{"gene":"SGTA","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":1998,"finding":"SGTA (SGT) was identified as a novel cellular protein containing three tetratricopeptide repeat (TPR) motifs that interacts with the parvovirus H-1 nonstructural protein NS1. The interaction was demonstrated by yeast two-hybrid and in vitro interaction assays. SGT was detected in both nucleus and cytoplasm of rat cells by immunofluorescence and subcellular fractionation, and was post-translationally modified upon parvovirus infection or NS protein expression.","method":"Yeast two-hybrid screen, in vitro interaction assay, immunofluorescence, subcellular fractionation, Western blot","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro binding and localization, single lab","pmids":["9557704"],"is_preprint":false},{"year":1998,"finding":"Human SGTA (hSGT) cDNA was isolated encoding a 313-amino acid protein with three tandem TPR motifs, ubiquitously expressed across human tissues, and mapped to chromosome 19p13. Homologues were identified in S. cerevisiae and C. elegans, establishing evolutionary conservation of the SGT family.","method":"cDNA cloning, Northern blot, fluorescence in situ hybridization (FISH), sequence analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and mapping, single lab, multiple methods","pmids":["9740675"],"is_preprint":false},{"year":2001,"finding":"SGTA (Ubp/Vpu-binding protein) localizes to both nucleus and cytoplasm and is loosely associated with microtubules in the cytoplasm (co-fluorescence with tubulin, but not tightly bound by cytoskeletal isolation). Expression of HIV-1 Vpu caused redistribution of SGTA and Gag to the cell periphery, and SGTA interacts with both Vpu and HIV-1 Gag structural protein.","method":"Immunofluorescence/confocal microscopy, cytoskeletal isolation, detergent extraction, flotation gradient analysis","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple localization methods in single lab; functional consequence (redistribution) shown","pmids":["11878889"],"is_preprint":false},{"year":2003,"finding":"SGTA interacts with the N-terminal signal peptide region of myostatin via its C-terminal third TPR motif. The interaction was identified by yeast two-hybrid and confirmed by GST pull-down and co-immunoprecipitation, suggesting a role for SGTA as a molecular chaperone in myostatin processing/secretion.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, deletion mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays, deletion mapping, single lab","pmids":["14623262"],"is_preprint":false},{"year":2003,"finding":"SGTA interacts with the ubiquitin-dependent endocytosis (UbE) motif of the growth hormone receptor (GHR) via its first TPR motif. Both precursor and mature forms of GHR interact with SGTA in vivo, and this interaction is independent of the ubiquitin-conjugating system.","method":"GST pull-down, co-immunoprecipitation, deletion mutagenesis of SGTA TPR motifs","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pull-down and co-IP with domain mapping, single lab","pmids":["12735788"],"is_preprint":false},{"year":2006,"finding":"SARS-CoV 7a protein interacts with SGTA; the interaction was identified by yeast two-hybrid and confirmed by co-immunoprecipitation and co-localization. The second TPR motif of SGTA (aa 125–158) was essential for the interaction with 7a.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization, deletion mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid confirmed by co-IP and colocalization, single lab","pmids":["16580632"],"is_preprint":false},{"year":2006,"finding":"SGTA interacts with Hsp90alpha and Hsp90beta. Disruption of the SGTA–Hsp90beta interaction by geldanamycin (Hsp90 inhibitor) increased nuclear localization of SGTA in HeLa cells. Nuclear import of SGTA was also significantly increased during staurosporine-induced apoptosis, indicating that subcellular localization of SGTA is linked to Hsp90 engagement and apoptotic state.","method":"Co-immunoprecipitation, confocal microscopy, Western blot of fractionated cells, pharmacological inhibition","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and localization with functional perturbation, single lab","pmids":["16580629"],"is_preprint":false},{"year":2006,"finding":"Human SGTA (hSGT) is required for progression through cell division; RNAi-mediated depletion of hSGT causes prometaphase arrest with persistent misaligned chromosomes near spindle poles, followed by apoptosis. SGTA interacts with Bag-6/Bat-3/Scythe and Hsp70 (confirmed by co-immunoprecipitation of Flag-hSGT and mass spectrometry), and these interactions occur in prometaphase. Bag-6 depletion phenocopies hSGT depletion (misaligned chromosomes and mitotic arrest), suggesting the hSGT–Bag-6 complex has a role in chromosome congression.","method":"RNAi knockdown, live-cell imaging (histone H2A-YFP), co-immunoprecipitation, mass spectrometry, truncation mutant analysis","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi with defined mitotic phenotype, reciprocal co-IP with MS identification, epistasis via Bag-6 depletion, single lab with multiple orthogonal methods","pmids":["16777091"],"is_preprint":false},{"year":2008,"finding":"The crystal structure of the TPR domain of human SGTA was determined, revealing typical TPR domain features. The TPR domain of SGTA is sufficient to bind HIV-1 Vpu and to reduce HIV-1 p24 secretion from cells, although less efficiently than full-length SGTA, indicating the N- and/or C-terminus also contribute. The SGTA binding site on Vpu was mapped by peptide array and confirmed by GST pull-down.","method":"X-ray crystallography, GST pull-down, peptide array, p24 ELISA (particle release assay)","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus in vitro binding assays and functional readout, single lab with multiple orthogonal methods","pmids":["18759457"],"is_preprint":false},{"year":2012,"finding":"SGTA is a component of the Bag6 (BAG6/Ubl4A/Trc35) complex and cooperates with Bag6 to prevent aggregation of dislocated ERAD substrates. Using NMR spectroscopy and biochemical assays, SGTA was shown to contain a noncanonical ubiquitin-like-binding domain (UBD) that binds an unconventional ubiquitin-like domain in Ubl4A (at least partly via electrostatic interactions), thereby recruiting SGTA to Bag6 and enhancing substrate loading onto Bag6 to prevent formation of nondegradable protein aggregates.","method":"NMR spectroscopy, biochemical binding assays, co-immunoprecipitation, ERAD substrate aggregation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure plus biochemical reconstitution and functional ERAD assay, multiple orthogonal methods","pmids":["23246001"],"is_preprint":false},{"year":2012,"finding":"SGTA actively antagonizes BAG6-mediated ubiquitination of mislocalized