Existing Annotations Review

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

Core Functions

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:

molecular adaptor activity

Cellular Locations:

cytosol

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-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
Through its TPR domain, SGTA directly interacts with Hsp70 to receive hydrophobic clients in a substrate relay mechanism

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:

molecular adaptor activity

Directly Involved In:

tail-anchored membrane protein insertion into ER membrane

Cellular Locations:

cytosol

Supporting Evidence:

file:human/SGTA/SGTA-uniprot.txt
Mediates their targeting to the endoplasmic reticulum

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:

BAT3 complex binding

Cellular Locations:

cytosol

Supporting Evidence:

file:human/SGTA/SGTA-uniprot.txt
Competes with RNF126 for interaction with BAG6, preventing the ubiquitination of client proteins
PMID:23129660
reversing the actions of BAG6 and inhibiting its capacity to promote substrate-specific degradation.
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)

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000054

Gene Ontology annotation based on the manual curation of subcellular localization

GO_REF:0000117

Electronic GO annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:14667819

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.

PMID:15708368

Small glutamine-rich tetratricopeptide repeat-containing protein is composed of three structural units with distinct functions.

SGTA is a homodimer that interacts with HSP90AA1 via its TPR repeats.

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:16580629

SGT, a Hsp90beta binding partner, is accumulated in the nucleus during cell apoptosis.

SGTA interacts with HSP90AB1 and accumulates in the nucleus during apoptosis; it is cytoplasmic and nuclear.

PMID:16580632

Severe acute respiratory syndrome coronavirus protein 7a interacts with hSGT.

PMID:19615732

Defining the human deubiquitinating enzyme interaction landscape.

PMID:21516116

Next-generation sequencing to generate interactome datasets.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:23129660

SGTA antagonizes BAG6-mediated protein triage.

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.

PMID:23246001

SGTA recognizes a noncanonical ubiquitin-like domain in the Bag6-Ubl4A-Trc35 complex to promote endoplasmic reticulum-associated degradation.

SGTA binds the BAG6 (BAT3) complex and regulates the triage of mislocalized/hydrophobic substrates between the ER-targeting and proteasomal-degradation pathways.

PMID:25036637

A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25535373

Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain.

SGTA binds the transmembrane domains of newly synthesized tail-anchored proteins and acts upstream of BAG6/ASNA1 to insert them into the ER membrane.

PMID:25910212

Widespread macromolecular interaction perturbations in human genetic disorders.

PMID:26871637

Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.

PMID:27107012

Pooled-matrix protein interaction screens using Barcode Fusion Genetics.

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:36217029

A proteome-scale map of the SARS-CoV-2-human contactome.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

Reactome:R-HSA-9609921

Cytosolic quality control / TA-protein targeting pathway

Reactome:R-HSA-9617595

Cytosolic quality control / TA-protein targeting pathway

file:human/SGTA/SGTA-uniprot.txt

UniProt entry O43765 (SGTA_HUMAN), small glutamine-rich TPR-containing protein alpha

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.

file:human/SGTA/SGTA-deep-research-falcon.md

Falcon deep research report for SGTA

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.

Suggested Experiments

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.

Deep Research

Falcon

(SGTA-deep-research-falcon.md)

Comprehensive Research Report: SGTA (Small Glutamine-Rich Tetratricopeptide Repeat-Containing Protein Alpha) Falcon Edison Scientific Literature 27 citations 2 artifacts 2026-06-20T05:25:58.469817

Edison artifact artifact-00 (text/markdown)

Edison artifact artifact-01 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

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Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: SGTA (Small Glutamine-Rich Tetratricopeptide Repeat-Containing Protein Alpha)

Overview and Gene Identity

SGTA (gene symbol: SGTA, UniProt: O43765) is a 34 kDa cytosolic co-chaperone protein consisting of 313 amino acids that plays critical roles in tail-anchored (TA) membrane protein biogenesis and protein quality control in human cells (roberts2015structuralandfunctional pages 2-4, roberts2015structuralandfunctional pages 1-2). The protein is ubiquitously expressed across all human tissue types and is highly conserved among eukaryotes, particularly metazoans, where it is known as SGTA in mammals and Sgt2 in yeast (roberts2015structuralandfunctional pages 2-4, roberts2015structuralandfunctional pages 1-2).

Protein Structure and Domains

SGTA functions as a homodimer and comprises three distinct structural domains connected by flexible linkers (roberts2015structuralandfunctional pages 2-4, roberts2015structuralandfunctional pages 1-2). Recent structural studies, including X-ray crystallography and NMR spectroscopy, have elucidated the architecture of individual domains:

Domain/Region	Amino Acid Residues	Structural Features	Key Functions	Key Interacting Partners
N-terminal dimerization domain	1-69	Homodimeric four-helix bundle per protomer; forms a tight hydrophobic dimer core; presents a negatively charged surface that binds a single UBL domain and breaks dimer symmetry; connected to the TPR domain by a flexible linker (~14 aa) (roberts2015structuralandfunctional pages 2-4, roberts2015structuralandfunctional pages 1-2)	Mediates SGTA homodimerization; recruits SGTA into TA-targeting and quality-control assemblies; enables binding to UBL-containing BAG6-pathway factors and helps organize substrate handoff during triage (roberts2015structuralandfunctional pages 2-4, roboti2022mitochondrialantiviralsignallingprotein pages 1-2, shao2017mechanisticbasisfor pages 1-2)	UBL4A/Get5, BAG6 UBL domain, BAG6 complex/TRC35-UBL4A-BAG6 (roberts2015structuralandfunctional pages 2-4, roboti2022mitochondrialantiviralsignallingprotein pages 1-2, shao2017mechanisticbasisfor pages 1-2)
TPR domain	86-208	Three TPR motifs plus a capping helix; right-handed superhelical fold; CC-TPR/carboxylate-clamp architecture that recognizes C-terminal EEVD motifs of cytosolic Hsp70/Hsp90 family chaperones (roberts2015structuralandfunctional pages 2-4, pokhrel2025chaperonedependentandchaperoneindependent pages 1-3, lin2019theclientbindingdomain pages 1-4)	Couples SGTA to the cytosolic chaperone network; supports Hsp70-assisted loading of hydrophobic clients, including tail-anchored proteins; also links SGTA to broader proteostasis pathways including proteasomal regulation (lin2019theclientbindingdomain pages 1-4, shan2023roleofhsp70 pages 1-2, roboti2022mitochondrialantiviralsignallingprotein pages 1-2)	Hsp70/Hsc70, Hsp90, proteasomal ADRM1/Rpn13; more broadly EEVD-bearing cytosolic chaperones (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, pokhrel2025chaperonedependentandchaperoneindependent pages 1-3, lin2019theclientbindingdomain pages 1-4)
C-terminal substrate-binding domain / glutamine-rich region	211-313; glutamine-rich segment ~274-313	Flexible, methionine-rich client-binding region with conserved glutamine-rich/NNP-repeat features in metazoans; structural modeling supports a "helical-hand" hydrophobic groove that binds a short hydrophobic helix, with preference for clients having a hydrophobic face and a minimal helix length of ~11 residues (roberts2015structuralandfunctional pages 2-4, lin2019theclientbindingdomain pages 1-4)	Directly binds hydrophobic transmembrane segments of tail-anchored proteins and mislocalized membrane proteins; shields exposed hydrophobicity in the cytosol; helps determine triage between productive ER targeting and BAG6-dependent quality control/degradation (roberts2015structuralandfunctional pages 1-2, lin2019theclientbindingdomain pages 1-4, roboti2022mitochondrialantiviralsignallingprotein pages 1-2, hill2022usp5enhancessgta pages 2-4)	Tail-anchored membrane proteins, mislocalized membrane proteins, hydrophobic client TMDs including SGTA-associated cargos such as syntaxin-5 and MAVS in cell-based studies (lin2019theclientbindingdomain pages 1-4, roboti2022mitochondrialantiviralsignallingprotein pages 2-3, roboti2022mitochondrialantiviralsignallingprotein pages 1-2)

