id: O43765
gene_symbol: SGTA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: SGTA (small glutamine-rich tetratricopeptide repeat-containing protein alpha, also called SGT or alpha-SGT) is a cytosolic TPR-domain co-chaperone that operates in the biogenesis and quality control of tail-anchored (TA) and other hydrophobic membrane proteins. Through its central TPR domain it binds the chaperones HSC70/HSPA8, HSP70 and HSP90 and regulates their ATPase activity, while its glutamine-rich and N-terminal dimerization regions mediate homodimerization and client capture. SGTA binds the transmembrane/hydrophobic segments of newly synthesized clients rapidly and, acting upstream of and together with the BAG6 complex and the ASNA1/TRC40 (GET) targeting pathway, delivers TA proteins to the endoplasmic reticulum membrane. It also functions as a quality-control rheostat; by competing with the E3 ligase RNF126 for BAG6 and promoting deubiquitination of mislocalized substrates, SGTA antagonizes BAG6-mediated ubiquitination and proteasomal triage, biasing hydrophobic clients toward maturation rather than degradation. SGTA is predominantly cytoplasmic but accumulates in the nucleus during apoptosis.
existing_annotations:
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: SGTA is a cytosolic co-chaperone that transiently associates with the ER membrane while delivering tail-anchored clients. Membrane is a peripheral, transient site rather than its core compartment.
    action: KEEP_AS_NON_CORE
    reason: SGTA acts in the cytosol; membrane association is transient during TA-protein delivery to the ER. Non-core localization.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006620
    label: post-translational protein targeting to endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: SGTA mediates post-translational targeting of hydrophobic/tail-anchored clients to the ER membrane. This is a core biological process for SGTA.
    action: ACCEPT
    reason: Directly supported by UniProt FUNCTION; SGTA delivers clients to the ER via the BAG6/TRC40 (GET) pathway. Falcon deep research describes SGTA as a central factor in the GET/TRC pathway mediating post-translational targeting and insertion of TA proteins into the ER membrane.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: Mediates their targeting to the endoplasmic reticulum
    - reference_id: file:human/SGTA/SGTA-deep-research-falcon.md
      supporting_text: This pathway mediates the post-translational targeting and insertion of TA proteins into the ER membrane
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: SGTA acts as a molecular adaptor/co-chaperone that bridges hydrophobic clients to the chaperone and targeting machinery. This is a core molecular function.
    action: ACCEPT
    reason: Supported by UniProt FUNCTION; SGTA links clients to HSP70/HSP90 and the BAG6/TRC40 targeting module, an adaptor role. Falcon deep research describes SGTA as receiving clients from Hsp70 via its TPR domain and bridging them to downstream targeting/quality-control factors.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: Co-chaperone that binds misfolded and hydrophobic patches-containing client proteins in the cytosol.
    - reference_id: file:human/SGTA/SGTA-deep-research-falcon.md
      supporting_text: Through its TPR domain, SGTA directly interacts with Hsp70 to receive hydrophobic clients in a substrate relay mechanism
- term:
    id: GO:0072380
    label: TRC complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: SGTA associates with the transmembrane-domain recognition complex (TRC/GET) targeting module together with ASNA1/TRC40 and the BAG6 complex.
    action: ACCEPT
    reason: Supported by UniProt FUNCTION (SGTA forms with ASNA1 and the BAG6 complex a targeting module); part of the TA-protein targeting machinery.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: with ASNA1 and the BAG6 complex a targeting module
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: SGTA accumulates in the nucleus, notably during apoptosis. Documented but secondary to its cytosolic function.
    action: KEEP_AS_NON_CORE
    reason: UniProt lists Nucleus (increased nuclear accumulation during apoptosis); a real but non-core localization relative to the cytosolic co-chaperone role.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: Increased nuclear accumulation seen during cell apoptosis.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: SGTA is predominantly cytoplasmic, where it captures clients and engages the chaperone/targeting machinery.
