{"gene":"GET4","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2010,"finding":"Crystal structure of yeast Get4-Get5 complex reveals they form a tight heterodimeric complex; Get4 interacts physically with Get3 (though transiently) and Get5 interacts with Sgt2, placing Get4/5 upstream of Get3 in the tail-anchored protein targeting pathway.","method":"Co-immunoprecipitation and X-ray crystallography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with Co-IP biochemistry; independently replicated by multiple labs in the same year (PMID:20106980, 20554915, 20206626)","pmids":["20106980"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of Get4 and an N-terminal fragment of Get5 from S. cerevisiae shows Get4/5 forms an intimate complex that dimerizes via the C-terminus of Get5; Get3 binds to a conserved surface on Get4 in a nucleotide-dependent manner, consistent with Get4/5 operating upstream of Get3.","method":"X-ray crystallography, biochemical binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional biochemical validation, replicated by concurrent structural studies","pmids":["20554915"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of Get4 reveals an alpha-solenoid fold with a conserved hydrophobic groove that accommodates the flexible C-terminal region in trans, providing a scaffold for protein-protein interactions in the GET pathway.","method":"X-ray crystallography (2Å resolution)","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure, consistent with concurrent structural studies from other labs","pmids":["20206626"],"is_preprint":false},{"year":2011,"finding":"Get3 interacts with the Get4-Get5 complex via an interface dominated by electrostatic forces; isothermal titration calorimetry and SAXS demonstrate that the Get3 homodimer interacts with two copies of the Get4-Get5 complex to form an extended conformation in solution.","method":"Isothermal titration calorimetry (ITC), small-angle X-ray scattering (SAXS), co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biophysical methods in a single study establishing stoichiometry and interaction surface","pmids":["22190685"],"is_preprint":false},{"year":2011,"finding":"A dimer of Sgt2 binds a single Get5 subunit; the Sgt2 TPR domain can directly bind multiple HSC family members; SAXS characterizes the domain arrangement of Sgt2 in solution within the Sgt2-Get4/Get5-HSC complex.","method":"Crystal structure of Sgt2 TPR domain, SAXS, biochemical binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with SAXS and biochemical assays, single lab but multiple orthogonal methods","pmids":["21832041"],"is_preprint":false},{"year":2012,"finding":"In the mammalian system, Trc35 (GET4 ortholog) forms a stable complex with Bag6 and Ubl4A; SGTA interacts with Ubl4A (the Get5 ortholog) via a noncanonical ubiquitin-like-binding domain, recruiting SGTA to the Bag6/Ubl4A/Trc35 complex to facilitate ERAD substrate handling.","method":"NMR spectroscopy, Co-immunoprecipitation, biochemical binding assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure combined with biochemical Co-IP assays; identifies interaction mechanism of the mammalian GET4-containing complex","pmids":["23246001"],"is_preprint":false},{"year":2013,"finding":"The nuclear BAG6-UBL4A-GET4 complex mediates DNA damage response (DDR) signaling; GET4 and UBL4A translocate to the nucleus upon DNA damage; BAG6 depletion eliminates both UBL4A and GET4 proteins; co-depletion (but not individual depletion) of GET4 and UBL4A confers resistance to DNA-damage-induced cell killing; GET4 (and BAG6) are required for optimal BRCA1 recruitment to DNA damage sites.","method":"siRNA knockdown, immunofluorescence, cell viability assays, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotypes and pathway placement (BRCA1 recruitment), single lab but multiple readouts","pmids":["23723067"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of the yeast Get3-Get4-Get5 complex in an ATP-bound state shows Get4 primes Get3 by promoting optimal configuration for substrate capture; Get4-mediated regulation of ATP hydrolysis by Get3 is essential to efficient TA-protein targeting, as demonstrated by structure-guided mutagenesis.","method":"X-ray crystallography, structure-guided mutagenesis, biochemical ATPase assays, TA-protein targeting assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional targeting assays in one rigorous study","pmids":["24727835"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of the Bag6-TRC35 (GET4) complex reveals that TRC35 binding occludes the Bag6 nuclear localization sequence from karyopherin α to retain Bag6 in the cytosol, and also protects TRC35 itself from RNF126-mediated ubiquitylation and degradation. The TRC35 hydrophobic patch binds Bag6, but Bag6 wraps around TRC35 on the opposite face relative to the yeast Get4-Get5 interface.","method":"X-ray crystallography, biochemical binding assays, ubiquitylation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional biochemical validation of nuclear localization regulation and ubiquitylation protection, single lab with multiple orthogonal methods","pmids":["29042515"],"is_preprint":false},{"year":2020,"finding":"In a patient with compound heterozygous missense variants in GET4, all three TRC complex proteins (GET4, BAG6, GET5) were reduced 70-90% at the protein level (with unchanged mRNA), indicating GET4 mutations destabilize the entire complex and increase its degradation; proteasome inhibition with bortezomib restored TRC protein levels and