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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. Reason: SGTA acts in the cytosol; membrane association is transient during TA-protein delivery to the ER. Non-core localization. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: SGTA mediates post-translational targeting of hydrophobic/tail-anchored clients to the ER membrane. This is a core biological process for SGTA. 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. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt Mediates their targeting to the endoplasmic reticulum file:human/SGTA/SGTA-deep-research-falcon.md This pathway mediates the post-translational targeting and insertion of TA proteins into the ER membrane |
| GO:0060090 molecular adaptor activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt Co-chaperone that binds misfolded and hydrophobic patches-containing client proteins in the cytosol. file:human/SGTA/SGTA-deep-research-falcon.md Through its TPR domain, SGTA directly interacts with Hsp70 to receive hydrophobic clients in a substrate relay mechanism |
| GO:0072380 TRC complex | IBA GO_REF:0000033 | ACCEPT | Summary: SGTA associates with the transmembrane-domain recognition complex (TRC/GET) targeting module together with ASNA1/TRC40 and the BAG6 complex. Reason: Supported by UniProt FUNCTION (SGTA forms with ASNA1 and the BAG6 complex a targeting module); part of the TA-protein targeting machinery. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt with ASNA1 and the BAG6 complex a targeting module |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: SGTA accumulates in the nucleus, notably during apoptosis. Documented but secondary to its cytosolic function. Reason: UniProt lists Nucleus (increased nuclear accumulation during apoptosis); a real but non-core localization relative to the cytosolic co-chaperone role. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt Increased nuclear accumulation seen during cell apoptosis. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: SGTA is predominantly cytoplasmic, where it captures clients and engages the chaperone/targeting machinery. Reason: Matches UniProt subcellular location; cytoplasm is the genuine principal compartment. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016020 membrane | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Automated membrane localization; SGTA transiently associates with the ER membrane during TA-protein delivery. Reason: Transient membrane association during client delivery; non-core relative to the cytosolic site of action. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0042802 identical protein binding | IEA GO_REF:0000117 | ACCEPT | Summary: SGTA forms a homodimer; identical protein binding (self-association) is a genuine, specific molecular feature. Reason: Supported by UniProt SUBUNIT (Homodimer); self-association is a real, specific interaction. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBUNIT: Homodimer |
| GO:0005515 protein binding | IPI PMID:14667819 Analysis of a high-throughput yeast two-hybrid system and it... | KEEP AS NON CORE | Summary: Interaction with UBL4A (P46379), a BAG6/GET-pathway component. Bare protein binding is uninformative; partner is targeting-pathway-related. Reason: Records a real interaction with a TA-targeting-pathway component (UBL4A), but bare protein binding is uninformative; not elevated to core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | KEEP AS NON CORE | Summary: High-throughput interactome capturing many partners. Bare protein binding is uninformative. Reason: High-throughput interactions; uninformative protein binding term, not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:16580632 Severe acute respiratory syndrome coronavirus protein 7a int... | KEEP AS NON CORE | Summary: Interaction (partner P59635). Bare protein binding is uninformative. Reason: Records a real interaction but bare protein binding is uninformative; not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:19615732 Defining the human deubiquitinating enzyme interaction lands... | KEEP AS NON CORE | Summary: Interaction with UBL4A (P11441), a BAG6-complex/GET-pathway component. Bare protein binding is uninformative. Reason: Records a real interaction with a targeting-pathway component (UBL4A), but bare protein binding is uninformative; not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | KEEP AS NON CORE | Summary: High-throughput interactome. Bare protein binding is uninformative. Reason: High-throughput interactions; uninformative protein binding term, not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | KEEP AS NON CORE | Summary: Liver interactome screen. Bare protein binding is uninformative. Reason: High-throughput interactions; uninformative protein binding term, not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Proteome-scale yeast two-hybrid interactome with many partners. Bare protein binding is uninformative. Reason: High-throughput interactions; uninformative protein binding term, not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: High-throughput interactome. Bare protein binding is uninformative. Reason: High-throughput interactions; uninformative protein binding term, not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | KEEP AS NON CORE | Summary: High-throughput interactome. Bare protein