    action: ACCEPT
    reason: Matches UniProt subcellular location; cytoplasm is the genuine principal compartment.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Automated membrane localization; SGTA transiently associates with the ER membrane during TA-protein delivery.
    action: KEEP_AS_NON_CORE
    reason: Transient membrane association during client delivery; non-core relative to the cytosolic site of action.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: SGTA forms a homodimer; identical protein binding (self-association) is a genuine, specific molecular feature.
    action: ACCEPT
    reason: Supported by UniProt SUBUNIT (Homodimer); self-association is a real, specific interaction.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBUNIT: Homodimer'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14667819
  qualifier: enables
  review:
    summary: Interaction with UBL4A (P46379), a BAG6/GET-pathway component. Bare protein binding is uninformative; partner is targeting-pathway-related.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction with a TA-targeting-pathway component (UBL4A), but bare protein binding is uninformative; not elevated to core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: High-throughput interactome capturing many partners. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; uninformative protein binding term, not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16580632
  qualifier: enables
  review:
    summary: Interaction (partner P59635). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but bare protein binding is uninformative; not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19615732
  qualifier: enables
  review:
    summary: Interaction with UBL4A (P11441), a BAG6-complex/GET-pathway component. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction with a targeting-pathway component (UBL4A), but bare protein binding is uninformative; not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: High-throughput interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; uninformative protein binding term, not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: Liver interactome screen. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; uninformative protein binding term, not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: Chaperone interaction network capturing SGTA with UBL4A (P11441), BAG6 (O95816) and SGTA self. Bare protein binding is uninformative; partners are targeting/chaperone-pathway-related.
    action: KEEP_AS_NON_CORE
    reason: Records real chaperone/targeting-pathway interactions, but bare protein binding is uninformative; the informative interactions are captured by BAG6 complex binding and identical protein binding.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale yeast two-hybrid interactome with many partners. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; uninformative protein binding term, not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: High-throughput interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; uninformative protein binding term, not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: High-throughput interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; uninformative protein binding term, not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107012
  qualifier: enables
  review:
    summary: High-throughput interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; uninformative protein binding term, not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: High-throughput interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; uninformative protein binding term, not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; uninformative protein binding term, not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36217029
  qualifier: enables
  review:
    summary: High-throughput interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; uninformative protein binding term, not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-maps interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; uninformative protein binding term, not core.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: SGTA self-interaction (homodimer) captured in a chaperone interaction network.
    action: ACCEPT
    reason: Consistent with UniProt SUBUNIT (Homodimer); a genuine, specific self-association.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBUNIT: Homodimer'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: SGTA self-interaction (homodimer) captured experimentally.
    action: ACCEPT
    reason: Consistent with UniProt SUBUNIT (Homodimer); a genuine, specific self-association.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBUNIT: Homodimer'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence-based nucleoplasm localization, consistent with the documented nuclear pool of SGTA.
    action: KEEP_AS_NON_CORE
    reason: Nuclear pool is real (UniProt Nucleus) but non-core relative to the cytosolic co-chaperone function.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: Increased nuclear accumulation seen during cell apoptosis.
- term:
    id: GO:1904294
    label: positive regulation of ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:23246001
  qualifier: involved_in
  review:
    summary: SGTA modulates ERAD-associated triage of mislocalized/hydrophobic substrates; depending on context it can promote or restrain the pathway. This positive-regulation annotation reflects one experimental context.
    action: KEEP_AS_NON_CORE
    reason: SGTA acts as a context-dependent rheostat in mislocalized-protein triage; ERAD regulation is a downstream consequence of its quality-control role.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: regulates their sorting to the proteasome when targeting fails
- term:
    id: GO:2000060
    label: positive regulation of ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:23246001
  qualifier: involved_in
  review:
    summary: SGTA influences ubiquitin-dependent degradation of triaged substrates; this positive-regulation annotation reflects a specific context within its rheostat role.
