualifier: involved_in
  review:
    summary: BAG2 stabilizes PINK1 by decreasing its ubiquitination; direct support for
      negative regulation of protein ubiquitination.
    action: ACCEPT
    reason: Direct experimental demonstration that BAG2 reduces client ubiquitination.
    supported_by:
    - reference_id: PMID:24383081
      supporting_text: stabilises PINK1 by decreasing its ubiquitination
      reference_section_type: ABSTRACT
- term:
    id: GO:0031397
    label: negative regulation of protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:25006867
  qualifier: involved_in
  review:
    summary: BAG2 inhibits ubiquitination of pathogenic ataxin-3; direct support for
      negative regulation of protein ubiquitination.
    action: ACCEPT
    reason: Direct experimental demonstration that BAG2 reduces client ubiquitination.
    supported_by:
    - reference_id: PMID:25006867
      supporting_text: stabilise pathogenic ataxin3-80Q by inhibiting its ubiquitination
      reference_section_type: ABSTRACT
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic
      process
  evidence_type: ISS
  original_reference_id: PMID:19228967
  qualifier: involved_in
  negated: true
  review:
    summary: The NOT annotation is well justified - BAG2 routes tau to a ubiquitin-INDEPENDENT
      proteasomal pathway while inhibiting CHIP, so it does not promote ubiquitin-dependent
      proteasomal catabolism.
    action: ACCEPT
    reason: BAG2 mediates ubiquitin-independent proteasomal degradation of tau and inhibits
      the ubiquitin-dependent CHIP route, supporting the negation.
    supported_by:
    - reference_id: PMID:19228967
      supporting_text: BAG2 mediates ubiquitin independent degradation of Tau through the
        proteasome
      reference_section_type: ABSTRACT
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:24383081
  qualifier: involved_in
  review:
    summary: BAG2 directly stabilizes PINK1 by decreasing its ubiquitination; core process.
    action: ACCEPT
    reason: Direct experimental demonstration of BAG2-mediated client stabilization.
    supported_by:
    - reference_id: PMID:24383081
      supporting_text: directly binds with and stabilises PINK1 by decreasing its
        ubiquitination
      reference_section_type: ABSTRACT
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:25006867
  qualifier: involved_in
  review:
    summary: BAG2 stabilizes pathogenic ataxin-3 by inhibiting its ubiquitination; core
      process.
    action: ACCEPT
    reason: Direct experimental demonstration of BAG2-mediated client stabilization.
    supported_by:
    - reference_id: PMID:25006867
      supporting_text: stabilise pathogenic ataxin3-80Q by inhibiting its ubiquitination
      reference_section_type: ABSTRACT
- term:
    id: GO:1901588
    label: dendritic microtubule
  evidence_type: ISS
  original_reference_id: PMID:19228967
  qualifier: colocalizes_with
  review:
    summary: Neuronal dendritic-microtubule colocalization from the tau-triage study;
      context-specific.
    action: KEEP_AS_NON_CORE
    reason: Highly specific neuronal localization; retain as non-core.
- term:
    id: GO:1901800
    label: positive regulation of proteasomal protein catabolic process
  evidence_type: ISS
  original_reference_id: PMID:19228967
  qualifier: involved_in
  review:
    summary: BAG2/HSP70 promotes ubiquitin-independent proteasomal degradation of tau;
      supported but client/context-specific.
    action: KEEP_AS_NON_CORE
    reason: Supported by the tau-triage mechanism but context-specific to neuronal tau
      handling.
    supported_by:
    - reference_id: PMID:19228967
      supporting_text: deliver Tau to the
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16207813
  qualifier: enables
  review:
    summary: The underlying interaction is BAG2 with CHIP (and HSC70); bare protein binding
      is too generic and is better captured by the specific chaperone/E3-ligase binding terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: protein binding is uninformative; the specific BAG2-CHIP and BAG2-HSC70
      interactions are represented by other terms in this review.