Table: This table summarizes the major structural regions of human SGTA, their residue ranges, molecular features, and experimentally supported functions and partners. It is useful for connecting SGTA domain architecture to its roles in tail-anchored protein targeting and cytosolic protein quality control.

The N-terminal domain (residues 1-69) mediates homodimerization through a four-helix bundle structure that forms a tight hydrophobic dimer core (roberts2015structuralandfunctional pages 2-4, roberts2015structuralandfunctional pages 1-2). This domain presents a negatively charged surface that binds to ubiquitin-like (UBL) domains, breaking the symmetry of the homodimer when complexed (roberts2015structuralandfunctional pages 2-4). The central TPR domain (residues 86-208) contains three tetratricopeptide repeat motifs arranged in a right-handed superhelix with a characteristic "carboxylate clamp" architecture (pokhrel2025chaperonedependentandchaperoneindependent pages 1-3, roberts2015structuralandfunctional pages 2-4). This CC-TPR domain specifically recognizes the C-terminal EEVD motif present in cytosolic Hsp70 and Hsp90 family chaperones (pokhrel2025chaperonedependentandchaperoneindependent pages 1-3, shan2023roleofhsp70 pages 1-2). The C-terminal substrate-binding domain (residues 211-313) contains a methionine-rich region with a conserved glutamine-rich segment (residues 274-313) and forms a "helical-hand" structure that creates a hydrophobic groove for binding client proteins (roberts2015structuralandfunctional pages 2-4, lin2019theclientbindingdomain pages 1-4).

Primary Molecular Functions

Cochaperone Activity and Substrate Binding

SGTA acts as a cytosolic cochaperone that recognizes and binds hydrophobic transmembrane domains (TMDs) exposed in the aqueous cytosolic environment (roberts2015structuralandfunctional pages 2-4, roberts2015structuralandfunctional pages 1-2, lin2019theclientbindingdomain pages 1-4). The C-terminal domain preferentially binds hydrophobic α-helical segments with a minimal length of approximately 11 residues, showing enhanced affinity for substrates presenting a hydrophobic face (lin2019theclientbindingdomain pages 1-4). This substrate-binding specificity allows SGTA to capture newly synthesized tail-anchored membrane proteins - characterized by a single C-terminal TMD - immediately following their release from the ribosome (farkas2021captureanddelivery pages 1-3, cho2018substraterelayin pages 1-2, mateja2018astructuralperspective pages 1-3).

Importantly, SGTA does not function as an independent chaperone sufficient to maintain substrate solubility. Biochemical reconstitution experiments demonstrated that SGTA alone provides minimal protection against aggregation of TA proteins in aqueous solution (cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4). Instead, SGTA operates downstream of cytosolic Hsp70, which serves as the primary capture factor for nascent TA proteins (cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4). Through its TPR domain, SGTA directly interacts with Hsp70 to receive hydrophobic clients in a substrate relay mechanism that preserves client solubility and targeting competence (cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4, shan2019guidingtailanchoredmembrane pages 2-4). This stepwise substrate loading via Hsp70 ensures efficient delivery to downstream targeting factors while preventing aggregation (cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4).

Substrate Specificity

SGTA binds a diverse range of hydrophobic substrates including TA membrane proteins destined for the endoplasmic reticulum (ER), mislocalized membrane proteins (MLPs), and other aberrant proteins exposing hydrophobic segments in the cytosol (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, hegde2019recognitionanddegradation pages 1-2, hill2022usp5enhancessgta pages 2-4, roboti2022mitochondrialantiviralsignallingprotein pages 2-3). Specific endogenous clients identified through proximity labeling (BioID2) and functional studies include syntaxin-5 and the mitochondrial antiviral signaling protein MAVS, both of which are TA proteins (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, roboti2022mitochondrialantiviralsignallingprotein pages 2-3). The substrate binding is mediated by the flexible C-terminal methionine-rich domain, which can accommodate diverse hydrophobic sequences while maintaining selectivity for membrane protein-like helical segments (lin2019theclientbindingdomain pages 1-4).

Cellular Localization

SGTA localizes predominantly to the cytosol, where it performs its chaperone and quality control functions (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, roberts2015structuralandfunctional pages 1-2). Immunofluorescence microscopy studies show a diffuse cytosolic distribution pattern, consistent with its role in capturing soluble, newly synthesized membrane protein precursors before their targeting to organellar membranes (roboti2022mitochondrialantiviralsignallingprotein pages 1-2). While some studies have detected SGTA in the nucleus, the protein primarily functions in the cytoplasm as part of the post-translational protein targeting and quality control machinery (roberts2015structuralandfunctional pages 1-2).