proteins and promotes their deubiquitination, reversing BAG6 pro-degradation activity. This SGTA-mediated deubiquitination is independent of SGTA's TPR motifs (and thus independent of Hsp70/Hsp90 chaperone interactions). Increasing steady-state SGTA levels specifically stabilizes a model mislocalized membrane protein (from amyloid precursor protein), an effect negated by restoring efficient ER delivery.","method":"Ubiquitination assays, Western blot of substrate stability, SGTA overexpression and knockdown, domain deletion analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function with defined biochemical readout, domain mapping, mechanistic rescue experiment, single lab with multiple orthogonal methods","pmids":["23129660"],"is_preprint":false},{"year":2012,"finding":"The dimerization domain of SGTA (yeast Sgt2) forms a complex with the UBL domain of Get5/UBL4A in the GET/TRC pathway for tail-anchored (TA) protein targeting. Crystal structures of both yeast and human UBD/UBL interfaces were determined, showing the interaction is mediated by electrostatics and has high-affinity with rapid kinetics, providing a refined model for SGTA's role in TA protein handoff.","method":"X-ray crystallography, biophysical studies (ITC, SPR or equivalent), biochemical interaction assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of yeast and human complexes with biophysical validation, multiple orthogonal methods","pmids":["23142665"],"is_preprint":false},{"year":2012,"finding":"The HERV-K(HML-2) Rec protein interacts with SGTA via the SGTA TPR motif, as shown by yeast two-hybrid, co-immunoprecipitation, pull-down, and co-localization. This interaction occurs in the cytoplasm and nucleoli. Rec interference with SGTA (a known negative regulator of androgen receptor, AR) resulted in up to 5-fold increase in AR transcriptional activity, and Rec-enhanced AR activity was used to transactivate HERV-K LTR.","method":"Yeast two-hybrid, co-immunoprecipitation, pull-down assay, co-localization, AR reporter assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays plus functional reporter readout, single lab","pmids":["22733359"],"is_preprint":false},{"year":2013,"finding":"BAG6's N-terminal ubiquitin-like (UBL) domain is essential for binding to SGTA. The UBL domain of UBL4A (a second subunit of the BAG6 complex) also competes with BAG6 for SGTA binding, such that SGTA can bind either BAG6 or UBL4A but not both simultaneously. The large central region of BAG6 (not its UBL or BAG domains) provides a binding site for tail-anchored protein substrates such as Sec61β.","method":"In vitro binding assays, GST pull-down, yeast heterologous subcellular localization assay, deletion mutagenesis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding with domain mapping and competition assay, single lab","pmids":["23533635"],"is_preprint":false},{"year":2014,"finding":"SGTA and the BAG6 complex compete for cytosolic mislocalized membrane proteins (MLPs) by recognition of exposed hydrophobicity. SGTA maintains MLPs in a non-ubiquitylated state, opposing BAG6-mediated ubiquitylation. When SGTA is overexpressed, proteasomal degradation of aberrant MLPs is delayed, steady-state MLP levels increase, and aggregation is promoted.","method":"Overexpression and knockdown, Western blot for ubiquitination and substrate levels, aggregation assays, cell biology assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with mechanistic readouts (ubiquitination, aggregation), single lab","pmids":["25179605"],"is_preprint":false},{"year":2014,"finding":"SGTA specifically associates with and negatively regulates androgen receptor (AR), glucocorticoid receptor (GR), and progesterone receptor (PR) activity, but has no effect on mineralocorticoid or estrogen receptors, in both yeast and mammalian reporter assays. SGTA knockdown/deletion enhances receptor activity; overexpression suppresses it. SGTA binds directly to Hsp70 and Hsp90 in vitro with similar affinities but predominantly precipitates with Hsp70 from cell lysates. SGTA overexpression completely abrogates FKBP52-mediated receptor regulation, placing SGTA at an early Hsp70-mediated step in the chaperone cycle.","method":"Yeast and mammalian reporter assays, siRNA knockdown, overexpression, in vitro binding assays, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple receptor systems, both yeast and mammalian assays, in vitro binding, genetic epistasis with FKBP52, multiple orthogonal methods in single study","pmids":["24753260"],"is_preprint":false},{"year":2015,"finding":"SGTA binds to the C-terminal region of the proteasomal ubiquitin receptor Rpn13 via its TPR domain. SGTA overexpression increases steady-state levels of mislocalized membrane proteins (MLPs), and this effect depends on the SGTA–Rpn13 interaction: overexpression of the Rpn13 SGTA-binding region or point mutations in the SGTA TPR domain that disrupt Rpn13 binding both substantially reduce MLP levels. This indicates SGTA can regulate substrate access to the proteasomal core at the 19S regulatory particle.","method":"Co-immunoprecipitation, point mutagenesis, overexpression, Western blot for MLP substrate levels","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis and functional MLP assay, single lab","pmids":["26169395"],"is_preprint":false},{"year":2020,"finding":"SGTA is selectively recruited to ribosomes synthesizing diverse membrane proteins, including those on the co-translational SRP-dependent ER delivery pathway. SGTA is recruited before the transmembrane domain (TMD) of nascent membrane proteins emerges from the ribosome. For co-translational pathway clients with multiple hydrophobic signals, SGTA reduces co-translational ubiquitination, complementing SRP function by masking TMDs during synthesis until ER translocon engagement.","method":"Ribosome association assay, nascent chain pulldown, ubiquitination assay, RNA interference knockdown","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ribosome recruitment shown biochemically, functional ubiquitination readout, single lab","pmids":["32216016"],"is_preprint":false}],"current_model":"SGTA is a dimeric cochaperone with an N-terminal dimerization domain, a central TPR domain (mediating interactions with Hsp70, Hsp90, Rpn13, and viral/client proteins), and a C-terminal glutamine-rich region; it acts as a cytosolic holdase that captures exposed hydrophobic transmembrane domains of nascent and mislocalized membrane proteins before they can be ubiquitylated by the BAG6 complex, actively promoting their deubiquitination and either productive ER delivery (via the GET/TRC40 pathway through interaction with UBL4A/Get5) or delayed proteasomal degradation, while also negatively regulating androgen, glucocorticoid, and progesterone receptor activity at an early Hsp70-mediated step in the steroid receptor chaperone cycle, and participating in mitotic chromosome congression through interaction with BAG6."