binding is uninformative. Reason: High-throughput interactions; uninformative protein binding term, not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | KEEP AS NON CORE | Summary: High-throughput interactome. Bare protein binding is uninformative. Reason: High-throughput interactions; uninformative protein binding term, not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: High-throughput interactome. Bare protein binding is uninformative. Reason: High-throughput interactions; uninformative protein binding term, not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Interactome study. Bare protein binding is uninformative. Reason: High-throughput interactions; uninformative protein binding term, not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:36217029 A proteome-scale map of the SARS-CoV-2-human contactome. | KEEP AS NON CORE | Summary: High-throughput interactome. Bare protein binding is uninformative. Reason: High-throughput interactions; uninformative protein binding term, not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-maps interactome. Bare protein binding is uninformative. Reason: High-throughput interactions; uninformative protein binding term, not core. Supporting Evidence: file:human/SGTA/SGTA-goa.tsv GO:0005515 protein binding |
| GO:0042802 identical protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | ACCEPT | Summary: SGTA self-interaction (homodimer) captured in a chaperone interaction network. Reason: Consistent with UniProt SUBUNIT (Homodimer); a genuine, specific self-association. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBUNIT: Homodimer |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | ACCEPT | Summary: SGTA self-interaction (homodimer) captured experimentally. Reason: Consistent with UniProt SUBUNIT (Homodimer); a genuine, specific self-association. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBUNIT: Homodimer |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Immunofluorescence-based nucleoplasm localization, consistent with the documented nuclear pool of SGTA. Reason: Nuclear pool is real (UniProt Nucleus) but non-core relative to the cytosolic co-chaperone function. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt Increased nuclear accumulation seen during cell apoptosis. |
| GO:1904294 positive regulation of ERAD pathway | IMP PMID:23246001 SGTA recognizes a noncanonical ubiquitin-like domain in the ... | KEEP AS NON CORE | 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. Reason: SGTA acts as a context-dependent rheostat in mislocalized-protein triage; ERAD regulation is a downstream consequence of its quality-control role. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt regulates their sorting to the proteasome when targeting fails |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | IMP PMID:23246001 SGTA recognizes a noncanonical ubiquitin-like domain in the ... | KEEP AS NON CORE | Summary: SGTA influences ubiquitin-dependent degradation of triaged substrates; this positive-regulation annotation reflects a specific context within its rheostat role. Reason: Downstream effect of SGTA's quality-control/triage function; context-dependent. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt regulates their sorting to the proteasome when targeting fails |
| GO:0071816 tail-anchored membrane protein insertion into ER membrane | IDA PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module... | ACCEPT | 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. 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. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt Functions upstream of the BAG6 complex and ASNA1, binding more rapidly the transmembrane domain of newly synthesized proteins file:human/SGTA/SGTA-deep-research-falcon.md 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 |
| GO:0036503 ERAD pathway | IDA PMID:23129660 SGTA antagonizes BAG6-mediated protein triage. | ACCEPT | Summary: SGTA acts within the ER-associated degradation/mislocalized-protein triage pathway, antagonizing BAG6-mediated ubiquitination. Reason: Supported by UniProt FUNCTION and PMID:23129660; SGTA is a documented regulator within the ERAD/mislocalized-protein catabolic process. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt involved in the regulation of the endoplasmic reticulum-associated misfolded protein |
| GO:1904293 negative regulation of ERAD pathway | IDA PMID:23129660 SGTA antagonizes BAG6-mediated protein triage. | ACCEPT | Summary: SGTA antagonizes BAG6-mediated ubiquitination and promotes deubiquitination of mislocalized substrates, thereby negatively regulating their ERAD-type degradation. 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. Supporting Evidence: PMID:23129660 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. file:human/SGTA/SGTA-deep-research-falcon.md Overexpression of SGTA increases the steady-state levels of MLPs by promoting their deubiquitination |
| GO:2000059 negative regulation of ubiquitin-dependent protein catabolic process | IDA PMID:23129660 SGTA antagonizes BAG6-mediated protein triage. | ACCEPT | Summary: By promoting deubiquitination of mislocalized substrates, SGTA negatively regulates their ubiquitin-dependent degradation. 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. Supporting Evidence: PMID:23129660 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. file:human/SGTA/SGTA-deep-research-falcon.md SGTA can also antagonize this degradation pathway |