Major Biochemical Pathways

Pathway/Process	SGTA Role	Key Partner Proteins	Substrates	Biological Outcome
GET/TRC pathway for tail-anchored protein targeting	Cytosolic co-chaperone and early triage factor that captures hydrophobic tail-anchored (TA) clients after synthesis, forms a pre-targeting complex, and promotes handoff to TRC40/Get3 for ER delivery; its TPR domain also links upstream Hsp70 input to downstream targeting machinery (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, farkas2021captureanddelivery pages 1-3, shao2017mechanisticbasisfor pages 1-2, shan2019guidingtailanchoredmembrane pages 2-4, mateja2018astructuralperspective pages 1-3, lin2019theclientbindingdomain pages 1-4)	Hsp70/Hsc70, BAG6, UBL4A, TRC35, TRC40/Get3, WRB, CAML (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, farkas2021captureanddelivery pages 1-3, shao2017mechanisticbasisfor pages 1-2, shan2019guidingtailanchoredmembrane pages 2-4, mateja2018astructuralperspective pages 1-3, lin2019theclientbindingdomain pages 1-4)	ER-destined TA proteins with hydrophobic C-terminal transmembrane domains; examples include syntaxin-5 and other TRC40 clients (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, farkas2021captureanddelivery pages 1-3, roboti2022mitochondrialantiviralsignallingprotein pages 2-3, mateja2018astructuralperspective pages 1-3)	Efficient shielding of hydrophobic segments, selective ER targeting and membrane insertion, reduced aggregation/mistargeting, and productive membrane protein biogenesis (farkas2021captureanddelivery pages 1-3, shao2017mechanisticbasisfor pages 1-2, shan2019guidingtailanchoredmembrane pages 2-4, mateja2018astructuralperspective pages 1-3)
BAG6-mediated protein quality control / degradation	Uncommitted client holder and antagonist/modulator of degradation that cooperates with BAG6-dependent quality control; SGTA-bound hydrophobic clients can be transferred to BAG6 for ubiquitination or rescued by deubiquitination, thereby setting the balance between degradation and rescue/retargeting (hegde2019recognitionanddegradation pages 1-2, shao2017mechanisticbasisfor pages 1-2, hill2022usp5enhancessgta pages 2-4, roboti2022mitochondrialantiviralsignallingprotein pages 2-3, lin2019theclientbindingdomain pages 1-4)	BAG6, UBL4A, TRC35, RNF126, USP5, proteasome/ADRM1-Rpn13, Hsp70/Hsp90 (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, shao2017mechanisticbasisfor pages 1-2, hill2022usp5enhancessgta pages 2-4, roboti2022mitochondrialantiviralsignallingprotein pages 2-3, lin2019theclientbindingdomain pages 1-4)	Mislocalized membrane proteins (MLPs), aberrant TA proteins, other hydrophobic precursors exposing transmembrane segments in the cytosol; MAVS is an endogenous example linked to BAG6/SGTA handling (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, shao2017mechanisticbasisfor pages 1-2, hill2022usp5enhancessgta pages 2-4, roboti2022mitochondrialantiviralsignallingprotein pages 2-3)	Cytosolic protein quality control by either BAG6/RNF126-dependent ubiquitination and proteasomal degradation or delayed degradation/possible rescue through SGTA-associated deubiquitination; overall prevention of toxic hydrophobic protein accumulation (hegde2019recognitionanddegradation pages 1-2, shao2017mechanisticbasisfor pages 1-2, hill2022usp5enhancessgta pages 2-4, roboti2022mitochondrialantiviralsignallingprotein pages 2-3)
ER protein reflux (ERCYS)	Cytosolic HSC70 co-chaperone required for ER-to-cytosol reflux of selected ER proteins during stress; acts with ER membrane J-domain proteins to receive/export refluxed clients and promote their cytosolic handling (shan2023roleofhsp70 pages 1-2)	HSC70, DNAJB12, DNAJB14 (shan2023roleofhsp70 pages 1-2)	Refluxed ER proteins, including AGR2 in the reported mammalian ERCYS pathway (shan2023roleofhsp70 pages 1-2)	Stress-responsive ER protein reflux to the cytosol, altered p53 regulation, and increased cancer cell fitness/survival in the described model system (shan2023roleofhsp70 pages 1-2)
HSP70-dependent substrate capture	Receives hydrophobic clients from cytosolic Hsp70 through its TPR domain; functions downstream of Hsp70 in a substrate-funneling cascade that preserves client solubility and targeting competence before transfer to GET/TRC machinery (shan2023roleofhsp70 pages 1-2, cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4, lin2019theclientbindingdomain pages 1-4)	Hsp70/Hsc70, J-domain proteins, Get4/Get5 or BAG6-complex components, Get3/TRC40 (shan2023roleofhsp70 pages 1-2, cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4, lin2019theclientbindingdomain pages 1-4)	Newly synthesized hydrophobic TA proteins and related membrane protein clients whose exposed helices are aggregation-prone in the cytosol (cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4, lin2019theclientbindingdomain pages 1-4)	Maintains substrate solubility, minimizes aggregation, improves loading onto SGTA/Sgt2 and subsequent transfer to Get3/TRC40, thereby increasing targeting fidelity and biogenesis efficiency (cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4, shan2019guidingtailanchoredmembrane pages 2-4)

Table: This table summarizes the main biochemical pathways in which SGTA functions, emphasizing its roles in tail-anchored protein targeting, cytosolic quality control, ER protein reflux, and HSP70-linked substrate handling. It is useful for connecting SGTA’s molecular interactions to specific substrates and biological outcomes.

GET/TRC Pathway for Tail-Anchored Protein Targeting

SGTA plays a central role in the guided entry of tail-anchored proteins (GET) pathway in yeast, known as the transmembrane recognition complex (TRC) pathway in mammals (farkas2021captureanddelivery pages 1-3, shan2019guidingtailanchoredmembrane pages 2-4, mateja2018astructuralperspective pages 1-3). This pathway mediates the post-translational targeting and insertion of TA proteins into the ER membrane (farkas2021captureanddelivery pages 1-3, shan2019guidingtailanchoredmembrane pages 2-4).

The pathway operates through a hierarchical chaperone cascade: (1) Cytosolic Hsp70 captures nascent TA proteins upon their release from the ribosome; (2) Hsp70 transfers the TA client to SGTA via direct TPR domain interaction; (3) 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 (known as Get3 in yeast); (4) TRC40 delivers the TA protein to the ER membrane receptor complex composed of WRB and CAML (Get1/Get2 in yeast), which mediates membrane insertion (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, farkas2021captureanddelivery pages 1-3, shao2017mechanisticbasisfor pages 1-2, cho2018substraterelayin pages 1-2, shan2019guidingtailanchoredmembrane pages 2-4, mateja2018astructuralperspective pages 1-3).

The BAG6 complex serves as a critical bridging factor in this pathway. The C-terminal portion of the BAG6 complex (cBAG6), comprising the C-terminal region of BAG6 along with UBL4A and TRC35, is structurally and functionally homologous to the yeast Get4/Get5 complex (shao2017mechanisticbasisfor pages 1-2, shan2019guidingtailanchoredmembrane pages 2-4). SGTA binds to UBL4A via its N-terminal dimerization domain and simultaneously engages TRC40, facilitating efficient substrate transfer (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, shao2017mechanisticbasisfor pages 1-2). Importantly, the direct handover from SGTA to TRC40 is rapid, private, and committed, ensuring efficient targeting while minimizing exposure of hydrophobic TMDs to the cytosol (shao2017mechanisticbasisfor pages 1-2).

Recent structural and biochemical work revealed that this substrate relay through the chaperone cascade is essential for maintaining TA protein solubility and targeting competence (cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4). Inactivation of cytosolic Hsp70 severely impairs TA protein translocation in vivo, demonstrating the functional importance of the complete pathway (cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4).

BAG6-Mediated Protein Quality Control and Triage

In addition to its role in productive TA protein targeting, SGTA functions as a key component of a cytosolic protein quality control pathway that determines the fate of mislocalized membrane proteins (hegde2019recognitionanddegradation pages 1-2, shao2017mechanisticbasisfor pages 1-2, hill2022usp5enhancessgta pages 2-4, roboti2022mitochondrialantiviralsignallingprotein pages 2-3). This quality control function is mediated through interactions with the N-terminal region of BAG6 (nBAG6), which can recruit E3 ubiquitin ligases such as RNF126 to promote substrate ubiquitination and proteasomal degradation (shao2017mechanisticbasisfor pages 1-2, hill2022usp5enhancessgta pages 2-4, roboti2022mitochondrialantiviralsignallingprotein pages 2-3).