},"narrative":{"mechanistic_narrative":"SGTA is a TPR-motif cochaperone that governs the cytosolic triage of nascent and mislocalized membrane proteins, capturing exposed hydrophobic transmembrane domains and arbitrating their fate between productive membrane delivery and proteasomal degradation [PMID:23129660, PMID:25179605]. It functions as a holdase that recognizes exposed hydrophobicity on mislocalized membrane proteins and maintains them in a non-ubiquitylated state, directly antagonizing BAG6-mediated ubiquitylation and promoting substrate deubiquitination — an activity independent of its TPR motifs and thus of Hsp70/Hsp90 engagement [PMID:23129660, PMID:25179605]. SGTA is itself a component of the BAG6 complex: its noncanonical ubiquitin-like-binding domain engages the unconventional UBL domain of UBL4A, while BAG6's N-terminal UBL domain also binds SGTA, with UBL4A and BAG6 competing for mutually exclusive SGTA binding [PMID:23246001, PMID:23533635]. Through its dimerization domain SGTA forms a high-affinity electrostatic complex with the Get5/UBL4A UBL domain in the GET/TRC tail-anchored protein targeting pathway, and it is recruited to ribosomes synthesizing membrane proteins before the transmembrane domain emerges, complementing SRP by masking hydrophobic signals and reducing co-translational ubiquitination [PMID:23142665, PMID:32216016]. SGTA also tunes substrate access to the proteasome by binding the 19S ubiquitin receptor Rpn13 via its TPR domain [PMID:26169395]. Independently of its membrane-protein triage role, SGTA binds Hsp70 and Hsp90 and acts at an early Hsp70-mediated step of the steroid receptor chaperone cycle to negatively regulate androgen, glucocorticoid, and progesterone receptor activity, abrogating FKBP52-mediated receptor potentiation [PMID:24753260]. SGTA is further required for mitotic chromosome congression, acting with BAG6 and Hsp70 in prometaphase, where its depletion causes misaligned chromosomes and mitotic arrest [PMID:16777091]. The TPR domain additionally serves as a docking site for multiple viral proteins, including HIV-1 Vpu and Gag [PMID:18759457].","teleology":[{"year":1998,"claim":"Establishing SGTA's existence and architecture answered what kind of protein it is — a conserved, ubiquitously expressed TPR-repeat protein found in both nucleus and cytoplasm — providing the structural framework for all later mechanism.","evidence":"cDNA cloning, FISH mapping, Northern blot, and yeast two-hybrid/in vitro binding to parvovirus NS1 in rat and human cells","pmids":["9740675","9557704"],"confidence":"Medium","gaps":["No cellular function assigned beyond viral protein binding","TPR-motif binding partners and their specificity undefined"]},{"year":2003,"claim":"Domain-resolved mapping of client binding showed individual TPR motifs recognize distinct partner sequences (myostatin signal peptide via TPR3, GHR UbE motif via TPR1), framing SGTA as a modular chaperone-like adaptor rather than a single-ligand binder.","evidence":"Yeast two-hybrid, GST pull-down, co-IP, and deletion mutagenesis of SGTA TPR motifs with myostatin and growth hormone receptor","pmids":["14623262","12735788"],"confidence":"Medium","gaps":["Functional consequence of these interactions for client processing not established","No demonstration of holdase or chaperone activity"]},{"year":2006,"claim":"Linking SGTA to Hsp90/Hsp70 and to mitosis showed it is a bona fide cochaperone with an essential cellular role, as its depletion blocks chromosome congression and triggers apoptosis through a BAG6- and Hsp70-associated complex.","evidence":"RNAi with live-cell imaging, reciprocal co-IP with MS identification of BAG6 and Hsp70, BAG6-depletion epistasis, and Hsp90 co-IP with localization shifts upon geldanamycin","pmids":["16777091","16580629"],"confidence":"High","gaps":["Molecular mechanism by which SGTA-BAG6 promotes congression unknown","Whether mitotic and chaperone roles are mechanistically linked unresolved"]},{"year":2008,"claim":"The crystal structure of the SGTA TPR domain defined the physical platform for partner binding and showed the TPR alone is sufficient (if less efficient) to bind viral Vpu and reduce particle release, localizing function to a defined module.","evidence":"X-ray crystallography of the TPR domain, peptide array mapping, GST pull-down, and HIV-1 p24 release assay","pmids":["18759457"],"confidence":"High","gaps":["Contribution of N- and C-terminal regions to binding not structurally defined","No structure of full-length SGTA or of client-bound complexes"]},{"year":2012,"claim":"A cluster of structural and biochemical studies established SGTA as a BAG6-complex subunit and a GET/TRC-pathway component: its UBL-binding domain engages UBL4A/Get5 to load substrates onto BAG6 and to hand off tail-anchored proteins, defining its place in membrane-protein targeting.","evidence":"NMR of the SGTA UBD–UBL4A interface, crystal structures of yeast and human SGTA dimerization-domain/Get5-UBL complexes, biophysical affinity measurements, and ERAD aggregation assays","pmids":["23246001","23142665"],"confidence":"High","gaps":["Precise handoff sequence from SGTA to TRC40 not kinetically resolved in vivo","Stoichiometry of SGTA dimer within the assembled complex unclear"]},{"year":2012,"claim":"Demonstrating that SGTA actively antagonizes BAG6-driven ubiquitylation and promotes deubiquitination of mislocalized proteins reframed it from a passive holdase to an active counterweight that can rescue substrates from degradation, with this activity mapped independently of the TPR/Hsp interactions.","evidence":"Ubiquitination and substrate-stability assays with SGTA gain/loss-of-function, domain deletion, and an ER-delivery rescue experiment using an APC-derived model substrate","pmids":["23129660"],"confidence":"High","gaps":["Whether SGTA recruits a deubiquitinase or shields lysines directly not determined","Domain responsible for the anti-ubiquitylation activity not finely mapped"]},{"year":2013,"claim":"Competition mapping clarified the architecture of substrate triage by showing SGTA binds BAG6 or UBL4A but not both at once, with BAG6's central region holding tail-anchored substrates, defining mutually exclusive complex states.","evidence":"In vitro binding, GST pull-down, competition assays, and yeast heterologous localization with domain deletions of BAG6/UBL4A and Sec61β substrate","pmids":["23533635"],"confidence":"Medium","gaps":["Regulation of the BAG6-vs-UBL4A switch in cells unknown","Functional consequence of each complex state for substrate fate not directly tested in mammalian cells"]},{"year":2014,"claim":"Two studies established the kinetic logic of the SGTA–BAG6 competition and extended