- term:
    id: GO:0010954
    label: positive regulation of protein processing
  evidence_type: IMP
  original_reference_id: PMID:16207813
  qualifier: involved_in
  review:
    summary: BAG2 stimulates chaperone-assisted maturation of CFTR; this is better captured
      as client stabilization/folding and negative regulation of ubiquitination. The
      generic "protein processing" term is a loose fit.
    action: KEEP_AS_NON_CORE
    reason: Supported for CFTR maturation but client/context-specific, and the term is a
      somewhat imprecise description of BAG2's CHIP-inhibition/stabilization mechanism.
    supported_by:
    - reference_id: PMID:16207813
      supporting_text: stimulates the chaperone-assisted maturation of CFTR
      reference_section_type: ABSTRACT
- term:
    id: GO:0044325
    label: transmembrane transporter binding
  evidence_type: IPI
  original_reference_id: PMID:16207813
  qualifier: enables
  review:
    summary: BAG2 recognizes CFTR (a transmembrane transporter) NBD1 peptides and stabilizes
      immature CFTR; transmembrane transporter binding is supported but client-specific.
    action: KEEP_AS_NON_CORE
    reason: CFTR is one client of BAG2; the binding is supported but not the universal
      core molecular function.
    supported_by:
    - reference_id: PMID:16207813
      supporting_text: also to stabilize immature CFTR conformations
      reference_section_type: DISCUSSION
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:16207813
  qualifier: involved_in
  review:
    summary: BAG2 stabilizes immature CFTR conformations in addition to inhibiting CHIP;
      protein stabilization is a core BAG2 process.
    action: ACCEPT
    reason: Direct evidence that BAG2 stabilizes a chaperone client (CFTR).
    supported_by:
    - reference_id: PMID:16207813
      supporting_text: also to stabilize immature CFTR conformations
      reference_section_type: DISCUSSION
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:16207813
  qualifier: enables
  review:
    summary: BAG2 binds HSC70 (a protein-folding chaperone) within CHIP complexes; chaperone
      binding is core.
    action: ACCEPT
    reason: Direct evidence of BAG2 association with HSC70 chaperone complexes underlies
      its co-chaperone function.
    supported_by:
    - reference_id: PMID:16207813
      supporting_text: the Hsc70 cochaperone
      reference_section_type: ABSTRACT
- term:
    id: GO:0101031
    label: protein folding chaperone complex
  evidence_type: IPI
  original_reference_id: PMID:16207813
  qualifier: part_of
  review:
    summary: BAG2 is a component of HSC70/CHIP chaperone complexes; membership in a
      protein-folding chaperone complex is core.
    action: ACCEPT
    reason: BAG2 is a main component of CHIP/HSC70 chaperone complexes, consistent with
      its co-chaperone role.
    supported_by:
    - reference_id: PMID:16207813
      supporting_text: We identified the Hsc70 cochaperone
      reference_section_type: ABSTRACT
- term:
    id: GO:0000774
    label: adenyl-nucleotide exchange factor activity
  evidence_type: IDA
  original_reference_id: PMID:24318877
  qualifier: enables
  review:
    summary: Direct biochemical demonstration of BAG2 NEF activity toward HSP70 (HSPA1A);
      this is the core molecular function.
    action: ACCEPT
    reason: BAG2 binds Hsp72 and functions in nucleotide/peptide release assays as a NEF,
      directly validating this molecular function.
    supported_by:
    - reference_id: PMID:24318877
      supporting_text: Proteins with Bcl2-associated anthanogene (BAG) domains act as nucleotide
        exchange factors (NEFs) for the molecular chaperone heat shock protein 70 (Hsp70).
      reference_section_type: ABSTRACT
    - reference_id: PMID:24318877
      supporting_text: their relative affinity values
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24318877
  qualifier: enables
  review:
    summary: The underlying interaction is BAG2 with HSP70 (HSPA1A); generic protein
      binding is uninformative and is captured by specific chaperone-binding/NEF terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is too general; the BAG2-HSP70 interaction is represented
      by heat shock protein binding and NEF activity.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252079
  qualifier: located_in
  review:
    summary: BAG2 is a cytosolic co-chaperone; cytosolic localization is the core
      compartment for its HSP70 NEF/CHIP-regulatory activity.
    action: ACCEPT
    reason: Consistent with BAG2 acting on cytosolic HSP70/HSC70 and CHIP complexes.
    supported_by:
    - reference_id: file:human/BAG2/BAG2-uniprot.txt
      supporting_text: Co-chaperone for HSP70 and HSC70 chaperone proteins
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0019538
    label: protein metabolic process
  evidence_type: IDA
  original_reference_id: PMID:9873015
  qualifier: acts_upstream_of_or_within
  review:
    summary: The cited reference (PMID:9873015) is about glycogen synthesis in muscle cells
      and does not concern BAG2; this is a wrong-reference curation error rather than a
      genuine (if over-broad) annotation.