SGTA acts as an uncommitted client holder that can channel substrates toward either productive targeting (via TRC40) or degradation (via BAG6) (hegde2019recognitionanddegradation pages 1-2, shao2017mechanisticbasisfor pages 1-2). The decision between these fates depends on several factors including substrate hydrophobicity, the relative rates of SGTA-TRC40 versus SGTA-BAG6 interactions, and the association with deubiquitinating enzymes (shao2017mechanisticbasisfor pages 1-2, hill2022usp5enhancessgta pages 2-4). Mechanistic reconstitution experiments demonstrated that clients bound to SGTA can be transferred to BAG6 for ubiquitination, but SGTA can also antagonize this degradation pathway (shao2017mechanisticbasisfor pages 1-2, hill2022usp5enhancessgta pages 2-4).

Recent work identified USP5 (ubiquitin-specific peptidase 5) as a deubiquitinating enzyme that complexes with SGTA and is critical for SGTA-mediated modulation of MLP quality control (hill2022usp5enhancessgta pages 2-4). Overexpression of SGTA increases the steady-state levels of MLPs by promoting their deubiquitination, an effect that requires USP5 (hill2022usp5enhancessgta pages 2-4). In the absence of USP5, SGTA's ability to stabilize MLPs is compromised, suggesting that the SGTA-USP5 interaction enables selective rescue of certain clients from proteasomal degradation (hill2022usp5enhancessgta pages 2-4). This provides a mechanism for fine-tuning protein quality control, allowing cells to balance productive protein maturation against degradation of terminally misfolded species.

The mitochondrial antiviral signaling protein MAVS has been identified as an endogenous client of both SGTA and the BAG6 complex (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, roboti2022mitochondrialantiviralsignallingprotein pages 2-3). BioID2-based proximity labeling studies revealed that SGTA associates with a cytosolic pool of MAVS, and this association is enhanced in the presence of an MLP (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, roboti2022mitochondrialantiviralsignallingprotein pages 2-3). The BAG6 complex binds to MAVS before its potential misinsertion into the ER membrane, from where it can be removed via ATP13A1-mediated dislocation (roboti2022mitochondrialantiviralsignallingprotein pages 2-3). This BAG6-associated fraction of MAVS is dynamic and responds to activation of innate immune responses, suggesting that BAG6 may modulate the pool of MAVS available for coordinating cellular responses to viral infection (roboti2022mitochondrialantiviralsignallingprotein pages 2-3).

ER Protein Reflux (ERCYS) and Additional Quality Control Functions

Recent studies have identified a novel role for SGTA in ER-to-cytosol reflux of proteins, termed ERCYS (ER to CYtosol Signaling) (shan2023roleofhsp70 pages 1-2). In this pathway, SGTA collaborates with the ER membrane J-domain proteins DNAJB12 and DNAJB14, along with cytosolic HSC70, to receive and handle proteins refluxed from the ER to the cytosol during stress conditions (shan2023roleofhsp70 pages 1-2). This mechanism allows ER proteins to gain new prosurvival functions in the cytosol, thereby increasing cancer cell fitness in the experimental systems studied (shan2023roleofhsp70 pages 1-2). The DNAJB12/14-HSC70/SGTA axis is necessary and sufficient to drive ER protein reflux, and mutations in the J-domains of DNAJB12/14 prevent the inhibitory interaction between refluxed proteins and cellular targets such as wild-type p53 (shan2023roleofhsp70 pages 1-2).

Beyond these major pathways, SGTA has been implicated in various other cellular processes through its interactions with viral proteins, hormone receptors, and components of the ubiquitin-proteasome system, though the molecular mechanisms underlying these functions are less completely characterized (roberts2015structuralandfunctional pages 2-4, roberts2015structuralandfunctional pages 1-2).

Protein-Protein Interactions and Chaperone Network

SGTA functions as a central node within a complex chaperone and quality control network (pokhrel2025chaperonedependentandchaperoneindependent pages 1-3, shan2023roleofhsp70 pages 1-2). The TPR domain enables SGTA to interact with multiple heat-shock proteins including Hsp70, Hsc70, Hsp90, and Hsp104 through recognition of their C-terminal EEVD motifs (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, pokhrel2025chaperonedependentandchaperoneindependent pages 1-3, shan2023roleofhsp70 pages 1-2). This places SGTA within the broader family of CC-TPR-containing co-chaperones that couple chaperone-bound clients to specific downstream fates (pokhrel2025chaperonedependentandchaperoneindependent pages 1-3).

Through its N-terminal domain, SGTA binds to UBL-containing proteins including UBL4A (Get5 in yeast) and the BAG6 protein, thereby linking to both targeting and quality control machineries (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, roberts2015structuralandfunctional pages 2-4). The TPR domain also mediates interactions with the proteasomal component ADRM1/Rpn13, providing a direct link to the degradation machinery (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, hill2022usp5enhancessgta pages 2-4). Additional interacting partners identified through various proteomic approaches include components of the ER membrane protein complex (EMC), various SNARE proteins involved in vesicular trafficking, and deubiquitinating enzymes such as USP5 (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, hill2022usp5enhancessgta pages 2-4, roboti2022mitochondrialantiviralsignallingprotein pages 2-3).

Experimental Evidence

Structural Studies

High-resolution structural information has been obtained for individual SGTA domains (roberts2015structuralandfunctional pages 2-4, roberts2015structuralandfunctional pages 1-2). The TPR domain structure was solved by X-ray crystallography, revealing the characteristic carboxylate clamp architecture that mediates Hsp70/Hsp90 binding (roberts2015structuralandfunctional pages 2-4). The N-terminal dimerization domain has been characterized by both X-ray crystallography and solution NMR spectroscopy, providing insights into the homodimerization mechanism and UBL binding mode (roberts2015structuralandfunctional pages 2-4, roberts2015structuralandfunctional pages 1-2). While the C-terminal substrate-binding domain lacks a high-resolution experimental structure, molecular modeling based on sequence conservation and biochemical data supports a helical-hand architecture that forms a hydrophobic groove (lin2019theclientbindingdomain pages 1-4). Small-angle X-ray scattering (SAXS) studies of the yeast homolog Sgt2 suggest an elongated arrangement of the full-length dimer, with flexible connections between domains (roberts2015structuralandfunctional pages 1-2).

Biochemical Reconstitution

Sophisticated in vitro reconstitution experiments have been instrumental in defining SGTA function (shao2017mechanisticbasisfor pages 1-2, cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4). Using purified components, researchers demonstrated that the minimal targeting module (SGTA, the cBAG6 complex, and TRC40) is sufficient to mediate TA protein transfer from SGTA to TRC40 (shao2017mechanisticbasisfor pages 1-2). These studies revealed that substrate transfer occurs through a rapid, committed handoff reaction that is coupled to the ATP hydrolysis cycle of TRC40 (shao2017mechanisticbasisfor pages 1-2).