| GO:0005515 protein binding | IPI PMID:15708368 Small glutamine-rich tetratricopeptide repeat-containing pro... | MODIFY | 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. Reason: The WITH partner HSP90AA1 (P07900) interacts via SGTA's TPR repeats; precisely captured as Hsp90 protein binding. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt Interacts (via TPR repeats) with HSP90AA1 |
| GO:0005515 protein binding | IPI PMID:16580629 SGT, a Hsp90beta binding partner, is accumulated in the nucl... | MODIFY | Summary: Interaction with HSP90AB1 (P08238). Bare protein binding is uninformative; the HSP90 interaction is better captured as Hsp90 protein binding. Reason: The WITH partner is HSP90AB1 (P08238); precisely captured as Hsp90 protein binding, consistent with SGTA's chaperone-binding role. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt Interacts with HSP90AB1 |
| GO:0005634 nucleus | IDA PMID:16580629 SGT, a Hsp90beta binding partner, is accumulated in the nucl... | KEEP AS NON CORE | Summary: Direct evidence for nuclear localization of SGTA (nuclear accumulation during apoptosis). Documented but secondary to cytosolic function. Reason: Nuclear pool is real (UniProt Nucleus) but non-core relative to the cytosolic co-chaperone role. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt Increased nuclear accumulation seen during cell apoptosis. |
| GO:0005737 cytoplasm | IDA PMID:16580629 SGT, a Hsp90beta binding partner, is accumulated in the nucl... | ACCEPT | Summary: Direct evidence for cytoplasmic localization of SGTA, its principal compartment. Reason: IDA-supported cytoplasm, matching UniProt; the genuine principal compartment. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9609921 | ACCEPT | Summary: Curated (Reactome) cytosolic localization, consistent with SGTA's principal compartment. Reason: Cytosol is the genuine principal compartment of SGTA; consistent with UniProt. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9617595 | ACCEPT | Summary: Curated (Reactome) cytosolic localization, consistent with SGTA's principal compartment. Reason: Cytosol is the genuine principal compartment of SGTA; consistent with UniProt. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:1904288 BAT3 complex binding | IPI PMID:23246001 SGTA recognizes a noncanonical ubiquitin-like domain in the ... | ACCEPT | 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. 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. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt Interacts with BAG6 (via ubiquitin-like domain) file:human/SGTA/SGTA-deep-research-falcon.md SGTA acts as an uncommitted client holder that can channel substrates toward either productive targeting (via TRC40) or degradation (via BAG6) |
| GO:0005515 protein binding | IPI PMID:23246001 SGTA recognizes a noncanonical ubiquitin-like domain in the ... | KEEP AS NON CORE | Summary: Interaction with UBL4A (P11441)/BAG6-complex components. Bare protein binding is uninformative; the informative term is BAG6 complex binding (also annotated). Reason: Real interaction with BAG6-complex machinery, but bare protein binding is uninformative; the specific interaction is captured by GO:1904288. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt Interacts with BAG6 (via ubiquitin-like domain) |
| GO:0005829 cytosol | IDA PMID:23246001 SGTA recognizes a noncanonical ubiquitin-like domain in the ... | ACCEPT | Summary: Direct evidence for cytosolic localization of SGTA, its principal compartment. Reason: IDA-supported cytosol, matching UniProt; the genuine principal compartment. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016020 membrane | IDA PMID:23246001 SGTA recognizes a noncanonical ubiquitin-like domain in the ... | KEEP AS NON CORE | Summary: SGTA detected at membranes, consistent with transient ER-membrane association during client delivery. Reason: Transient membrane association during TA-protein delivery; non-core relative to the cytosolic site of action. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005737 cytoplasm | IDA GO_REF:0000054 | ACCEPT | Summary: Direct evidence for cytoplasmic localization of SGTA, its principal compartment. Reason: IDA-supported cytoplasm, matching UniProt; the genuine principal compartment. Supporting Evidence: file:human/SGTA/SGTA-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
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Download this section (compressed HTML)Q: 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?
Q: How does SGTA regulation of HSC70/HSP70 ATPase activity contribute to client capture and handoff to the TRC40/GET pathway?
Q: Does the nuclear accumulation of SGTA during apoptosis reflect a distinct, chaperone-independent function?
Q: 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?
Experiment: 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.
Experiment: Quantitative ubiquitination/deubiquitination assays of a model mislocalized substrate under varying SGTA, BAG6 and RNF126 levels to map the maturation-versus-degradation equilibrium.
Experiment: Define the SGTA client repertoire by proximity labeling in cells, distinguishing bona fide TA/hydrophobic clients from high-throughput interactome noise.
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