    action: KEEP_AS_NON_CORE
    reason: Downstream effect of SGTA's quality-control/triage function; context-dependent.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: regulates their sorting to the proteasome when targeting fails
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:25535373
  qualifier: involved_in
  review:
    summary: SGTA participates in the insertion of tail-anchored proteins into the ER membrane, binding their transmembrane domains and feeding them into the targeting pathway. This is a core process for SGTA.
    action: ACCEPT
    reason: Directly supported (IDA) and by UniProt FUNCTION; the precise TA-protein insertion process is central to SGTA's role. Falcon deep research corroborates the hierarchical chaperone cascade in which SGTA, with the BAG6 complex, hands TA clients to TRC40 for ER membrane insertion.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: Functions upstream of the BAG6 complex and ASNA1, binding more rapidly the transmembrane domain of newly synthesized proteins
    - reference_id: file:human/SGTA/SGTA-deep-research-falcon.md
      supporting_text: SGTA, together with the heterotrimeric BAG6 complex (comprising BAG6, UBL4A, and TRC35), forms a pre-targeting complex that facilitates TA protein handoff to the central targeting factor TRC40
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IDA
  original_reference_id: PMID:23129660
  qualifier: involved_in
  review:
    summary: SGTA acts within the ER-associated degradation/mislocalized-protein triage pathway, antagonizing BAG6-mediated ubiquitination.
    action: ACCEPT
    reason: Supported by UniProt FUNCTION and PMID:23129660; SGTA is a documented regulator within the ERAD/mislocalized-protein catabolic process.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: involved in the regulation of the endoplasmic reticulum-associated misfolded protein
- term:
    id: GO:1904293
    label: negative regulation of ERAD pathway
  evidence_type: IDA
  original_reference_id: PMID:23129660
  qualifier: involved_in
  review:
    summary: SGTA antagonizes BAG6-mediated ubiquitination and promotes deubiquitination of mislocalized substrates, thereby negatively regulating their ERAD-type degradation.
    action: ACCEPT
    reason: Directly supported by PMID:23129660; SGTA reverses BAG6 actions and inhibits substrate-specific degradation. Falcon deep research independently summarizes SGTA antagonizing the BAG6-mediated degradation pathway and (with USP5) promoting deubiquitination of mislocalized proteins to increase their steady-state levels.
    supported_by:
    - reference_id: PMID:23129660
      supporting_text: SGTA actively promotes the deubiquitination of mislocalized proteins that are already covalently modified, thus reversing the actions of BAG6 and inhibiting its capacity to promote substrate-specific degradation.
    - reference_id: file:human/SGTA/SGTA-deep-research-falcon.md
      supporting_text: Overexpression of SGTA increases the steady-state levels of MLPs by promoting their deubiquitination
- term:
    id: GO:2000059
    label: negative regulation of ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:23129660
  qualifier: involved_in
  review:
    summary: By promoting deubiquitination of mislocalized substrates, SGTA negatively regulates their ubiquitin-dependent degradation.
    action: ACCEPT
    reason: Directly supported by PMID:23129660; SGTA maintains hydrophobic substrates in non-ubiquitinated states and reverses BAG6-mediated ubiquitination. Falcon deep research corroborates that SGTA acts as an uncommitted client holder able to antagonize the BAG6/RNF126 degradation route.
    supported_by:
    - reference_id: PMID:23129660
      supporting_text: SGTA actively promotes the deubiquitination of mislocalized proteins that are already covalently modified, thus reversing the actions of BAG6 and inhibiting its capacity to promote substrate-specific degradation.
    - reference_id: file:human/SGTA/SGTA-deep-research-falcon.md
      supporting_text: SGTA can also antagonize this degradation pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15708368
  qualifier: enables
  review:
    summary: Interaction with HSP90AA1 (P07900) via the TPR repeats (and SLC2A1). Bare protein binding is uninformative; the HSP90 interaction is better captured as Hsp90 protein binding.
    action: MODIFY
    reason: The WITH partner HSP90AA1 (P07900) interacts via SGTA's TPR repeats; precisely captured as Hsp90 protein binding.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: Interacts (via TPR repeats) with HSP90AA1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16580629
  qualifier: enables
  review:
    summary: Interaction with HSP90AB1 (P08238). Bare protein binding is uninformative; the HSP90 interaction is better captured as Hsp90 protein binding.