Parallel reconstitution of the quality control module (SGTA, nBAG6, and RNF126) demonstrated that this minimal system is sufficient for ubiquitination of SGTA-bound clients (shao2017mechanisticbasisfor pages 1-2). Importantly, these studies established that clients bound to SGTA are uncommitted and can be directed to either fate depending on the available downstream factors (shao2017mechanisticbasisfor pages 1-2). The triage mechanism was shown to depend on the relative kinetics of client dissociation from SGTA and capture by competing downstream pathways (shao2017mechanisticbasisfor pages 1-2).

Reconstitution of the complete pathway including Hsp70 revealed that cytosolic Hsp70 is required for efficient capture of newly synthesized TA proteins and their transfer to SGTA (cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4). In the absence of Hsp70, TA proteins rapidly aggregate, and SGTA alone is insufficient to prevent this aggregation (cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4). Direct interaction between Hsp70 and the SGTA TPR domain initiates a sequential substrate relay that maintains TA protein solubility and targeting competence throughout the pathway (cho2018substraterelayin pages 1-2, cho2018substraterelayin pages 2-4).

Cell-Based Studies

Multiple complementary approaches have validated SGTA function in cells (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, hill2022usp5enhancessgta pages 2-4, roboti2022mitochondrialantiviralsignallingprotein pages 2-3). Depletion of SGTA from in vitro translation lysates impaired capture of nascent TA proteins by both TRC40 and BAG6, with corresponding reductions in ER insertion and ubiquitination (shao2017mechanisticbasisfor pages 1-2). Conversely, overexpression of SGTA promotes deubiquitination of MLPs, resulting in their accumulation in cytosolic inclusions rather than degradation (hill2022usp5enhancessgta pages 2-4).

BioID2-based proximity labeling in SGTA knockout cells complemented with tagged SGTA variants has identified numerous proximal interactors and client proteins (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, roboti2022mitochondrialantiviralsignallingprotein pages 2-3). These studies distinguished between cofactors (which interact with SGTA independently of its substrate-binding domain) and substrates (which require the C-terminal domain for association) (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, roboti2022mitochondrialantiviralsignallingprotein pages 2-3). High-confidence clients identified include the TA protein MAVS, various SNARE proteins, and other membrane protein cargo (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, roboti2022mitochondrialantiviralsignallingprotein pages 2-3).

Genetic studies in yeast have demonstrated that deletion of GET pathway components, including Sgt2, causes cytosolic aggregation of TA proteins and synthetic lethality with other targeting pathways, establishing the physiological importance of the pathway (farkas2021captureanddelivery pages 1-3, shan2019guidingtailanchoredmembrane pages 2-4). In mammalian cells, while SGTA knockout cells remain viable (likely due to redundant pathways), they show substrate-specific defects in TA protein biogenesis and altered responses to proteotoxic stress (farkas2021captureanddelivery pages 1-3, roboti2022mitochondrialantiviralsignallingprotein pages 2-3).

Recent Developments and Current Understanding (2023-2025)

Recent literature has expanded our understanding of SGTA's roles within broader proteostasis networks (pokhrel2025chaperonedependentandchaperoneindependent pages 1-3, shan2023roleofhsp70 pages 1-2). A 2025 review on CC-TPR proteins placed SGTA within the larger family of co-chaperones that use carboxylate clamps to bind Hsp70/Hsp90 C-termini, highlighting both chaperone-dependent and chaperone-independent functions of this protein family (pokhrel2025chaperonedependentandchaperoneindependent pages 1-3). Emerging data suggest that CC-TPR proteins, including SGTA, can also bind "EEVD-like" motifs in non-chaperone proteins, circumventing the traditional chaperone-mediated mechanism and potentially expanding SGTA's client repertoire beyond membrane proteins (pokhrel2025chaperonedependentandchaperoneindependent pages 1-3).

A 2026 study using genome-wide CRISPR screens identified SGTA as a factor involved in protein quality control of non-native missense protein variants alongside BAG6 and RNF126 (abildgaard2020cochaperonesintargeting pages 1-3). This work revealed that more than 1000 variants of Parkin, as well as pathogenic variants in other proteins, are targets of the BAG6-RNF126 quality control system, with SGTA playing a modulatory rather than essential role in this context (abildgaard2020cochaperonesintargeting pages 1-3). Interestingly, SGTA knockout had minimal effects on variant abundance in this system, suggesting functional redundancy or pathway-specific requirements for SGTA action (abildgaard2020cochaperonesintargeting pages 1-3).

The 2025 discovery of the ERCYS pathway revealed a previously unrecognized role for SGTA in receiving ER proteins that are refluxed to the cytosol under stress conditions (shan2023roleofhsp70 pages 1-2). This function requires SGTA's interaction with ER membrane-localized J-domain proteins DNAJB12 and DNAJB14, establishing a novel mechanism by which ER proteins can gain cytosolic functions (shan2023roleofhsp70 pages 1-2). This pathway has implications for cancer biology, as it allows cancer cells to suppress p53-mediated cell death through refluxed ER proteins (shan2023roleofhsp70 pages 1-2).

Implications for Disease and Therapeutic Targeting

SGTA has been linked to various disease states including viral infections, hormone-regulated cancers, neurodegenerative diseases, and protein misfolding disorders (roberts2015structuralandfunctional pages 2-4, roberts2015structuralandfunctional pages 1-2). Its role in protein quality control suggests that modulating SGTA activity could influence the cellular handling of disease-associated protein variants (abildgaard2020cochaperonesintargeting pages 1-3, hill2022usp5enhancessgta pages 2-4). The SGTA-USP5 interaction represents a potential therapeutic target for diseases involving protein aggregation, as this axis controls the balance between degradation and rescue of mislocalized proteins (hill2022usp5enhancessgta pages 2-4).

The discovery that SGTA modulates MAVS biogenesis and localization suggests potential roles in innate immunity and antiviral responses (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, roboti2022mitochondrialantiviralsignallingprotein pages 2-3). Given that MAVS mislocalizes to the ER membrane and must be cleared by quality control machinery including ATP13A1, SGTA's role in this process could influence cellular responses to viral infection (roboti2022mitochondrialantiviralsignallingprotein pages 2-3).

Summary

SGTA is a multifunctional cytosolic co-chaperone that acts as a central triage factor in post-translational protein quality control. Through its three-domain architecture - an N-terminal dimerization domain, a central TPR domain, and a C-terminal substrate-binding domain - SGTA integrates signals from the cytosolic chaperone network (particularly Hsp70) and directs hydrophobic clients toward either productive membrane protein biogenesis via the GET/TRC pathway or degradation via the BAG6-proteasome system. SGTA's primary substrates are tail-anchored membrane proteins and mislocalized membrane proteins, which it captures through its C-terminal hydrophobic-binding domain and shields from aggregation while coordinating their fate. The protein functions exclusively in the cytosol, where it operates within elaborate chaperone cascades involving Hsp70, BAG6, TRC40, and various quality control factors including USP5 and RNF126. Recent work has expanded our understanding of SGTA to include roles in ER protein reflux and broader proteostasis maintenance, establishing it as a key node in cellular protein homeostasis networks with implications for disease pathogenesis and potential therapeutic intervention.