    action: REMOVE
    reason: The cited reference (PMID:9873015, "Control of glycogen synthesis in cultured
      human muscle cells") contains no evidence for any BAG2 role - it is a database
      mis-attribution. The annotation is unlikely to be correct based on the combined
      evidence and should be removed at source rather than merely downgraded.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: TAS
  original_reference_id: PMID:9873016
  qualifier: involved_in
  review:
    summary: As an HSP70/HSC70 chaperone regulator, BAG2 participates in protein folding;
      supported by the foundational BAG-family chaperone-regulator study.
    action: ACCEPT
    reason: BAG2 modulates HSP70/HSC70 chaperone activity, consistent with a protein folding
      role.
    supported_by:
    - reference_id: PMID:9873016
      supporting_text: modulating their
      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:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16207813
  title: BAG-2 acts as an inhibitor of the chaperone-associated ubiquitin ligase CHIP.
  findings: []
- id: PMID:18457437
  title: Identification of intracellular proteins associated with the EBV-encoded
    nuclear antigen 5 using an efficient TAP procedure and FT-ICR mass spectrometry.
  findings: []
- id: PMID:19228967
  title: The cochaperone BAG2 sweeps paired helical filament- insoluble tau from the
    microtubule.
  findings: []
- id: PMID:22365833
  title: Dynamic protein-protein interaction wiring of the human spliceosome.
  findings: []
- id: PMID:22810586
  title: Interpreting cancer genomes using systematic host network perturbations by
    tumour virus proteins.
  findings: []
- id: PMID:24318877
  title: Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70)
    generates functionally distinct complexes in vitro.
  findings: []
- id: PMID:24383081
  title: The BAG2 protein stabilises PINK1 by decreasing its ubiquitination.
  findings: []
- id: PMID:24510904
  title: Unbiased screen for interactors of leucine-rich repeat kinase 2 supports
    a common pathway for sporadic and familial Parkinson disease.
  findings: []
- id: PMID:24981860
  title: Human-chromatin-related protein interactions identify a demethylase complex
    required for chromosome segregation.
  findings: []
- id: PMID:25006867
  title: The BAG2 and BAG5 proteins inhibit the ubiquitination of pathogenic ataxin3-80Q.
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25852190
  title: Integrative analysis of kinase networks in TRAIL-induced apoptosis provides
    a source of potential targets for combination therapy.
  findings: []
- id: PMID:25959826
  title: Quantitative interaction proteomics of neurodegenerative disease proteins.
  findings: []
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
- id: PMID:28386764
  title: Roles of tau protein in health and disease.
  findings: []
- id: PMID:29513927
  title: Comparative Protein Interaction Network Analysis Identifies Shared and Distinct
    Functions for the Human ROCO Proteins.
  findings: []
- id: PMID:29568061
  title: An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein
    interactions and subcellular localizations.
  findings: []
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry
    in Intact Cell Nuclei.
  findings: []
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing
    transforming levels of KRAS(G13D).
  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
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34831344
  title: 'With or without You: Co-Chaperones Mediate Health and Disease by Modifying
    Chaperone Function and Protein Triage.'
  full_text_unavailable: true
  findings:
  - statement: Review framing BAG2 as an HSP70/HSC70 co-chaperone that modulates chaperone
      function and protein triage decisions (folding/stabilization vs degradation) in
      health and disease, consistent with its inhibition of CHIP/STUB1-mediated client
      ubiquitination.
- id: PMID:35167623
  title: DNAJB1-PRKACA in HEK293T cells induces LINC00473 overexpression that depends
    on PKA signaling.
  findings: []
- id: PMID:35266954
  title: The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation,
    and toxicity.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:37045861
  title: Interactome dynamics of RAF1-BRAF kinase monomers and dimers.
  findings: []
- id: PMID:39300217
  title: BAG2, MAD2L1, and MDK are cancer-driver genes and candidate targets for novel
    therapies in malignant pleural mesothelioma.
  full_text_unavailable: true
  findings:
  - statement: BAG2 is identified as a candidate cancer-driver gene and diagnostic-adjunct
      biomarker in malignant pleural mesothelioma, being significantly upregulated in
      tumor RNA-seq and showing moderate-to-strong immunohistochemical expression in
      mesothelioma but not in reactive mesothelium; this is a disease-association rather
      than a new molecular function for BAG2.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:9873015
  title: Control of glycogen synthesis in cultured human muscle cells.