syntaxin 5 Golgi localization, confirming proteasomal degradation of the complex.","method":"Patient fibroblast studies, immunoblotting, proteasome inhibitor treatment, immunofluorescence of TA protein targeting","journal":"Journal of inherited metabolic disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function patient cells with defined molecular phenotype and pharmacological rescue, single report","pmids":["32395830"],"is_preprint":false},{"year":2021,"finding":"Yeast Get4/5 binds directly and with high affinity to ribosomes, positioning Sgt2 close to the ribosomal tunnel exit to facilitate capture of tail-anchored proteins by Sgt2; contact sites of Get4/5 on the ribosome overlap with those of SRP, and SRP's high-affinity binding upon internal TM domain exposure prevents Get4/5 ribosome binding, providing a mechanism for partitioning TA proteins into GET vs. SRP pathways at the tunnel exit.","method":"Ribosome binding assays, cross-linking, fluorescence anisotropy, in vitro translation/targeting assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical assays establishing direct ribosome binding and competitive mechanism with SRP, published in peer-reviewed journal","pmids":["33542241"],"is_preprint":false},{"year":2021,"finding":"GET4 knockout in colorectal cancer cells causes nuclear translocation of BAG6, demonstrating that GET4 is required for cytoplasmic retention of BAG6; cytoplasmic BAG6 mediates p53 acetylation leading to reduced p21 expression and cell cycle progression.","method":"CRISPR-Cas9 knockout, immunofluorescence, in vitro and in vivo tumor growth assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — CRISPR KO with defined localization phenotype and downstream pathway readout, single lab","pmids":["34704338"],"is_preprint":false},{"year":2024,"finding":"Genome-wide CRISPR screen identifies GET4 (and BAG6) as suppressors of mitochondria-ER contact sites (MERCS); loss of GET4 increases MERCS, mitochondrial calcium uptake upon ER-Ca2+ release, and mitochondrial respiration; GET4 and BAG6 interact with known MERCS proteins IP3R and GRP75; loss of GET4 is neuroprotective in a Drosophila Alzheimer's disease model.","method":"Genome-wide CRISPR screen, flow cytometry-based MERCS reporter, microscopy, Co-immunoprecipitation, calcium imaging, Drosophila in vivo model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen validated by arrayed screen and multiple microscopy methods, Co-IP for interaction, in vivo model; single lab","pmids":["38467609"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of the S. cerevisiae Get3-Get4/5 complex at 3.2 Å resolution reveals that Get4/5 remodels Get3's TA-binding chamber by unfolding helices forming the lateral walls (termed the 'lateral gate'), making the chamber more solvent accessible; mutagenesis of lateral gate residues affects both Get4/5 binding affinity and ATPase activity; the Sgt2-binding domain of Get5 is positioned near the lateral gate opening, supporting a model of lateral, protected TA transfer from Sgt2 to Get3.","method":"Cryo-EM structure determination (3.2 Å), molecular dynamics simulations, mutagenesis, ATPase assays, binding affinity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure combined with mutagenesis and functional assays in a single study; single lab but multiple orthogonal methods","pmids":["40902977"],"is_preprint":false},{"year":2025,"finding":"A circRNA-encoded protein (SNX25-215) binds GET4 and inhibits the BAG6-GET4 interaction, thereby exposing the BAG6 nuclear localization sequence and promoting BAG6 nuclear translocation; this GET4-BAG6 interaction normally retains BAG6 in the cytoplasm and is disrupted by SNX25-215 binding at amino acids H207 and E214.","method":"Co-immunoprecipitation, molecular docking, subcellular fractionation, immunofluorescence","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and molecular docking with localization readout; single lab, limited mechanistic follow-up on GET4 specifically","pmids":["41120269"],"is_preprint":false}],"current_model":"GET4 (yeast Get4; mammalian TRC35) is a core scaffolding component of the GET/TRC pathway that adopts an alpha-solenoid fold and forms a tight complex with Get5/UBL4A; this Get4/5 complex directly binds ribosomes to position Sgt2 near the tunnel exit for capture of newly synthesized tail-anchored (TA) proteins, then promotes nucleotide-dependent handover of TA substrates to the Get3 ATPase by binding a conserved surface on Get3, priming Get3's optimal ATP-bound conformation for substrate capture and regulating its ATPase activity; in the metazoan context, TRC35/GET4 additionally retains the multifunctional scaffold BAG6 in the cytoplasm by occluding its nuclear localization sequence, protects the complex from RNF126-mediated ubiquitylation, participates in ERAD and DNA damage response signaling as part of the nuclear BAG6-UBL4A-GET4 complex, and suppresses mitochondria-ER contact sites through interactions with IP3R and GRP75."