SGTA's regulatory reach: SGTA delays degradation and promotes aggregation when overexpressed, and at the receptor level it acts at an early Hsp70 step to negatively regulate AR, GR, and PR but not MR or ER.","evidence":"Overexpression/knockdown with ubiquitination and aggregation readouts; yeast and mammalian steroid receptor reporter assays, in vitro Hsp70/Hsp90 binding, and FKBP52 epistasis","pmids":["25179605","24753260"],"confidence":"High","gaps":["How SGTA discriminates among receptor classes mechanistically unclear","Whether membrane-protein triage and receptor regulation share the same SGTA pool not addressed"]},{"year":2015,"claim":"Identifying the SGTA–Rpn13 interaction connected SGTA to the proteasome end of the pathway, showing it can gate substrate access at the 19S regulatory particle through its TPR domain.","evidence":"Co-IP, TPR point mutagenesis, and Rpn13-fragment overexpression with MLP substrate-level readouts","pmids":["26169395"],"confidence":"Medium","gaps":["Whether SGTA delivers or withholds substrates at Rpn13 not directly distinguished","Structural basis of TPR–Rpn13 binding undefined"]},{"year":2020,"claim":"Showing SGTA is recruited to ribosomes before TMD emergence revealed it acts co-translationally, complementing SRP by masking hydrophobic signals and reducing co-translational ubiquitination, extending its triage role to the earliest stage of membrane-protein synthesis.","evidence":"Ribosome association and nascent-chain pulldown assays, co-translational ubiquitination readouts, and RNAi knockdown","pmids":["32216016"],"confidence":"Medium","gaps":["Recruitment mechanism to the ribosome before TMD exposure unknown","Relationship between co-translational SGTA and the post-translational BAG6 complex not resolved"]},{"year":null,"claim":"It remains unresolved how SGTA's multiple roles — co-translational TMD masking, post-translational BAG6-complex triage, proteasomal gating, steroid receptor regulation, and mitotic congression — are partitioned and regulated within a single cell.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No model integrating the chaperone, receptor, and mitotic functions","Regulatory inputs controlling which SGTA complex assembles are unknown","No in vivo demonstration of how substrate commitment between delivery and degradation is decided"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[10,14,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,11,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,10,16]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,6,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,14,9]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[11,17,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7]}],"complexes":["BAG6 complex (BAG6/UBL4A/TRC35)","GET/TRC targeting machinery"],"partners":["BAG6","UBL4A","HSP70","HSP90","RPN13","AR","VPU"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43765","full_name":"Small glutamine-rich tetratricopeptide repeat-containing protein alpha","aliases":["Alpha-SGT","Vpu-binding protein","UBP"],"length_aa":313,"mass_kda":34.1,"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 (PubMed:28104892). Functions in tail-anchored/type II transmembrane proteins membrane insertion constituting with ASNA1 and the BAG6 complex a targeting module (PubMed:28104892). Functions upstream of the BAG6 complex and ASNA1, binding more rapidly the transmembrane domain of newly synthesized proteins (PubMed:25535373, PubMed:28104892). It is also involved in the regulation of the endoplasmic reticulum-associated misfolded protein catabolic process via its interaction with BAG6: collaborates with the BAG6 complex to maintain hydrophobic substrates in non-ubiquitinated states (PubMed:23129660, PubMed:25179605). Competes with RNF126 for interaction with BAG6, preventing the ubiquitination of client proteins associated with the BAG6 complex (PubMed:27193484). Binds directly to HSC70 and HSP70 and regulates their ATPase activity (PubMed:18759457) (Microbial infection) In case of infection by polyomavirus, involved in the virus endoplasmic reticulum membrane penetration and infection via interaction with DNAJB12, DNAJB14 and HSPA8/Hsc70 (PubMed:24675744)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O43765/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SGTA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ARPC3","stoichiometry":0.2},{"gene":"BTF3","stoichiometry":0.2},{"gene":"GDI2","stoichiometry":0.2},{"gene":"HSPA8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SGTA","total_profiled":1310},"omim":[{"mim_id":"620526","title":"SMALL GLUTAMINE-RICH TETRATRICOPEPTIDE REPEAT COCHAPERONE, BETA; SGTB","url":"https://www.omim.org/entry/620526"},{"mim_id":"613945","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 5, BETA; DNAJC5B","url":"https://www.omim.org/entry/613945"},{"mim_id":"612056","title":"GUIDED ENTRY OF TAIL-ANCHORED PROTEINS FACTOR 4; GET4","url":"https://www.omim.org/entry/612056"},{"mim_id":"611203","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 5; DNAJC5","url":"https://www.omim.org/entry/611203"},{"mim_id":"603419","title":"SMALL GLUTAMINE-RICH TETRATRICOPEPTIDE REPEAT-CONTAINING COCHAPERONE, ALPHA; SGTA","url":"https://www.omim.org/entry/603419"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SGTA"},"hgnc":{"alias_symbol":["UBP","SGT1","Vpu","hSGT","alphaSGT"],"prev_symbol":["SGT"]},"alphafold":{"accession":"O43765","domains":[{"cath_id":"1.20.5.420","chopping":"1-70","consensus_level":"medium","plddt":87.3337,"start":1,"end":70},{"cath_id":"1.25.40.10","chopping":"85-207","consensus_level":"medium","plddt":97.1181,"start":85,"end":207}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43765","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43765-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43765-F1-predicted_aligned_error_v6.png","plddt_mean":81.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SGTA","jax_strain_url":"https://www.jax.org/strain/search?query=SGTA"},"sequence":{"accession":"O43765","fasta_url":"https://rest.uniprot.org/uniprotkb/O43765.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43765/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43765"}},"corpus_meta":[{"pmid":"18200009","id":"PMC_18200009","title":"Tetherin 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/30635083","citation_count":23,"is_preprint":false},{"pmid":"18332089","id":"PMC_18332089","title":"Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA), a candidate gene for polycystic ovary syndrome.","date":"2008","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18332089","citation_count":23,"is_preprint":false},{"pmid":"22110710","id":"PMC_22110710","title":"The HIV-1 Vpu viroporin inhibitor BIT225 does not affect Vpu-mediated tetherin antagonism.