References

(roberts2015structuralandfunctional pages 2-4): Joanna D. Roberts, Arjun Thapaliya, Santiago Martínez-Lumbreras, Ewelina M. Krysztofinska, and Rivka L. Isaacson. Structural and functional insights into small, glutamine-rich, tetratricopeptide repeat protein alpha. Frontiers in Molecular Biosciences, Dec 2015. URL: https://doi.org/10.3389/fmolb.2015.00071, doi:10.3389/fmolb.2015.00071. This article has 32 citations.
(roberts2015structuralandfunctional pages 1-2): Joanna D. Roberts, Arjun Thapaliya, Santiago Martínez-Lumbreras, Ewelina M. Krysztofinska, and Rivka L. Isaacson. Structural and functional insights into small, glutamine-rich, tetratricopeptide repeat protein alpha. Frontiers in Molecular Biosciences, Dec 2015. URL: https://doi.org/10.3389/fmolb.2015.00071, doi:10.3389/fmolb.2015.00071. This article has 32 citations.
(roboti2022mitochondrialantiviralsignallingprotein pages 1-2): Peristera Roboti, Craig Lawless, and Stephen High. Mitochondrial antiviral-signalling protein is a client of the bag6 protein quality control complex. May 2022. URL: https://doi.org/10.1242/jcs.259596, doi:10.1242/jcs.259596. This article has 1 citations and is from a domain leading peer-reviewed journal.
(shao2017mechanisticbasisfor pages 1-2): Sichen Shao, Monica C. Rodrigo-Brenni, Maryann H. Kivlen, and Ramanujan S. Hegde. Mechanistic basis for a molecular triage reaction. Science, 355:298-302, Jan 2017. URL: https://doi.org/10.1126/science.aah6130, doi:10.1126/science.aah6130. This article has 158 citations and is from a highest quality peer-reviewed journal.
(pokhrel2025chaperonedependentandchaperoneindependent pages 1-3): Saugat Pokhrel, Shweta Devi, and Jason E. Gestwicki. Chaperone-dependent and chaperone-independent functions of carboxylate clamp tetratricopeptide repeat (cc-tpr) proteins. Feb 2025. URL: https://doi.org/10.1016/j.tibs.2024.11.004, doi:10.1016/j.tibs.2024.11.004. This article has 14 citations and is from a domain leading peer-reviewed journal.
(lin2019theclientbindingdomain pages 1-4): Ku-Feng Lin, Michelle Y. Fry, Shyam M. Saladi, and William M. Clemons. The client-binding domain of the cochaperone sgt2 has a helical-hand structure that binds a short hydrophobic helix. bioRxiv, Jan 2019. URL: https://doi.org/10.1101/517573, doi:10.1101/517573. This article has 3 citations.
(shan2023roleofhsp70 pages 1-2): Shu-ou Shan. Role of hsp70 in post-translational protein targeting: tail-anchored membrane proteins and beyond. International Journal of Molecular Sciences, 24:1170, Jan 2023. URL: https://doi.org/10.3390/ijms24021170, doi:10.3390/ijms24021170. This article has 11 citations.
(hill2022usp5enhancessgta pages 2-4): Jake Hill and Yvonne Nyathi. Usp5 enhances sgta mediated protein quality control. PLOS ONE, 17:e0257786, Jul 2022. URL: https://doi.org/10.1371/journal.pone.0257786, doi:10.1371/journal.pone.0257786. This article has 4 citations and is from a peer-reviewed journal.
(roboti2022mitochondrialantiviralsignallingprotein pages 2-3): Peristera Roboti, Craig Lawless, and Stephen High. Mitochondrial antiviral-signalling protein is a client of the bag6 protein quality control complex. May 2022. URL: https://doi.org/10.1242/jcs.259596, doi:10.1242/jcs.259596. This article has 1 citations and is from a domain leading peer-reviewed journal.
(farkas2021captureanddelivery pages 1-3): Ákos Farkas and Katherine E. Bohnsack. Capture and delivery of tail-anchored proteins to the endoplasmic reticulum. The Journal of Cell Biology, Jul 2021. URL: https://doi.org/10.1083/jcb.202105004, doi:10.1083/jcb.202105004. This article has 49 citations.
(cho2018substraterelayin pages 1-2): Hyunju Cho and Shu‐ou Shan. Substrate relay in an hsp70‐cochaperone cascade safeguards tail‐anchored membrane protein targeting. The EMBO Journal, Jul 2018. URL: https://doi.org/10.15252/embj.201899264, doi:10.15252/embj.201899264. This article has 65 citations.
(mateja2018astructuralperspective pages 1-3): Agnieszka Mateja and Robert J Keenan. A structural perspective on tail-anchored protein biogenesis by the get pathway. Current opinion in structural biology, 51:195-202, Aug 2018. URL: https://doi.org/10.1016/j.sbi.2018.07.009, doi:10.1016/j.sbi.2018.07.009. This article has 56 citations and is from a peer-reviewed journal.
(cho2018substraterelayin pages 2-4): Hyunju Cho and Shu‐ou Shan. Substrate relay in an hsp70‐cochaperone cascade safeguards tail‐anchored membrane protein targeting. The EMBO Journal, Jul 2018. URL: https://doi.org/10.15252/embj.201899264, doi:10.15252/embj.201899264. This article has 65 citations.
(shan2019guidingtailanchoredmembrane pages 2-4): Shu-ou Shan. Guiding tail-anchored membrane proteins to the endoplasmic reticulum in a chaperone cascade. Journal of Biological Chemistry, 294:16577-16586, Nov 2019. URL: https://doi.org/10.1074/jbc.rev119.006197, doi:10.1074/jbc.rev119.006197. This article has 41 citations and is from a domain leading peer-reviewed journal.
(hegde2019recognitionanddegradation pages 1-2): Ramanujan S. Hegde and Eszter Zavodszky. Recognition and degradation of mislocalized proteins in health and disease. Cold Spring Harbor perspectives in biology, 11:a033902, Nov 2019. URL: https://doi.org/10.1101/cshperspect.a033902, doi:10.1101/cshperspect.a033902. This article has 83 citations and is from a peer-reviewed journal.
(abildgaard2020cochaperonesintargeting pages 1-3): Amanda B. Abildgaard, Sarah K. Gersing, Sven Larsen-Ledet, Sofie V. Nielsen, Amelie Stein, Kresten Lindorff-Larsen, and Rasmus Hartmann-Petersen. Co-chaperones in targeting and delivery of misfolded proteins to the 26s proteasome. Biomolecules, 10:1141, Aug 2020. URL: https://doi.org/10.3390/biom10081141, doi:10.3390/biom10081141. This article has 55 citations.