    action: MODIFY
    reason: The WITH partner is HSP90AB1 (P08238); precisely captured as Hsp90 protein binding, consistent with SGTA's chaperone-binding role.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: Interacts with HSP90AB1
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:16580629
  qualifier: located_in
  review:
    summary: Direct evidence for nuclear localization of SGTA (nuclear accumulation during apoptosis). Documented but secondary to cytosolic function.
    action: KEEP_AS_NON_CORE
    reason: Nuclear pool is real (UniProt Nucleus) but non-core relative to the cytosolic co-chaperone role.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: Increased nuclear accumulation seen during cell apoptosis.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16580629
  qualifier: located_in
  review:
    summary: Direct evidence for cytoplasmic localization of SGTA, its principal compartment.
    action: ACCEPT
    reason: IDA-supported cytoplasm, matching UniProt; the genuine principal compartment.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9609921
  qualifier: located_in
  review:
    summary: Curated (Reactome) cytosolic localization, consistent with SGTA's principal compartment.
    action: ACCEPT
    reason: Cytosol is the genuine principal compartment of SGTA; consistent with UniProt.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9617595
  qualifier: located_in
  review:
    summary: Curated (Reactome) cytosolic localization, consistent with SGTA's principal compartment.
    action: ACCEPT
    reason: Cytosol is the genuine principal compartment of SGTA; consistent with UniProt.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:1904288
    label: BAT3 complex binding
  evidence_type: IPI
  original_reference_id: PMID:23246001
  qualifier: enables
  review:
    summary: SGTA binds the BAG6 (BAT3) complex via the BAG6 ubiquitin-like domain. This is a core, specific molecular function central to its triage/targeting role.
    action: ACCEPT
    reason: Directly supported by UniProt SUBUNIT and PMID:23246001; BAG6-complex binding is central to SGTA's quality-control function. Falcon deep research frames this interaction as the basis for SGTA acting as an uncommitted client holder that channels substrates between productive TRC40 targeting and BAG6-mediated degradation.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: Interacts with BAG6 (via ubiquitin-like domain)
    - reference_id: file:human/SGTA/SGTA-deep-research-falcon.md
      supporting_text: SGTA acts as an uncommitted client holder that can channel substrates toward either productive targeting (via TRC40) or degradation (via BAG6)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23246001
  qualifier: enables
  review:
    summary: Interaction with UBL4A (P11441)/BAG6-complex components. Bare protein binding is uninformative; the informative term is BAG6 complex binding (also annotated).
    action: KEEP_AS_NON_CORE
    reason: Real interaction with BAG6-complex machinery, but bare protein binding is uninformative; the specific interaction is captured by GO:1904288.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: Interacts with BAG6 (via ubiquitin-like domain)
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:23246001
  qualifier: located_in
  review:
    summary: Direct evidence for cytosolic localization of SGTA, its principal compartment.
    action: ACCEPT
    reason: IDA-supported cytosol, matching UniProt; the genuine principal compartment.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:23246001
  qualifier: located_in
  review:
    summary: SGTA detected at membranes, consistent with transient ER-membrane association during client delivery.
    action: KEEP_AS_NON_CORE
    reason: Transient membrane association during TA-protein delivery; non-core relative to the cytosolic site of action.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: Direct evidence for cytoplasmic localization of SGTA, its principal compartment.
    action: ACCEPT
    reason: IDA-supported cytoplasm, matching UniProt; the genuine principal compartment.
    supported_by:
    - reference_id: file:human/SGTA/SGTA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000054
  title: Gene Ontology annotation based on the manual curation of subcellular localization
  findings: []
- id: GO_REF:0000117
  title: Electronic GO annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:14667819
  title: Analysis of a high-throughput yeast two-hybrid system and its use to predict the function of intracellular proteins encoded within the human MHC class III region.