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22110710","citation_count":23,"is_preprint":false},{"pmid":"32216016","id":"PMC_32216016","title":"SGTA associates with nascent membrane protein precursors.","date":"2020","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/32216016","citation_count":22,"is_preprint":false},{"pmid":"26169395","id":"PMC_26169395","title":"Binding of SGTA to Rpn13 selectively modulates protein quality control.","date":"2015","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/26169395","citation_count":22,"is_preprint":false},{"pmid":"32127461","id":"PMC_32127461","title":"The HIV-1 Accessory Protein Vpu Downregulates Peroxisome Biogenesis.","date":"2020","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/32127461","citation_count":22,"is_preprint":false},{"pmid":"9841226","id":"PMC_9841226","title":"The genomic organization of Isopeptidase T-3 (ISOT-3), a new member of the ubiquitin specific protease family (UBP).","date":"1998","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9841226","citation_count":22,"is_preprint":false},{"pmid":"15823605","id":"PMC_15823605","title":"Vpu-mediated CD4 down-regulation and degradation is conserved among highly divergent SIV(cpz) strains.","date":"2005","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/15823605","citation_count":21,"is_preprint":false},{"pmid":"22524181","id":"PMC_22524181","title":"HIV-1 Vpu interference with innate cell-mediated immune mechanisms.","date":"2012","source":"Current HIV research","url":"https://pubmed.ncbi.nlm.nih.gov/22524181","citation_count":20,"is_preprint":false},{"pmid":"29490283","id":"PMC_29490283","title":"Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29490283","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46104,"output_tokens":5116,"usd":0.107526,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12897,"output_tokens":4279,"usd":0.08573,"stage2_stop_reason":"end_turn"},"total_usd":0.193256,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical SGTA protein (small glutamine-rich tetratricopeptide repeat-containing protein alpha). The gene symbol SGTA has aliases including SGT, hSGT, alphaSGT. The aliases UBP and Vpu listed in the HGNC aliases are confusing — I need to be careful here.\n\nLooking at the HGNC aliases provided: UBP, Vpu, hSGT, alphaSGT, SGT — these all refer to SGTA. However, the vast majority of papers in this corpus are about HIV-1 Vpu (viral protein U), which is a completely different entity (a viral protein, not a human gene). The \"UBP\" alias here appears to refer to \"Vpu-binding protein\" (UBP/SGT), not HIV-1 Vpu itself.\n\nI need to carefully separate:\n1. Papers about SGTA/SGT/hSGT/UBP (the human cochaperone protein) — INCLUDE\n2. Papers about HIV-1 Vpu (viral protein) — EXCLUDE as these are about a viral gene, not the human SGTA protein\n3. Papers about ubiquitin-specific proteases (UBP family deubiquitinases) — EXCLUDE as symbol collision\n\nThe relevant SGTA papers are: 30, 31, 32, 37, 38, 40, 46, 57, 61, 63, 65, 68, 73, 75, 77, 80, 87, 91, 94, 95\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"SGTA (SGT) was identified as a novel cellular protein containing three tetratricopeptide repeat (TPR) motifs that interacts with the parvovirus H-1 nonstructural protein NS1. The interaction was demonstrated by yeast two-hybrid and in vitro interaction assays. SGT was detected in both nucleus and cytoplasm of rat cells by immunofluorescence and subcellular fractionation, and was post-translationally modified upon parvovirus infection or NS protein expression.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro interaction assay, immunofluorescence, subcellular fractionation, Western blot\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro binding and localization, single lab\",\n      \"pmids\": [\"9557704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human SGTA (hSGT) cDNA was isolated encoding a 313-amino acid protein with three tandem TPR motifs, ubiquitously expressed across human tissues, and mapped to chromosome 19p13. Homologues were identified in S. cerevisiae and C. elegans, establishing evolutionary conservation of the SGT family.\",\n      \"method\": \"cDNA cloning, Northern blot, fluorescence in situ hybridization (FISH), sequence analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and mapping, single lab, multiple methods\",\n      \"pmids\": [\"9740675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SGTA (Ubp/Vpu-binding protein) localizes to both nucleus and cytoplasm and is loosely associated with microtubules in the cytoplasm (co-fluorescence with tubulin, but not tightly bound by cytoskeletal isolation). Expression of HIV-1 Vpu caused redistribution of SGTA and Gag to the cell periphery, and SGTA interacts with both Vpu and HIV-1 Gag structural protein.\",\n      \"method\": \"Immunofluorescence/confocal microscopy, cytoskeletal isolation, detergent extraction, flotation gradient analysis\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple localization methods in single lab; functional consequence (redistribution) shown\",\n      \"pmids\": [\"11878889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SGTA interacts with the N-terminal signal peptide region of myostatin via its C-terminal third TPR motif. The interaction was identified by yeast two-hybrid and confirmed by GST pull-down and co-immunoprecipitation, suggesting a role for SGTA as a molecular chaperone in myostatin processing/secretion.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, deletion mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays, deletion mapping, single lab\",\n      \"pmids\": [\"14623262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SGTA interacts with the ubiquitin-dependent endocytosis (UbE) motif of the growth hormone receptor (GHR) via its first TPR motif. Both precursor and mature forms of GHR interact with SGTA in vivo, and this interaction is independent of the ubiquitin-conjugating system.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, deletion mutagenesis of SGTA TPR motifs\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pull-down and co-IP with domain mapping, single lab\",\n      \"pmids\": [\"12735788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SARS-CoV 7a protein interacts with SGTA; the interaction was identified by yeast two-hybrid and confirmed by co-immunoprecipitation and co-localization. The second TPR motif of SGTA (aa 125–158) was essential for the interaction with 7a.