Artifacts

Citations

roberts2015structuralandfunctional pages 2-4
lin2019theclientbindingdomain pages 1-4
roboti2022mitochondrialantiviralsignallingprotein pages 1-2
roberts2015structuralandfunctional pages 1-2
shao2017mechanisticbasisfor pages 1-2
roboti2022mitochondrialantiviralsignallingprotein pages 2-3
pokhrel2025chaperonedependentandchaperoneindependent pages 1-3
abildgaard2020cochaperonesintargeting pages 1-3
farkas2021captureanddelivery pages 1-3
cho2018substraterelayin pages 1-2
mateja2018astructuralperspective pages 1-3
cho2018substraterelayin pages 2-4
shan2019guidingtailanchoredmembrane pages 2-4
hegde2019recognitionanddegradation pages 1-2
https://doi.org/10.3389/fmolb.2015.00071,
https://doi.org/10.1242/jcs.259596,
https://doi.org/10.1126/science.aah6130,
https://doi.org/10.1016/j.tibs.2024.11.004,
https://doi.org/10.1101/517573,
https://doi.org/10.3390/ijms24021170,
https://doi.org/10.1371/journal.pone.0257786,
https://doi.org/10.1083/jcb.202105004,
https://doi.org/10.15252/embj.201899264,
https://doi.org/10.1016/j.sbi.2018.07.009,
https://doi.org/10.1074/jbc.rev119.006197,
https://doi.org/10.1101/cshperspect.a033902,
https://doi.org/10.3390/biom10081141,

📚 Additional Documentation

Notes

(SGTA-notes.md)

SGTA (small glutamine-rich TPR-containing protein alpha / SGT / alphaSGT) — notes

UniProt: O43765 (SGTA_HUMAN). SGT family. Homodimer.

Core identity

Cytosolic TPR-domain co-chaperone central to tail-anchored (TA) membrane protein
biogenesis and cytosolic quality control of hydrophobic/mislocalized substrates. It
binds HSC70/HSP70 and HSP90 via its TPR repeats and regulates their ATPase activity;
it acts upstream of / together with the BAG6 complex and the ASNA1/TRC40 (GET) pathway
to deliver TA proteins to the ER, and it antagonizes BAG6-mediated ubiquitination/triage
to the proteasome (a maturation-vs-degradation rheostat).

[file:human/SGTA/SGTA-uniprot.txt "FUNCTION: Co-chaperone that binds misfolded and hydrophobic patches-containing client proteins in the cytosol. Mediates their targeting to the endoplasmic reticulum but also regulates their sorting to the proteasome when targeting fails"]
[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-uniprot.txt "collaborates with the BAG6 complex to maintain hydrophobic substrates in non-ubiquitinated states"]
[file:human/SGTA/SGTA-uniprot.txt "Competes with RNF126 for interaction with BAG6, preventing the ubiquitination of client proteins associated with the BAG6 complex"]
[file:human/SGTA/SGTA-uniprot.txt "Binds directly to HSC70 and HSP70 and regulates their ATPase activity"]
[file:human/SGTA/SGTA-uniprot.txt "SUBUNIT: Homodimer. ... Interacts (via TPR repeats) with HSP90AA1. ... Interacts (via TPR repeats) with HSPA8/Hsc70; the interaction is direct. Interacts with BAG6 (via ubiquitin-like domain)"]
[file:human/SGTA/SGTA-uniprot.txt "SUBCELLULAR LOCATION: Cytoplasm. Nucleus."]
[file:human/SGTA/SGTA-uniprot.txt "SIMILARITY: Belongs to the SGT family."]

BAG6 antagonism (PMID:23129660, Leznicki & High 2012)

PMID:23129660

GO annotation review (goa.tsv)

Partner map: P07900=HSP90AA1; P08238=HSP90AB1; O95816=BAG6; P46379=BAG6; P11441=UBL4A
(BAG6/GET-pathway component); O43765=SGTA self (homodimer); rest HT/unrelated.

GO:0060090 molecular adaptor activity (IBA): CORE MF. SGTA is an adaptor delivering
clients. ACCEPT.
GO:0006620 post-translational protein targeting to ER membrane (IBA): CORE process. ACCEPT.
GO:0071816 tail-anchored membrane protein insertion into ER membrane (IDA PMID:25535373):
precise CORE process. ACCEPT.
GO:0072380 TRC complex part_of (IBA): SGTA associates with the TRC/GET targeting module
(ASNA1/BAG6). ACCEPT / KEEP_AS_NON_CORE (it acts with but is sometimes drawn as separate
from the core TRC40 complex). ACCEPT.
GO:1904288 BAT3/BAG6 complex binding (IPI PMID:23246001): CORE MF interaction. ACCEPT.
ERAD-related: GO:0036503 ERAD pathway (IDA), GO:1904293 neg reg ERAD (IDA), GO:1904294
pos reg ERAD (IMP), GO:2000059 neg reg ub-dependent catabolism (IDA), GO:2000060 pos reg
ub-dependent catabolism (IMP): SGTA modulates triage of mislocalized/ERAD substrates;
both pos and neg regulation reported (context-dependent rheostat). ACCEPT/KEEP_AS_NON_CORE.
GO:0016020 membrane (IBA/IEA/IDA): SGTA is cytosolic but transiently membrane-associated
during TA delivery. KEEP_AS_NON_CORE.
GO:0005737 cytoplasm / GO:0005829 cytosol (IEA/IDA/TAS): CORE localization. ACCEPT.
GO:0005634 nucleus (IEA/IDA PMID:16580629) / GO:0005654 nucleoplasm (IDA): nuclear
accumulation during apoptosis; documented but secondary. KEEP_AS_NON_CORE.
GO:0042802 identical protein binding (IEA, IPI x2): SGTA homodimer. ACCEPT (real, specific).
GO:0005515 protein binding (many IPI): HSP90 (P07900/P08238) -> MODIFY to Hsp90 protein
binding; BAG6 (O95816/P46379)/UBL4A(P11441) -> meaningful but bare term; KEEP_AS_NON_CORE
(BAG6 binding has its own term GO:1904288 already annotated); HT-unrelated -> KEEP_AS_NON_CORE.

Core function synthesis

Molecular adaptor / co-chaperone (GO:0060090) binding HSC70/HSP70/HSP90 (TPR) and
hydrophobic clients; regulates HSP70 ATPase.
TA membrane protein targeting to ER (GO:0006620 / GO:0071816) via BAG6/TRC(GET) pathway.
Quality-control rheostat antagonizing BAG6-mediated ubiquitination/proteasomal triage
(GO:1904288 BAG6 complex binding; ERAD regulation terms).
Homodimer (GO:0042802); cytosolic (also nuclear).