},"narrative":{"mechanistic_narrative":"GET4 (mammalian TRC35; yeast Get4) is a core alpha-solenoid scaffolding subunit of the GET/TRC pathway for post-translational targeting of tail-anchored (TA) membrane proteins to the endoplasmic reticulum [PMID:20206626]. It forms a tight, intimate heterodimer with Get5/UBL4A that dimerizes through the Get5 C-terminus and recruits the upstream co-chaperone Sgt2/SGTA, placing Get4/5 upstream of the Get3 ATPase [PMID:20106980, PMID:20554915, PMID:21832041]. Get4/5 binds directly and with high affinity to ribosomes, positioning Sgt2 near the tunnel exit to capture nascent TA proteins, and competes with SRP for overlapping ribosomal contact sites to partition substrates between the GET and SRP pathways [PMID:33542241]. GET4 then engages a conserved surface on the Get3 homodimer in a nucleotide-dependent manner, with two Get4/5 copies binding one Get3 dimer, and acts as a regulator of the substrate handover: it primes Get3 into the optimal ATP-bound conformation and controls its ATPase activity by remodeling Get3's lateral 'gate' to open the TA-binding chamber, enabling lateral, protected transfer of substrate from Sgt2 to Get3 [PMID:22190685, PMID:24727835, PMID:40902977]. In the metazoan complex, TRC35/GET4 binds BAG6 on a face opposite the yeast Get4-Get5 interface, occluding the BAG6 nuclear localization sequence to retain BAG6 in the cytoplasm and protecting TRC35 from RNF126-mediated ubiquitylation; disruption of this interaction (for example by the circRNA-encoded protein SNX25-215 binding GET4 residues H207/E214) drives BAG6 nuclear translocation [PMID:29042515, PMID:41120269]. Beyond TA targeting, GET4 participates as part of the nuclear BAG6-UBL4A-GET4 complex in DNA damage response signaling and BRCA1 recruitment, suppresses mitochondria-ER contact sites through interactions with IP3R and GRP75, and through cytoplasmic BAG6 regulates p53 acetylation and cell cycle progression [PMID:23723067, PMID:34704338, PMID:38467609]. Compound heterozygous GET4 missense variants destabilize the entire TRC complex, reducing GET4, BAG6, and GET5 protein levels via proteasomal degradation and impairing TA-protein targeting [PMID:32395830].","teleology":[{"year":2010,"claim":"Established that Get4 is a structured alpha-solenoid scaffold that forms an intimate heterodimer with Get5 and bridges Sgt2 to Get3, defining its position upstream of the Get3 ATPase in TA targeting.","evidence":"Co-IP and X-ray crystallography of yeast Get4-Get5 and Get4 alone","pmids":["20106980","20554915","20206626"],"confidence":"High","gaps":["Transient nature of the Get4-Get3 interaction left the substrate handover mechanism undefined","Stoichiometry of the Get3-Get4/5 assembly not yet resolved"]},{"year":2011,"claim":"Defined the architecture and stoichiometry of the upstream targeting complex, showing a Get3 dimer engages two Get4/5 copies via an electrostatic interface and that an Sgt2 dimer binds a single Get5.","evidence":"ITC, SAXS, crystallography of the Sgt2 TPR domain, and Co-IP in yeast","pmids":["22190685","21832041"],"confidence":"High","gaps":["How nucleotide state of Get3 couples to the handover step not established","Direct substrate transfer not visualized"]},{"year":2012,"claim":"Extended the scaffold to the mammalian system, showing TRC35/GET4 forms a stable BAG6-UBL4A-TRC35 complex that recruits SGTA, establishing conservation of the targeting machinery and its link to ERAD.","evidence":"NMR, Co-IP, and biochemical binding assays in mammalian cells","pmids":["23246001"],"confidence":"High","gaps":["Functional consequences of TRC35 within BAG6 complex beyond recruitment unclear","Role in ERAD substrate fate not mechanistically dissected"]},{"year":2013,"claim":"Revealed a nuclear, non-targeting role for GET4 in the DNA damage response, where the BAG6-UBL4A-GET4 complex supports BRCA1 recruitment and cell survival after damage.","evidence":"siRNA knockdown, immunofluorescence, viability assays, and subcellular fractionation","pmids":["23723067"],"confidence":"Medium","gaps":["Molecular mechanism by which GET4 promotes BRCA1 recruitment unknown","Whether GET4's nuclear and TA-targeting roles are mechanistically separable not addressed"]},{"year":2014,"claim":"Provided the mechanistic basis for substrate handover, showing Get4 primes Get3 into the ATP-bound conformation optimal for capture and regulates Get3 ATPase activity essential for efficient targeting.","evidence":"Crystal structure of Get3-Get4-Get5, structure-guided mutagenesis, ATPase and TA-targeting assays in yeast","pmids":["24727835"],"confidence":"High","gaps":["The conformational changes in Get3's substrate chamber not yet resolved","Coupling of Sgt2-to-Get3 transfer to this priming step not directly visualized"]},{"year":2017,"claim":"Showed TRC35/GET4 controls BAG6 localization and complex stability by occluding the BAG6 nuclear localization sequence and shielding TRC35 from RNF126-mediated ubiquitylation.","evidence":"Crystal structure of Bag6-TRC35, binding and ubiquitylation assays","pmids":["29042515"],"confidence":"High","gaps":["Signals that trigger release of BAG6 for nuclear entry not identified","Whether the metazoan Bag6 interface is mutually exclusive with Get5-type binding not fully resolved"]},{"year":2020,"claim":"Linked GET4 to human disease, demonstrating that compound heterozygous missense variants destabilize the entire TRC complex via proteasomal degradation and impair TA-protein targeting.","evidence":"Patient fibroblast immunoblotting, proteasome inhibitor rescue, and TA-protein localization imaging","pmids":["32395830"],"confidence":"Medium","gaps":["Single patient report; genotype-phenotype spectrum undefined","Causal link between TRC destabilization and specific clinical features not established"]},{"year":2021,"claim":"Identified the ribosomal docking step, showing Get4/5 binds ribosomes directly to position Sgt2 at the tunnel exit and competes with SRP to partition TA versus secretory substrates.","evidence":"Ribosome binding, cross-linking, fluorescence