  findings: []
- id: PMID:15708368
  title: Small glutamine-rich tetratricopeptide repeat-containing protein is composed of three structural units with distinct functions.
  findings:
  - statement: SGTA is a homodimer that interacts with HSP90AA1 via its TPR repeats.
    reference_section_type: RESULTS
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:16580629
  title: 'SGT, a Hsp90beta binding partner, is accumulated in the nucleus during cell apoptosis.'
  findings:
  - statement: SGTA interacts with HSP90AB1 and accumulates in the nucleus during apoptosis; it is cytoplasmic and nuclear.
    reference_section_type: RESULTS
- id: PMID:16580632
  title: 'Severe acute respiratory syndrome coronavirus protein 7a interacts with hSGT.'
  findings: []
- id: PMID:19615732
  title: Defining the human deubiquitinating enzyme interaction landscape.
  findings: []
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:23129660
  title: SGTA antagonizes BAG6-mediated protein triage.
  findings:
  - statement: SGTA antagonizes BAG6-mediated ubiquitination by promoting deubiquitination of mislocalized proteins, reversing BAG6 actions and inhibiting substrate-specific degradation; it biases mislocalized hydrophobic clients toward maturation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed ("SGTA antagonizes BAG6-mediated protein triage"); establishes SGTA's quality-control rheostat role - antagonizing BAG6 ubiquitination and biasing clients toward maturation (GO:0051087 BAT3/BAG6 complex binding core function).
- id: PMID:23246001
  title: SGTA recognizes a noncanonical ubiquitin-like domain in the Bag6-Ubl4A-Trc35 complex to promote endoplasmic reticulum-associated degradation.
  findings:
  - statement: SGTA binds the BAG6 (BAT3) complex and regulates the triage of mislocalized/hydrophobic substrates between the ER-targeting and proteasomal-degradation pathways.
    reference_section_type: RESULTS
- 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:25535373
  title: Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain.
  findings:
  - statement: SGTA binds the transmembrane domains of newly synthesized tail-anchored proteins and acts upstream of BAG6/ASNA1 to insert them into the ER membrane.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the BAG6 tail-anchor-targeting module relevant to SGTA's TA-protein ER-insertion role. Title corrected to verbatim PubMed (previously a paraphrase).
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
- id: PMID:27107012
  title: Pooled-matrix protein interaction screens using Barcode Fusion Genetics.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:36217029
  title: A proteome-scale map of the SARS-CoV-2-human contactome.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: Reactome:R-HSA-9609921
  title: Cytosolic quality control / TA-protein targeting pathway
  findings: []
- id: Reactome:R-HSA-9617595
  title: Cytosolic quality control / TA-protein targeting pathway
  findings: []
- id: file:human/SGTA/SGTA-uniprot.txt
  title: UniProt entry O43765 (SGTA_HUMAN), small glutamine-rich TPR-containing protein alpha
  findings:
  - statement: SGTA is a cytosolic homodimeric TPR co-chaperone that binds HSC70/HSP70/HSP90 and hydrophobic clients, mediates tail-anchored protein targeting to the ER via the BAG6/ASNA1 (GET) pathway, and antagonizes BAG6-mediated ubiquitination to bias clients toward maturation over degradation. Cytoplasmic and nuclear.
    reference_section_type: OTHER
- id: file:human/SGTA/SGTA-deep-research-falcon.md
  title: Falcon deep research report for SGTA
  findings:
  - statement: SGTA is a cytosolic TPR co-chaperone whose TPR domain receives hydrophobic clients from Hsp70 (recognizing the C-terminal EEVD motif of Hsp70/Hsp90), captures tail-anchored membrane proteins via its C-terminal helical-hand domain, and acts as an uncommitted client holder that triages clients between TRC40-mediated ER targeting and BAG6-mediated ubiquitination/degradation; SGTA can antagonize the degradation pathway and (with USP5) promote deubiquitination of mislocalized proteins.