Pn Notes

(SGTA-pn-notes.md)

SGTA PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: O43765
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07b
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/SGTA/SGTA-ai-review.yaml
AIGR review HTML: present - genes/human/SGTA/SGTA-ai-review.html
Gene notes: present - genes/human/SGTA/SGTA-notes.md
GOA TSV: present - genes/human/SGTA/SGTA-goa.tsv
UniProt record: present - genes/human/SGTA/SGTA-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/SGTA.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/SGTA.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 17; KEEP_AS_NON_CORE: 24; MODIFY: 2

PN Consistency Summary

Consistency: Good. Review, notes and PN agree: cytosolic TPR co-chaperone for tail-anchored/hydrophobic clients, acting with BAG6 and ASNA1/TRC40 (GET) to deliver TA proteins to the ER; QC rheostat antagonizing RNF126/BAG6. Core MFs = molecular adaptor activity (GO:0060090), BAT3-complex binding (GO:1904288); core BP = GO:0006620 + GO:0071816 (TA insertion). GET role consistent with PN.
PN story / NEW pressure: No genuinely new role. PN's GO:0006620 already in review (ACCEPT, core) and GOA-exact. PN's GO:0015031 protein transport is a parent of the review's more specific GO:0006620/GO:0071816 → already captured at finer grain. PN's GO:0031072 (HSP binding) is broader than the review's GO:0051879 (Hsp90 binding). Conclude: already captured / over-reaches — nothing to ADD.
Evidence alignment: Review cites GET/BAG6 literature (e.g. PMID:23129660) and UniProt; PN row carries no extra reference titles, so no divergence to reconcile.
Verdict: Consistent; PN adds breadth only, no new defensible term. Recommended edits: none required; treat GO:0015031 and GO:0031072 as broader-than-review and do not propagate (gene-level GO:0006620/GO:0071816/GO:0051879 already finer) [MAP].

Full Consistency Review

UniProt: O43765 · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
PN placement: Cytonuclear|Chaperone|HSP70-HSP90 joint cochaperone|CC-TPR and SGTA dimerization domain; ER proteostasis|Protein transport|GET pathway component ; PN-node mapping: mapped → GO:0031072 (HSP binding, more_specific_than_existing_goa), GO:0015031 (protein transport, new), GO:0006620 (post-translational ER targeting, already_in_goa_exact)
Consistency: Good. Review, notes and PN agree: cytosolic TPR co-chaperone for tail-anchored/hydrophobic clients, acting with BAG6 and ASNA1/TRC40 (GET) to deliver TA proteins to the ER; QC rheostat antagonizing RNF126/BAG6. Core MFs = molecular adaptor activity (GO:0060090), BAT3-complex binding (GO:1904288); core BP = GO:0006620 + GO:0071816 (TA insertion). GET role consistent with PN.
PN story / NEW pressure: No genuinely new role. PN's GO:0006620 already in review (ACCEPT, core) and GOA-exact. PN's GO:0015031 protein transport is a parent of the review's more specific GO:0006620/GO:0071816 → already captured at finer grain. PN's GO:0031072 (HSP binding) is broader than the review's GO:0051879 (Hsp90 binding). Conclude: already captured / over-reaches — nothing to ADD.
Mapping strategy: Both PN projections that aren't already exact (GO:0015031, GO:0031072) are BROADER than the review's terms (TOMM20/HSPA8/RAB7A precedent: reject broader). PN already self-flags them new/more_specific but they should not displace the gene-level specific terms. No mapping change warranted.
Evidence alignment: Review cites GET/BAG6 literature (e.g. PMID:23129660) and UniProt; PN row carries no extra reference titles, so no divergence to reconcile.
Verdict: Consistent; PN adds breadth only, no new defensible term. Recommended edits: none required; treat GO:0015031 and GO:0031072 as broader-than-review and do not propagate (gene-level GO:0006620/GO:0071816/GO:0051879 already finer) [MAP].

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07b
review_yaml: genes/human/SGTA/SGTA-ai-review.yaml
PN workbook rows: 2

PN row 1: Cytonuclear proteostasis | Chaperone | HSP70-HSP90 system integration | HSP70-HSP90 joint cochaperone | CC-TPR and SGTA dimerization domain containing

UniProt: O43765
In branches: CY, ER
PN-node mapping records (path + ancestors):
- [subtype] Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration|HSP70-HSP90 joint cochaperone|CC-TPR and SGTA dimerization domain containing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a family/domain/subtype label. It classifies PN members but is not itself a GO annotation target; any functional assertion should come from a parent role mapping or gene-specific review.
- [type] Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration|HSP70-HSP90 joint cochaperone
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0031072 heat shock protein binding]
  rationale: This PN type groups joint HSP70/HSP90 cochaperones. The shared mechanistic assertion is binding heat-shock-protein chaperones, while narrower domain labels remain non-mapping unless they carry an independent activity.
- [group] Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
- [class] Cytonuclear proteostasis|Chaperone
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
- [branch] Cytonuclear proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: ER proteostasis | Protein transport | GET pathway component

UniProt: O43765
In branches: CY, ER
PN-node mapping records (path + ancestors):
- [group] ER proteostasis|Protein transport|GET pathway component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane]
  rationale: The PN GET-pathway group covers machinery for post-translational delivery of tail-anchored membrane proteins to the ER. GO does not model the GET pathway directly in the local cache, and the closest supported process term is post-translational targeting to the ER membrane.
- [class] ER proteostasis|Protein transport
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0015031 protein transport]
  rationale: The PN ER Protein transport class groups ER-targeting and ER-insertion pathways. GO protein transport is the appropriate propagation target, while the source class remains ER-specific and broader than any single GO transport subtype.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (3)

GO:0031072 heat shock protein binding | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration|HSP70-HSP90 joint cochaperone
GO:0015031 protein transport | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Protein transport
GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Protein transport|GET pathway component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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.

SGTA

Gene Description

Existing Annotations Review

Core Functions

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.

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.

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: SGTA (Small Glutamine-Rich Tetratricopeptide Repeat-Containing Protein Alpha)

Overview and Gene Identity

Protein Structure and Domains

Primary Molecular Functions

Cochaperone Activity and Substrate Binding

Substrate Specificity

Cellular Localization

Major Biochemical Pathways

GET/TRC Pathway for Tail-Anchored Protein Targeting

BAG6-Mediated Protein Quality Control and Triage

ER Protein Reflux (ERCYS) and Additional Quality Control Functions

Protein-Protein Interactions and Chaperone Network

Experimental Evidence

Structural Studies

Biochemical Reconstitution

Cell-Based Studies

Recent Developments and Current Understanding (2023-2025)

Implications for Disease and Therapeutic Targeting

Summary

Artifacts

Citations

📚 Additional Documentation

Notes

SGTA (small glutamine-rich TPR-containing protein alpha / SGT / alphaSGT) — notes

Core identity

BAG6 antagonism (PMID:23129660, Leznicki & High 2012)

GO annotation review (goa.tsv)

Core function synthesis

Pn Notes

SGTA PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Cytonuclear proteostasis | Chaperone | HSP70-HSP90 system integration | HSP70-HSP90 joint cochaperone | CC-TPR and SGTA dimerization domain containing

PN row 2: ER proteostasis | Protein transport | GET pathway component

Projected GO annotations (3)

Note

📄 View Raw YAML