  findings: []
- id: PMID:9873016
  title: An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators.
  findings: []
- id: Reactome:R-HSA-5252079
  title: HSP110s exchange ATP for ADP on HSP70s:ADP
  findings: []
- id: file:human/BAG2/BAG2-uniprot.txt
  title: BAG2 UniProtKB record (O95816)
  findings: []
- id: file:human/BAG2/BAG2-notes.md
  title: Manual BAG2 curation notes
  findings: []
core_functions:
- description: BAG2 acts as a nucleotide-exchange factor (NEF) for the HSP70/HSC70 molecular
    chaperones, binding the chaperone ATPase domain via its BAG domain and promoting ADP
    release to regulate the chaperone cycle and client release.
  molecular_function:
    id: GO:0000774
    label: adenyl-nucleotide exchange factor activity
  directly_involved_in:
  - id: GO:0006457
    label: protein folding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/BAG2/BAG2-uniprot.txt
    supporting_text: a nucleotide-exchange factor (NEF) promoting the release of ADP from
    reference_section_type: DATABASE_ENTRY
  - reference_id: PMID:24318877
    supporting_text: Proteins with Bcl2-associated anthanogene (BAG) domains act as nucleotide
      exchange factors (NEFs) for the molecular chaperone heat shock protein 70 (Hsp70).
    reference_section_type: ABSTRACT
- description: BAG2 inhibits the chaperone-associated E3 ubiquitin ligase CHIP (STUB1) by
    abrogating CHIP/E2 cooperation, thereby negatively regulating ubiquitination of chaperone
    clients and shifting protein triage away from degradation.
  molecular_function:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  directly_involved_in:
  - id: GO:0031397
    label: negative regulation of protein ubiquitination
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:16207813
    supporting_text: BAG-2 inhibits the ubiquitin ligase activity of CHIP by abrogating
      the CHIP/E2 cooperation
    reference_section_type: ABSTRACT
- description: BAG2 stabilizes specific chaperone clients (e.g., immature CFTR, PINK1,
    polyglutamine-expanded ataxin-3) by decreasing their ubiquitination, contributing to
    chaperone-assisted protein quality control.
  molecular_function:
    id: GO:0051087
    label: protein-folding chaperone binding
  directly_involved_in:
  - id: GO:0050821
    label: protein stabilization
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:24383081
    supporting_text: directly binds with and stabilises PINK1 by decreasing its ubiquitination
    reference_section_type: ABSTRACT
  - reference_id: PMID:25006867
    supporting_text: stabilise pathogenic ataxin3-80Q by inhibiting its ubiquitination
    reference_section_type: ABSTRACT
proposed_new_terms: []
suggested_questions:
- question: Given BAG2's notably lower affinity for HSP70 compared with BAG1 and BAG3, what
    determines its selective recruitment to specific clients and to CHIP complexes in vivo?
  experts:
  - Gestwicki JE
  - Höhfeld J
- question: Is the neuronal microtubule-tethered, ubiquitin-independent tau-degradation role
    of BAG2 a specialized function distinct from its general cytosolic co-chaperone activity?
  experts:
  - Kosik KS
- question: Does BAG2-mediated inhibition of CHIP/STUB1 stabilize HSP70-family chaperones
    (e.g., HSP72/HSPA1A) and pro-survival clients to confer apoptosis resistance, and is this
    a generalizable mechanism across the cancer contexts (mesothelioma, gastric, fibrolamellar)
    where BAG2 is reported to be upregulated?
  experts:
  - Behl C
  - Höhfeld J
suggested_experiments:
- hypothesis: BAG2 selectively inhibits CHIP-mediated ubiquitination of a defined subset of
    HSP70 clients rather than acting as a global CHIP inhibitor.
  description: Reconstitute HSC70/CHIP/E2 ubiquitination assays with purified BAG2 across a
    panel of clients (CFTR NBD1, PINK1, ataxin-3, tau) and quantify client-specific
    suppression of ubiquitination versus NEF activity.
  experiment_type: in vitro reconstituted ubiquitination assay
- hypothesis: BAG2 routes misfolded tau to ubiquitin-independent proteasomal degradation via
    microtubule tethering of the BAG2/HSP70 complex.
  description: Use neurons with BAG2 BAG-domain or microtubule-association mutants and measure
    Sarkosyl-insoluble/phospho-tau clearance, proteasome dependence, and ubiquitin
    requirement.
  experiment_type: cell-based tau clearance / proteasome dependence assay