    reference_section_type: OTHER
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: 'LLM-synthesized (Edison/Falcon) report. The narrative is internally consistent with UniProt and the verified primary literature (Shao 2017 Science triage reaction; Cho & Shan 2018 Hsp70 substrate relay; Roboti 2022 MAVS/BAG6; Hill & Nyathi 2022 USP5; Roberts 2015 structural review), and its claims used here are anchored to verbatim supporting_text. Underlying cited papers are referenced by short-name only and were not individually PubMed-verified, so marked UNVERIFIED for the synthesis itself. Some claims (e.g. a "2026 CRISPR screen", ERCYS reflux pathway, EEVD-like non-chaperone motifs) are not used as annotation support.'
core_functions:
- description: Cytosolic TPR co-chaperone and molecular adaptor that binds hydrophobic/tail-anchored client proteins and the HSC70/HSP70/HSP90 chaperones, delivering clients to the ER membrane via the BAG6 complex and the ASNA1/TRC40 (GET) targeting pathway.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/SGTA/SGTA-uniprot.txt
    supporting_text: Co-chaperone that binds misfolded and hydrophobic patches-containing client proteins in the cytosol.
  - reference_id: file:human/SGTA/SGTA-uniprot.txt
    supporting_text: Functions upstream of the BAG6 complex and ASNA1, binding more rapidly the transmembrane domain of newly synthesized proteins
  - reference_id: file:human/SGTA/SGTA-deep-research-falcon.md
    supporting_text: Through its TPR domain, SGTA directly interacts with Hsp70 to receive hydrophobic clients in a substrate relay mechanism
- description: Post-translational targeting and insertion of tail-anchored membrane proteins into the ER membrane, acting upstream of and together with the BAG6/TRC40 targeting module.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/SGTA/SGTA-uniprot.txt
    supporting_text: Mediates their targeting to the endoplasmic reticulum
  directly_involved_in:
  - id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
- description: Quality-control rheostat for mislocalized/hydrophobic substrates; by binding the BAG6 complex and competing with RNF126, SGTA antagonizes BAG6-mediated ubiquitination and promotes deubiquitination, biasing clients toward maturation rather than proteasomal degradation.
  molecular_function:
    id: GO:1904288
    label: BAT3 complex binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/SGTA/SGTA-uniprot.txt
    supporting_text: Competes with RNF126 for interaction with BAG6, preventing the ubiquitination of client proteins
  - reference_id: PMID:23129660
    supporting_text: reversing the actions of BAG6 and inhibiting its capacity to promote substrate-specific degradation.
  - reference_id: file:human/SGTA/SGTA-deep-research-falcon.md
    supporting_text: SGTA acts as an uncommitted client holder that can channel substrates toward either productive targeting (via TRC40) or degradation (via BAG6)
proposed_new_terms: []
suggested_questions:
- question: What determines whether SGTA biases a given hydrophobic client toward ER targeting/maturation versus proteasomal degradation, and how is this rheostat set by BAG6/RNF126 stoichiometry?
- question: How does SGTA regulation of HSC70/HSP70 ATPase activity contribute to client capture and handoff to the TRC40/GET pathway?
- question: Does the nuclear accumulation of SGTA during apoptosis reflect a distinct, chaperone-independent function?
- question: How does the SGTA-USP5 deubiquitinase axis (reported by Hill & Nyathi 2022 and summarized in the falcon deep research) select which mislocalized clients are rescued from BAG6/RNF126-mediated degradation versus committed to the proteasome?
suggested_experiments:
- description: In vitro reconstitution of tail-anchored protein delivery using purified SGTA, BAG6 complex and TRC40/ASNA1 to measure SGTA's contribution to client capture and handoff kinetics, with TPR-domain and dimerization mutants.
- description: Quantitative ubiquitination/deubiquitination assays of a model mislocalized substrate under varying SGTA, BAG6 and RNF126 levels to map the maturation-versus-degradation equilibrium.
- description: Define the SGTA client repertoire by proximity labeling in cells, distinguishing bona fide TA/hydrophobic clients from high-throughput interactome noise.