anisotropy, and in vitro targeting assays in yeast","pmids":["33542241"],"confidence":"High","gaps":["Structural basis of Get4/5-ribosome contact not resolved","How the SRP/GET partitioning decision is made in vivo not established"]},{"year":2021,"claim":"Demonstrated a cancer-relevant consequence of GET4-mediated BAG6 retention, where GET4 loss drives BAG6 nuclear translocation, p53 acetylation, p21 reduction, and tumor growth.","evidence":"CRISPR-Cas9 knockout, immunofluorescence, in vitro and in vivo tumor assays in colorectal cancer cells","pmids":["34704338"],"confidence":"Medium","gaps":["Direct mechanism linking nuclear BAG6 to p53 acetylation not defined","Generalizability beyond colorectal context unknown"]},{"year":2024,"claim":"Uncovered a role in organelle contact biology, identifying GET4 (with BAG6) as a suppressor of mitochondria-ER contact sites that interacts with IP3R and GRP75 and modulates mitochondrial calcium and respiration.","evidence":"Genome-wide CRISPR screen, MERCS reporter, microscopy, Co-IP, calcium imaging, and a Drosophila Alzheimer's model","pmids":["38467609"],"confidence":"Medium","gaps":["Whether GET4 acts at contacts via TA targeting or an independent mechanism unclear","Direct versus indirect nature of IP3R/GRP75 interactions not dissected"]},{"year":2025,"claim":"Defined how Get4/5 remodels Get3 for protected substrate transfer, showing it unfolds a 'lateral gate' to open the TA-binding chamber positioned near the Sgt2-binding domain.","evidence":"Cryo-EM at 3.2 A, molecular dynamics, mutagenesis, ATPase and binding assays in yeast","pmids":["40902977"],"confidence":"High","gaps":["The TA substrate itself not captured in the structure","Timing of gate closure and ATP hydrolysis during transfer not resolved"]},{"year":2025,"claim":"Showed the GET4-BAG6 interaction is a regulatable node, with a circRNA-encoded protein binding GET4 at H207/E214 to disrupt the interface and release BAG6 to the nucleus.","evidence":"Co-IP, molecular docking, subcellular fractionation, and immunofluorescence","pmids":["41120269"],"confidence":"Medium","gaps":["Co-IP and docking without structural validation of the binding site","Physiological contexts in which this regulation operates not established"]},{"year":null,"claim":"How GET4's well-defined cytoplasmic TA-targeting scaffold function mechanistically connects to its distinct nuclear DDR, p53/cell-cycle, and mitochondria-ER contact roles in metazoans remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified mechanism linking targeting and nuclear/contact-site functions","Signals controlling GET4 partitioning between cytoplasmic and nuclear complexes unknown","Whether moonlighting roles depend on intact TRC complex or free GET4 not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,4,7,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7,13]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5,9]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,7,10,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,9]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6]}],"complexes":["Get4/Get5 complex","BAG6-UBL4A-GET4 (TRC) complex","Get3-Get4/5 targeting complex"],"partners":["GET5","UBL4A","BAG6","GET3","SGTA","RNF126","IP3R","GRP75"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7L5D6","full_name":"Golgi to ER traffic protein 4 homolog","aliases":["Conserved edge-expressed protein","Transmembrane domain recognition complex 35 kDa subunit","TRC35"],"length_aa":327,"mass_kda":36.5,"function":"As part of a cytosolic protein quality control complex, the BAG6/BAT3 complex, maintains misfolded and hydrophobic patches-containing proteins in a soluble state and participates in their proper delivery to the endoplasmic reticulum or alternatively can promote their sorting to the proteasome where they undergo degradation (PubMed:20676083, PubMed:21636303, PubMed:21743475, PubMed:28104892, PubMed:32395830). The BAG6/BAT3 complex is involved in the post-translational delivery of tail-anchored/type II transmembrane proteins to the endoplasmic reticulum membrane. Recruited to ribosomes, it interacts with the transmembrane region of newly synthesized tail-anchored proteins and together with SGTA and ASNA1 mediates their delivery to the endoplasmic reticulum (PubMed:20676083, PubMed:25535373, PubMed:28104892). Client proteins that cannot be properly delivered to the endoplasmic reticulum are ubiquitinated and sorted to the proteasome (PubMed:28104892). Similarly, the BAG6/BAT3 complex also functions as a sorting platform for proteins of the secretory pathway that are mislocalized to the cytosol either delivering them to the proteasome for degradation or to the endoplasmic reticulum (PubMed:21743475). The BAG6/BAT3 complex also plays a role in the endoplasmic reticulum-associated degradation (ERAD), a quality control mechanism that eliminates unwanted proteins of the endoplasmic reticulum through their retrotranslocation to the cytosol and their targeting to the proteasome. It maintains these retrotranslocated proteins in an unfolded yet soluble state condition in the cytosol to ensure their proper delivery to the proteasome (PubMed:21636303)","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q7L5D6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GET4","classification":"Not