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization, deletion mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid confirmed by co-IP and colocalization, single lab\",\n      \"pmids\": [\"16580632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SGTA interacts with Hsp90alpha and Hsp90beta. Disruption of the SGTA–Hsp90beta interaction by geldanamycin (Hsp90 inhibitor) increased nuclear localization of SGTA in HeLa cells. Nuclear import of SGTA was also significantly increased during staurosporine-induced apoptosis, indicating that subcellular localization of SGTA is linked to Hsp90 engagement and apoptotic state.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, Western blot of fractionated cells, pharmacological inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and localization with functional perturbation, single lab\",\n      \"pmids\": [\"16580629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human SGTA (hSGT) is required for progression through cell division; RNAi-mediated depletion of hSGT causes prometaphase arrest with persistent misaligned chromosomes near spindle poles, followed by apoptosis. SGTA interacts with Bag-6/Bat-3/Scythe and Hsp70 (confirmed by co-immunoprecipitation of Flag-hSGT and mass spectrometry), and these interactions occur in prometaphase. Bag-6 depletion phenocopies hSGT depletion (misaligned chromosomes and mitotic arrest), suggesting the hSGT–Bag-6 complex has a role in chromosome congression.\",\n      \"method\": \"RNAi knockdown, live-cell imaging (histone H2A-YFP), co-immunoprecipitation, mass spectrometry, truncation mutant analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi with defined mitotic phenotype, reciprocal co-IP with MS identification, epistasis via Bag-6 depletion, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16777091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The crystal structure of the TPR domain of human SGTA was determined, revealing typical TPR domain features. The TPR domain of SGTA is sufficient to bind HIV-1 Vpu and to reduce HIV-1 p24 secretion from cells, although less efficiently than full-length SGTA, indicating the N- and/or C-terminus also contribute. The SGTA binding site on Vpu was mapped by peptide array and confirmed by GST pull-down.\",\n      \"method\": \"X-ray crystallography, GST pull-down, peptide array, p24 ELISA (particle release assay)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus in vitro binding assays and functional readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18759457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SGTA is a component of the Bag6 (BAG6/Ubl4A/Trc35) complex and cooperates with Bag6 to prevent aggregation of dislocated ERAD substrates. Using NMR spectroscopy and biochemical assays, SGTA was shown to contain a noncanonical ubiquitin-like-binding domain (UBD) that binds an unconventional ubiquitin-like domain in Ubl4A (at least partly via electrostatic interactions), thereby recruiting SGTA to Bag6 and enhancing substrate loading onto Bag6 to prevent formation of nondegradable protein aggregates.\",\n      \"method\": \"NMR spectroscopy, biochemical binding assays, co-immunoprecipitation, ERAD substrate aggregation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure plus biochemical reconstitution and functional ERAD assay, multiple orthogonal methods\",\n      \"pmids\": [\"23246001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SGTA actively antagonizes BAG6-mediated ubiquitination of mislocalized proteins and promotes their deubiquitination, reversing BAG6 pro-degradation activity. This SGTA-mediated deubiquitination is independent of SGTA's TPR motifs (and thus independent of Hsp70/Hsp90 chaperone interactions). Increasing steady-state SGTA levels specifically stabilizes a model mislocalized membrane protein (from amyloid precursor protein), an effect negated by restoring efficient ER delivery.\",\n      \"method\": \"Ubiquitination assays, Western blot of substrate stability, SGTA overexpression and knockdown, domain deletion analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function with defined biochemical readout, domain mapping, mechanistic rescue experiment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23129660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The dimerization domain of SGTA (yeast Sgt2) forms a complex with the UBL domain of Get5/UBL4A in the GET/TRC pathway for tail-anchored (TA) protein targeting. Crystal structures of both yeast and human UBD/UBL interfaces were determined, showing the interaction is mediated by electrostatics and has high-affinity with rapid kinetics, providing a refined model for SGTA's role in TA protein handoff.\",\n      \"method\": \"X-ray crystallography, biophysical studies (ITC, SPR or equivalent), biochemical interaction assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of yeast and human complexes with biophysical validation, multiple orthogonal methods\",\n      \"pmids\": [\"23142665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The HERV-K(HML-2) Rec protein interacts with SGTA via the SGTA TPR motif, as shown by yeast two-hybrid, co-immunoprecipitation, pull-down, and co-localization. This interaction occurs in the cytoplasm and nucleoli. Rec interference with SGTA (a known negative regulator of androgen receptor, AR) resulted in up to 5-fold increase in AR transcriptional activity, and Rec-enhanced AR activity was used to transactivate HERV-K LTR.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, pull-down assay, co-localization, AR reporter assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays plus functional reporter readout, single lab\",\n      \"pmids\": [\"22733359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BAG6's N-terminal ubiquitin-like (UBL) domain is essential for binding to SGTA. The UBL domain of UBL4A (a second subunit of the BAG6 complex) also competes with BAG6 for SGTA binding, such that SGTA can bind either BAG6 or UBL4A but not both simultaneously. The large central region of BAG6 (not its UBL or BAG domains) provides a binding site for tail-anchored protein substrates such as Sec61β.\",\n      \"method\": \"In vitro binding assays, GST pull-down, yeast heterologous subcellular localization assay, deletion mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding with domain mapping and competition assay, single lab\",\n      \"pmids\": [\"23533635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SGTA and the BAG6 complex compete for cytosolic mislocalized membrane proteins (MLPs) by recognition of exposed hydrophobicity. SGTA maintains MLPs in a non-ubiquitylated state, opposing BAG6-mediated ubiquitylation. When SGTA is overexpressed, proteasomal degradation of aberrant MLPs is delayed, steady-state MLP levels increase, and aggregation is promoted.