Classified","n_dependent_lines":349,"n_total_lines":1208,"dependency_fraction":0.2889072847682119},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000239857","cell_line_id":"CID001608","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"BAG6","stoichiometry":10.0},{"gene":"UBL4A","stoichiometry":10.0},{"gene":"BAG6;BAT3","stoichiometry":10.0},{"gene":"RNF126","stoichiometry":4.0},{"gene":"ERLIN2","stoichiometry":4.0},{"gene":"RAB3A","stoichiometry":0.2},{"gene":"PSMC5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001608","total_profiled":1310},"omim":[{"mim_id":"620200","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIy; CDG2Y","url":"https://www.omim.org/entry/620200"},{"mim_id":"612056","title":"GUIDED ENTRY OF TAIL-ANCHORED PROTEINS FACTOR 4; GET4","url":"https://www.omim.org/entry/612056"},{"mim_id":"601913","title":"GUIDED ENTRY OF TAIL-ANCHORED PROTEINS FACTOR 3, ATPase; GET3","url":"https://www.omim.org/entry/601913"},{"mim_id":"601118","title":"CALCIUM-MODULATING LIGAND; CAMLG","url":"https://www.omim.org/entry/601118"},{"mim_id":"312070","title":"UBIQUITIN-LIKE 4A; UBL4A","url":"https://www.omim.org/entry/312070"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Mitotic chromosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GET4"},"hgnc":{"alias_symbol":["CGI-20","H_NH1244M04.5","CEE","TRC35"],"prev_symbol":["C7orf20"]},"alphafold":{"accession":"Q7L5D6","domains":[{"cath_id":"1.25.40.10","chopping":"28-141","consensus_level":"medium","plddt":96.0331,"start":28,"end":141}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L5D6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L5D6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L5D6-F1-predicted_aligned_error_v6.png","plddt_mean":87.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GET4","jax_strain_url":"https://www.jax.org/strain/search?query=GET4"},"sequence":{"accession":"Q7L5D6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7L5D6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7L5D6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L5D6"}},"corpus_meta":[{"pmid":"23246001","id":"PMC_23246001","title":"SGTA 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\"Co-immunoprecipitation and X-ray crystallography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with Co-IP biochemistry; independently replicated by multiple labs in the same year (PMID:20106980, 20554915, 20206626)\",\n      \"pmids\": [\"20106980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of Get4 and an N-terminal fragment of Get5 from S. cerevisiae shows Get4/5 forms an intimate complex that dimerizes via the C-terminus of Get5; Get3 binds to a conserved surface on Get4 in a nucleotide-dependent manner, consistent with Get4/5 operating upstream of Get3.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional biochemical validation, replicated by concurrent structural studies\",\n      \"pmids\": [\"20554915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of Get4 reveals an alpha-solenoid fold with a conserved hydrophobic groove that accommodates the flexible C-terminal region in trans, providing a scaffold for protein-protein interactions in the GET pathway.\",\n      \"method\": \"X-ray crystallography (2Å resolution)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure, consistent with concurrent structural studies from other labs\",\n      \"pmids\": [\"20206626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Get3 interacts with the Get4-Get5 complex via an interface dominated by electrostatic forces; isothermal titration calorimetry and SAXS demonstrate that the Get3 homodimer interacts with two copies of the Get4-Get5 complex to form an extended conformation in solution.\",\n      \"method\": \"Isothermal titration calorimetry (ITC), small-angle X-ray scattering (SAXS), co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biophysical methods in a single study establishing stoichiometry and interaction surface\",\n      \"pmids\": [\"22190685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A dimer of Sgt2 binds a single Get5 subunit; the Sgt2 TPR domain can directly bind multiple HSC family members; SAXS characterizes the domain arrangement of Sgt2 in solution within the Sgt2-Get4/Get5-HSC complex.\",\n      \"method\": \"Crystal structure of Sgt2 TPR domain, SAXS, biochemical binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with SAXS and biochemical assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21832041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In the mammalian system, Trc35 (GET4 ortholog) forms a stable complex with Bag6 and Ubl4A; SGTA interacts with Ubl4A (the Get5 ortholog) via a noncanonical ubiquitin-like-binding domain, recruiting SGTA to the Bag6/Ubl4A/Trc35 complex to facilitate ERAD substrate handling.\",\n      \"method\": \"NMR spectroscopy, Co-immunoprecipitation, biochemical binding assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure combined with biochemical Co-IP assays; identifies interaction mechanism of the mammalian GET4-containing complex\",\n      \"pmids\": [\"23246001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The nuclear BAG6-UBL4A-GET4 complex mediates DNA damage response (DDR) signaling; GET4 and UBL4A translocate to the nucleus upon DNA damage; BAG6 depletion eliminates both UBL4A and GET4 proteins; co-depletion (but not individual depletion) of GET4 and UBL4A confers resistance to DNA-damage-induced cell killing; GET4 (and BAG6) are required for optimal BRCA1 recruitment to DNA damage sites.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, cell viability assays, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotypes and pathway placement (BRCA1 recruitment), single lab but multiple readouts\",\n      \"pmids\": [\"23723067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the yeast Get3-Get4-Get5 complex in an ATP-bound state shows Get4 primes Get3 by promoting optimal configuration for substrate capture; Get4-mediated regulation of ATP hydrolysis by Get3 is essential to efficient TA-protein targeting, as demonstrated by structure-guided mutagenesis.\",\n      \"method\": \"X-ray crystallography, structure-guided mutagenesis, biochemical ATPase assays, TA-protein targeting assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional targeting assays in one rigorous study\",\n      \"pmids\": [\"24727835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of the Bag6-TRC35 (GET4) complex reveals that TRC35 binding occludes the Bag6 nuclear localization sequence from karyopherin α to retain Bag6 in the cytosol, and also protects TRC35 itself from RNF126-mediated ubiquitylation and degradation. The TRC35 hydrophobic patch binds Bag6, but Bag6 wraps around TRC35 on the opposite face relative to the yeast Get4-Get5 interface.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays, ubiquitylation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional biochemical validation of nuclear localization regulation and ubiquitylation protection, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29042515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In a patient with compound heterozygous missense variants in GET4, all three TRC complex proteins (GET4, BAG6, GET5) were reduced 70-90% at the protein level (with unchanged mRNA), indicating GET4 mutations destabilize the entire complex and increase its degradation; proteasome inhibition with bortezomib restored TRC protein levels and syntaxin 5 Golgi localization, confirming proteasomal degradation of the complex.\",\n      \"method\": \"Patient fibroblast studies, immunoblotting, proteasome inhibitor treatment, immunofluorescence of TA protein targeting\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function patient cells with defined molecular phenotype and pharmacological rescue, single report\",\n      \"pmids\": [\"32395830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yeast Get4/5 binds directly and with high affinity to ribosomes, positioning Sgt2 close to the ribosomal tunnel exit to facilitate capture of tail-anchored proteins by Sgt2; contact sites of Get4/5 on the ribosome overlap with those of SRP, and SRP's high-affinity binding upon internal TM domain exposure prevents Get4/5 ribosome binding, providing a mechanism for partitioning TA proteins into GET vs. SRP pathways at the tunnel exit.\",\n      \"method\": \"Ribosome binding assays, cross-linking, fluorescence anisotropy, in vitro translation/targeting assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical assays establishing direct ribosome binding and competitive mechanism with SRP, published in peer-reviewed journal\",\n      \"pmids\": [\"33542241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GET4 knockout in colorectal cancer cells causes nuclear translocation of BAG6, demonstrating that GET4 is required for cytoplasmic retention of BAG6; cytoplasmic BAG6 mediates p53 acetylation leading to reduced p21 expression and cell cycle progression.\",\n      \"method\": \"CRISPR-Cas9 knockout, immunofluorescence, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — CRISPR KO with defined localization phenotype and downstream pathway readout, single lab\",\n      \"pmids\": [\"34704338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Genome-wide CRISPR screen identifies GET4 (and BAG6) as suppressors of mitochondria-ER contact sites (MERCS); loss of GET4 increases MERCS, mitochondrial calcium uptake upon ER-Ca2+ release, and mitochondrial respiration; GET4 and BAG6 interact with known MERCS proteins IP3R and GRP75; loss of GET4 is neuroprotective in a Drosophila Alzheimer's disease model.\",\n      \"method\": \"Genome-wide CRISPR screen, flow cytometry-based MERCS reporter, microscopy, Co-immunoprecipitation, calcium imaging, Drosophila in vivo model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen validated by arrayed screen and multiple microscopy methods, Co-IP for interaction, in vivo model; single lab\",\n      \"pmids\": [\"38467609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of the S. cerevisiae Get3-Get4/5 complex at 3.2 Å resolution reveals that Get4/5 remodels Get3's TA-binding chamber by unfolding helices forming the lateral walls (termed the 'lateral gate'), making the chamber more solvent accessible; mutagenesis of lateral gate residues affects both Get4/5 binding affinity and ATPase activity; the Sgt2-binding domain of Get5 is positioned near the lateral gate opening, supporting a model of lateral, protected TA transfer from Sgt2 to Get3.\",\n      \"method\": \"Cryo-EM structure determination (3.2 Å), molecular dynamics simulations, mutagenesis, ATPase assays, binding affinity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure combined with mutagenesis and functional assays in a single study; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40902977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A circRNA-encoded protein (SNX25-215) binds GET4 and inhibits the BAG6-GET4 interaction, thereby exposing the BAG6 nuclear localization sequence and promoting BAG6 nuclear translocation; this GET4-BAG6 interaction normally retains BAG6 in the cytoplasm and is disrupted by SNX25-215 binding at amino acids H207 and E214.