\",\n      \"method\": \"Overexpression and knockdown, Western blot for ubiquitination and substrate levels, aggregation assays, cell biology assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with mechanistic readouts (ubiquitination, aggregation), single lab\",\n      \"pmids\": [\"25179605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SGTA specifically associates with and negatively regulates androgen receptor (AR), glucocorticoid receptor (GR), and progesterone receptor (PR) activity, but has no effect on mineralocorticoid or estrogen receptors, in both yeast and mammalian reporter assays. SGTA knockdown/deletion enhances receptor activity; overexpression suppresses it. SGTA binds directly to Hsp70 and Hsp90 in vitro with similar affinities but predominantly precipitates with Hsp70 from cell lysates. SGTA overexpression completely abrogates FKBP52-mediated receptor regulation, placing SGTA at an early Hsp70-mediated step in the chaperone cycle.\",\n      \"method\": \"Yeast and mammalian reporter assays, siRNA knockdown, overexpression, in vitro binding assays, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple receptor systems, both yeast and mammalian assays, in vitro binding, genetic epistasis with FKBP52, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24753260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SGTA binds to the C-terminal region of the proteasomal ubiquitin receptor Rpn13 via its TPR domain. SGTA overexpression increases steady-state levels of mislocalized membrane proteins (MLPs), and this effect depends on the SGTA–Rpn13 interaction: overexpression of the Rpn13 SGTA-binding region or point mutations in the SGTA TPR domain that disrupt Rpn13 binding both substantially reduce MLP levels. This indicates SGTA can regulate substrate access to the proteasomal core at the 19S regulatory particle.\",\n      \"method\": \"Co-immunoprecipitation, point mutagenesis, overexpression, Western blot for MLP substrate levels\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis and functional MLP assay, single lab\",\n      \"pmids\": [\"26169395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SGTA is selectively recruited to ribosomes synthesizing diverse membrane proteins, including those on the co-translational SRP-dependent ER delivery pathway. SGTA is recruited before the transmembrane domain (TMD) of nascent membrane proteins emerges from the ribosome. For co-translational pathway clients with multiple hydrophobic signals, SGTA reduces co-translational ubiquitination, complementing SRP function by masking TMDs during synthesis until ER translocon engagement.\",\n      \"method\": \"Ribosome association assay, nascent chain pulldown, ubiquitination assay, RNA interference knockdown\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome recruitment shown biochemically, functional ubiquitination readout, single lab\",\n      \"pmids\": [\"32216016\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SGTA is a dimeric cochaperone with an N-terminal dimerization domain, a central TPR domain (mediating interactions with Hsp70, Hsp90, Rpn13, and viral/client proteins), and a C-terminal glutamine-rich region; it acts as a cytosolic holdase that captures exposed hydrophobic transmembrane domains of nascent and mislocalized membrane proteins before they can be ubiquitylated by the BAG6 complex, actively promoting their deubiquitination and either productive ER delivery (via the GET/TRC40 pathway through interaction with UBL4A/Get5) or delayed proteasomal degradation, while also negatively regulating androgen, glucocorticoid, and progesterone receptor activity at an early Hsp70-mediated step in the steroid receptor chaperone cycle, and participating in mitotic chromosome congression through interaction with BAG6.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SGTA is a TPR-motif cochaperone that governs the cytosolic triage of nascent and mislocalized membrane proteins, capturing exposed hydrophobic transmembrane domains and arbitrating their fate between productive membrane delivery and proteasomal degradation [#10, #14]. It functions as a holdase that recognizes exposed hydrophobicity on mislocalized membrane proteins and maintains them in a non-ubiquitylated state, directly antagonizing BAG6-mediated ubiquitylation and promoting substrate deubiquitination — an activity independent of its TPR motifs and thus of Hsp70/Hsp90 engagement [#10, #14]. SGTA is itself a component of the BAG6 complex: its noncanonical ubiquitin-like-binding domain engages the unconventional UBL domain of UBL4A, while BAG6's N-terminal UBL domain also binds SGTA, with UBL4A and BAG6 competing for mutually exclusive SGTA binding [#9, #13]. Through its dimerization domain SGTA forms a high-affinity electrostatic complex with the Get5/UBL4A UBL domain in the GET/TRC tail-anchored protein targeting pathway, and it is recruited to ribosomes synthesizing membrane proteins before the transmembrane domain emerges, complementing SRP by masking hydrophobic signals and reducing co-translational ubiquitination [#11, #17]. SGTA also tunes substrate access to the proteasome by binding the 19S ubiquitin receptor Rpn13 via its TPR domain [#16]. Independently of its membrane-protein triage role, SGTA binds Hsp70 and Hsp90 and acts at an early Hsp70-mediated step of the steroid receptor chaperone cycle to negatively regulate androgen, glucocorticoid, and progesterone receptor activity, abrogating FKBP52-mediated receptor potentiation [#15]. SGTA is further required for mitotic chromosome congression, acting with BAG6 and Hsp70 in prometaphase, where its depletion causes misaligned chromosomes and mitotic arrest [#7]. The TPR domain additionally serves as a docking site for multiple viral proteins, including HIV-1 Vpu and Gag [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing SGTA's existence and architecture answered what kind of protein it is — a conserved, ubiquitously expressed TPR-repeat protein found in both nucleus and cytoplasm — providing the structural framework for all later mechanism.\",\n      \"evidence\": \"cDNA cloning, FISH mapping, Northern blot, and yeast two-hybrid/in vitro binding to parvovirus NS1 in rat and human cells\",\n      \"pmids\": [\"9740675\", \"9557704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cellular function assigned beyond viral protein binding\", \"TPR-motif binding partners and their specificity undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Domain-resolved mapping of client binding showed individual TPR motifs recognize distinct partner sequences (myostatin signal peptide via TPR3, GHR UbE motif via TPR1), framing SGTA as a modular chaperone-like adaptor rather than a single-ligand binder.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-IP, and deletion mutagenesis of SGTA TPR motifs with myostatin and growth hormone receptor\",\n      \"pmids\": [\"14623262\", \"12735788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of these interactions for client processing not established\", \"No demonstration of holdase or chaperone activity\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linking SGTA to Hsp90/Hsp70 and to mitosis showed it is a bona fide cochaperone with an essential cellular role, as its depletion blocks chromosome congression and triggers apoptosis through a BAG6- and Hsp70-associated complex.