\",\n      \"method\": \"Co-immunoprecipitation, molecular docking, subcellular fractionation, immunofluorescence\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and molecular docking with localization readout; single lab, limited mechanistic follow-up on GET4 specifically\",\n      \"pmids\": [\"41120269\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GET4 (yeast Get4; mammalian TRC35) is a core scaffolding component of the GET/TRC pathway that adopts an alpha-solenoid fold and forms a tight complex with Get5/UBL4A; this Get4/5 complex directly binds ribosomes to position Sgt2 near the tunnel exit for capture of newly synthesized tail-anchored (TA) proteins, then promotes nucleotide-dependent handover of TA substrates to the Get3 ATPase by binding a conserved surface on Get3, priming Get3's optimal ATP-bound conformation for substrate capture and regulating its ATPase activity; in the metazoan context, TRC35/GET4 additionally retains the multifunctional scaffold BAG6 in the cytoplasm by occluding its nuclear localization sequence, protects the complex from RNF126-mediated ubiquitylation, participates in ERAD and DNA damage response signaling as part of the nuclear BAG6-UBL4A-GET4 complex, and suppresses mitochondria-ER contact sites through interactions with IP3R and GRP75.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GET4 (mammalian TRC35; yeast Get4) is a core alpha-solenoid scaffolding subunit of the GET/TRC pathway for post-translational targeting of tail-anchored (TA) membrane proteins to the endoplasmic reticulum [#2]. It forms a tight, intimate heterodimer with Get5/UBL4A that dimerizes through the Get5 C-terminus and recruits the upstream co-chaperone Sgt2/SGTA, placing Get4/5 upstream of the Get3 ATPase [#0, #1, #4]. Get4/5 binds directly and with high affinity to ribosomes, positioning Sgt2 near the tunnel exit to capture nascent TA proteins, and competes with SRP for overlapping ribosomal contact sites to partition substrates between the GET and SRP pathways [#10]. GET4 then engages a conserved surface on the Get3 homodimer in a nucleotide-dependent manner, with two Get4/5 copies binding one Get3 dimer, and acts as a regulator of the substrate handover: it primes Get3 into the optimal ATP-bound conformation and controls its ATPase activity by remodeling Get3's lateral 'gate' to open the TA-binding chamber, enabling lateral, protected transfer of substrate from Sgt2 to Get3 [#3, #7, #13]. In the metazoan complex, TRC35/GET4 binds BAG6 on a face opposite the yeast Get4-Get5 interface, occluding the BAG6 nuclear localization sequence to retain BAG6 in the cytoplasm and protecting TRC35 from RNF126-mediated ubiquitylation; disruption of this interaction (for example by the circRNA-encoded protein SNX25-215 binding GET4 residues H207/E214) drives BAG6 nuclear translocation [#8, #14]. Beyond TA targeting, GET4 participates as part of the nuclear BAG6-UBL4A-GET4 complex in DNA damage response signaling and BRCA1 recruitment, suppresses mitochondria-ER contact sites through interactions with IP3R and GRP75, and through cytoplasmic BAG6 regulates p53 acetylation and cell cycle progression [#6, #11, #12]. Compound heterozygous GET4 missense variants destabilize the entire TRC complex, reducing GET4, BAG6, and GET5 protein levels via proteasomal degradation and impairing TA-protein targeting [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that Get4 is a structured alpha-solenoid scaffold that forms an intimate heterodimer with Get5 and bridges Sgt2 to Get3, defining its position upstream of the Get3 ATPase in TA targeting.\",\n      \"evidence\": \"Co-IP and X-ray crystallography of yeast Get4-Get5 and Get4 alone\",\n      \"pmids\": [\"20106980\", \"20554915\", \"20206626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transient nature of the Get4-Get3 interaction left the substrate handover mechanism undefined\", \"Stoichiometry of the Get3-Get4/5 assembly not yet resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the architecture and stoichiometry of the upstream targeting complex, showing a Get3 dimer engages two Get4/5 copies via an electrostatic interface and that an Sgt2 dimer binds a single Get5.\",\n      \"evidence\": \"ITC, SAXS, crystallography of the Sgt2 TPR domain, and Co-IP in yeast\",\n      \"pmids\": [\"22190685\", \"21832041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nucleotide state of Get3 couples to the handover step not established\", \"Direct substrate transfer not visualized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended the scaffold to the mammalian system, showing TRC35/GET4 forms a stable BAG6-UBL4A-TRC35 complex that recruits SGTA, establishing conservation of the targeting machinery and its link to ERAD.\",\n      \"evidence\": \"NMR, Co-IP, and biochemical binding assays in mammalian cells\",\n      \"pmids\": [\"23246001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of TRC35 within BAG6 complex beyond recruitment unclear\", \"Role in ERAD substrate fate not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a nuclear, non-targeting role for GET4 in the DNA damage response, where the BAG6-UBL4A-GET4 complex supports BRCA1 recruitment and cell survival after damage.\",\n      \"evidence\": \"siRNA knockdown, immunofluorescence, viability assays, and subcellular fractionation\",\n      \"pmids\": [\"23723067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which GET4 promotes BRCA1 recruitment unknown\", \"Whether GET4's nuclear and TA-targeting roles are mechanistically separable not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the mechanistic basis for substrate handover, showing Get4 primes Get3 into the ATP-bound conformation optimal for capture and regulates Get3 ATPase activity essential for efficient targeting.\",\n      \"evidence\": \"Crystal structure of Get3-Get4-Get5, structure-guided mutagenesis, ATPase and TA-targeting assays in yeast\",\n      \"pmids\": [\"24727835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The conformational changes in Get3's substrate chamber not yet resolved\", \"Coupling of Sgt2-to-Get3 transfer to this priming step not directly visualized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed TRC35/GET4 controls BAG6 localization and complex stability by occluding the BAG6 nuclear localization sequence and shielding TRC35 from RNF126-mediated ubiquitylation.\",\n      \"evidence\": \"Crystal structure of Bag6-TRC35, binding and ubiquitylation assays\",\n      \"pmids\": [\"29042515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals that trigger release of BAG6 for nuclear entry not identified\", \"Whether the metazoan Bag6 interface is mutually exclusive with Get5-type binding not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked GET4 to human disease, demonstrating that compound heterozygous missense variants destabilize the entire TRC complex via proteasomal degradation and impair TA-protein targeting.\",\n      \"evidence\": \"Patient fibroblast immunoblotting, proteasome inhibitor rescue, and TA-protein localization imaging\",\n      \"pmids\": [\"32395830\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient report; genotype-phenotype spectrum undefined\", \"Causal link between TRC destabilization and specific clinical features not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the ribosomal docking step, showing Get4/5 binds ribosomes directly to position Sgt2 at the tunnel exit and competes with SRP to partition TA versus secretory substrates.\",\n      \"evidence\": \"Ribosome binding, cross-linking, fluorescence anisotropy, and in vitro targeting assays in yeast\",\n      \"pmids\": [\"33542241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Get4/5-ribosome contact not resolved\", \"How the SRP/GET partitioning decision is made in vivo not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a cancer-relevant consequence of GET4-mediated BAG6 retention, where GET4 loss drives BAG6 nuclear translocation, p53 acetylation, p21 reduction, and tumor growth.\",\n      \"evidence\": \"CRISPR-Cas9 knockout, immunofluorescence, in vitro and in vivo tumor assays in colorectal cancer cells\",\n      \"pmids\": [\"34704338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking nuclear BAG6 to p53 acetylation not defined\", \"Generalizability beyond colorectal context unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a role in organelle contact biology, identifying GET4 (with BAG6) as a suppressor of mitochondria-ER contact sites that interacts with IP3R and GRP75 and modulates mitochondrial calcium and respiration.\",\n      \"evidence\": \"Genome-wide CRISPR screen, MERCS reporter, microscopy, Co-IP, calcium imaging, and a Drosophila Alzheimer's model\",\n      \"pmids\": [\"38467609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GET4 acts at contacts via TA targeting or an independent mechanism unclear\", \"Direct versus indirect nature of IP3R/GRP75 interactions not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined how Get4/5 remodels Get3 for protected substrate transfer, showing it unfolds a 'lateral gate' to open the TA-binding chamber positioned near the Sgt2-binding domain.\",\n      \"evidence\": \"Cryo-EM at 3.2 A, molecular dynamics, mutagenesis, ATPase and binding assays in yeast\",\n      \"pmids\": [\"40902977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The TA substrate itself not captured in the structure\", \"Timing of gate closure and ATP hydrolysis during transfer not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed the GET4-BAG6 interaction is a regulatable node, with a circRNA-encoded protein binding GET4 at H207/E214 to disrupt the interface and release BAG6 to the nucleus.\",\n      \"evidence\": \"Co-IP, molecular docking, subcellular fractionation, and immunofluorescence\",\n      \"pmids\": [\"41120269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP and docking without structural validation of the binding site\", \"Physiological contexts in which this regulation operates not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GET4's well-defined cytoplasmic TA-targeting scaffold function mechanistically connects to its distinct nuclear DDR, p53/cell-cycle, and mitochondria-ER contact roles in metazoans remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified mechanism linking targeting and nuclear/contact-site functions\", \"Signals controlling GET4 partitioning between cytoplasmic and nuclear complexes unknown\", \"Whether moonlighting roles depend on intact TRC complex or free GET4 not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 4, 7, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7, 13]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 7, 10, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"Get4/Get5 complex\", \"BAG6-UBL4A-GET4 (TRC) complex\", \"Get3-Get4/5 targeting complex\"],\n    \"partners\": [\"GET5\", \"UBL4A\", \"BAG6\", \"GET3\", \"SGTA\", \"RNF126\", \"IP3R\", \"GRP75\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}