\",\n      \"evidence\": \"RNAi with live-cell imaging, reciprocal co-IP with MS identification of BAG6 and Hsp70, BAG6-depletion epistasis, and Hsp90 co-IP with localization shifts upon geldanamycin\",\n      \"pmids\": [\"16777091\", \"16580629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which SGTA-BAG6 promotes congression unknown\", \"Whether mitotic and chaperone roles are mechanistically linked unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The crystal structure of the SGTA TPR domain defined the physical platform for partner binding and showed the TPR alone is sufficient (if less efficient) to bind viral Vpu and reduce particle release, localizing function to a defined module.\",\n      \"evidence\": \"X-ray crystallography of the TPR domain, peptide array mapping, GST pull-down, and HIV-1 p24 release assay\",\n      \"pmids\": [\"18759457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of N- and C-terminal regions to binding not structurally defined\", \"No structure of full-length SGTA or of client-bound complexes\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A cluster of structural and biochemical studies established SGTA as a BAG6-complex subunit and a GET/TRC-pathway component: its UBL-binding domain engages UBL4A/Get5 to load substrates onto BAG6 and to hand off tail-anchored proteins, defining its place in membrane-protein targeting.\",\n      \"evidence\": \"NMR of the SGTA UBD–UBL4A interface, crystal structures of yeast and human SGTA dimerization-domain/Get5-UBL complexes, biophysical affinity measurements, and ERAD aggregation assays\",\n      \"pmids\": [\"23246001\", \"23142665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise handoff sequence from SGTA to TRC40 not kinetically resolved in vivo\", \"Stoichiometry of SGTA dimer within the assembled complex unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that SGTA actively antagonizes BAG6-driven ubiquitylation and promotes deubiquitination of mislocalized proteins reframed it from a passive holdase to an active counterweight that can rescue substrates from degradation, with this activity mapped independently of the TPR/Hsp interactions.\",\n      \"evidence\": \"Ubiquitination and substrate-stability assays with SGTA gain/loss-of-function, domain deletion, and an ER-delivery rescue experiment using an APC-derived model substrate\",\n      \"pmids\": [\"23129660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SGTA recruits a deubiquitinase or shields lysines directly not determined\", \"Domain responsible for the anti-ubiquitylation activity not finely mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Competition mapping clarified the architecture of substrate triage by showing SGTA binds BAG6 or UBL4A but not both at once, with BAG6's central region holding tail-anchored substrates, defining mutually exclusive complex states.\",\n      \"evidence\": \"In vitro binding, GST pull-down, competition assays, and yeast heterologous localization with domain deletions of BAG6/UBL4A and Sec61β substrate\",\n      \"pmids\": [\"23533635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulation of the BAG6-vs-UBL4A switch in cells unknown\", \"Functional consequence of each complex state for substrate fate not directly tested in mammalian cells\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two studies established the kinetic logic of the SGTA–BAG6 competition and extended SGTA's regulatory reach: SGTA delays degradation and promotes aggregation when overexpressed, and at the receptor level it acts at an early Hsp70 step to negatively regulate AR, GR, and PR but not MR or ER.\",\n      \"evidence\": \"Overexpression/knockdown with ubiquitination and aggregation readouts; yeast and mammalian steroid receptor reporter assays, in vitro Hsp70/Hsp90 binding, and FKBP52 epistasis\",\n      \"pmids\": [\"25179605\", \"24753260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SGTA discriminates among receptor classes mechanistically unclear\", \"Whether membrane-protein triage and receptor regulation share the same SGTA pool not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying the SGTA–Rpn13 interaction connected SGTA to the proteasome end of the pathway, showing it can gate substrate access at the 19S regulatory particle through its TPR domain.\",\n      \"evidence\": \"Co-IP, TPR point mutagenesis, and Rpn13-fragment overexpression with MLP substrate-level readouts\",\n      \"pmids\": [\"26169395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SGTA delivers or withholds substrates at Rpn13 not directly distinguished\", \"Structural basis of TPR–Rpn13 binding undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing SGTA is recruited to ribosomes before TMD emergence revealed it acts co-translationally, complementing SRP by masking hydrophobic signals and reducing co-translational ubiquitination, extending its triage role to the earliest stage of membrane-protein synthesis.\",\n      \"evidence\": \"Ribosome association and nascent-chain pulldown assays, co-translational ubiquitination readouts, and RNAi knockdown\",\n      \"pmids\": [\"32216016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recruitment mechanism to the ribosome before TMD exposure unknown\", \"Relationship between co-translational SGTA and the post-translational BAG6 complex not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SGTA's multiple roles — co-translational TMD masking, post-translational BAG6-complex triage, proteasomal gating, steroid receptor regulation, and mitotic congression — are partitioned and regulated within a single cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No model integrating the chaperone, receptor, and mitotic functions\", \"Regulatory inputs controlling which SGTA complex assembles are unknown\", \"No in vivo demonstration of how substrate commitment between delivery and degradation is decided\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [10, 14, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 11, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 10, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 6, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 14, 9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [11, 17, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"BAG6 complex (BAG6/UBL4A/TRC35)\", \"GET/TRC targeting machinery\"],\n    \"partners\": [\"BAG6\", \"UBL4A\", \"HSP70\", \"HSP90\", \"RPN13\", \"AR\", \"Vpu\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}