GET4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0140597 protein carrier chaperone	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic annotation of GET4's protein-carrier (chaperone) activity. As a scaffold of the Bag6 pre-targeting complex, GET4 helps capture and carry TA cargo for loading onto GET3/TRC40. Conserved across the GET4 family. Reason: Core molecular function; GET4 is the bridging scaffold that loads TA cargo onto GET3, supported by IMP and the Bag6-complex mechanism. Supporting Evidence: PMID:20676083 facilitates TA protein capture by TRC40
GO:0045048 protein insertion into ER membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic annotation of the (parent) ER protein-insertion process. GET4 contributes to TA-protein delivery to the ER, though it acts at the pre-targeting/loading step rather than catalyzing insertion. Reason: Correct but generic parent of the specific TA-insertion/targeting terms; GET4's role is upstream loading. Supporting Evidence: PMID:20676083 facilitates TA protein capture by TRC40
GO:0071818 BAT3 complex	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic annotation of GET4/TRC35 as a constitutive subunit of the BAT3/BAG6 complex (BAG6 + UBL4A + GET4/TRC35). Conserved and directly demonstrated. Reason: Core cellular component; GET4 is a defining subunit of the Bag6/BAT3 complex. Supporting Evidence: file:human/GET4/GET4-uniprot.txt Component of the BAG6/BAT3 complex, at least composed of BAG6,
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Electronic transfer of the cytosolic localization from the UniProt subcellular location, consistent with multiple experimental IDA annotations. Reason: Correct compartment; GET4 is a cytosolic scaffold. Supporting Evidence: file:human/GET4/GET4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0045048 protein insertion into ER membrane	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro-based electronic assignment of the parent ER protein-insertion process, consistent with GET4's role in the TA-targeting pathway. Reason: Correct but generic parent term; GET4 functions at the pre-targeting/loading step. Supporting Evidence: PMID:20676083 facilitates TA protein capture by TRC40
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	KEEP AS NON CORE	Summary: High-throughput interactome dataset capturing GET4 protein interactions. The bare protein binding term is uninformative. Reason: Bare protein binding from a high-throughput screen; uninformative for the core MF. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets
GO:0005515 protein binding	IPI PMID:24722188 Protein interaction network of alternatively spliced isoform...	KEEP AS NON CORE	Summary: Alternatively-spliced isoform interactome (brain) capturing GET4 interactions. The bare protein binding term is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: PMID:24722188 Protein interaction network of alternatively spliced isoforms from brain
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Proteome-scale human interactome map capturing GET4 interactions including the functionally relevant GET3 partner. Bare protein binding is uninformative. Reason: Records real interactions (including GET3) but bare protein binding is uninformative. Supporting Evidence: file:human/GET4/GET4-uniprot.txt Q7L5D6; O43681: GET3
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: Human interactome architecture study capturing GET4 interactions including GET3 and BAG6. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/GET4/GET4-uniprot.txt Q7L5D6; P46379-2: BAG6
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: HuRI binary interactome (Y2H) capturing GET4 partners. Bare protein binding is uninformative. Reason: High-throughput Y2H interactome; bare protein binding is uninformative. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Proteome-scale cell-specific interactome capturing GET4 interactions. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Multimodal cell map study capturing GET4 protein interactions. Bare protein binding is uninformative. Reason: High-throughput cell map; bare protein binding is uninformative. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics
GO:0031647 regulation of protein stability	IMP PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po...	KEEP AS NON CORE	Summary: The Bag6/UBL4A/TRC35 complex acts as a holdase maintaining retrotranslocated polypeptides soluble for proteasomal degradation; GET4/TRC35 also keeps BAG6 in the cytosol. This stability-regulation role is a secondary quality-control function of the complex. Reason: Real but secondary quality-control/holdase role of the Bag6 complex, distinct from GET4's core TA pre-targeting function. Supporting Evidence: PMID:21636303 improve ERAD efficiency
GO:0140597 protein carrier chaperone	IMP PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po...	ACCEPT	Summary: Mutant-phenotype evidence for GET4/TRC35's protein-carrier (chaperone) role within the Bag6 holdase complex that chaperones polypeptides for delivery. Supports the core carrier MF. Reason: Core molecular function; GET4 acts as a carrier/chaperone scaffold in the Bag6 complex. Supporting Evidence: PMID:21636303 holdase
GO:0005515 protein binding	IPI PMID:34887561 Structural insights into metazoan pretargeting GET complexes...	KEEP AS NON CORE	Summary: IPI capturing the functionally central GET4-GET3 interaction from the cryo-EM study of the metazoan pretargeting GET complex. The bare protein binding term is uninformative. Reason: Records the real and important GET3 interaction, but bare protein binding is uninformative; the informative MF is captured by GO:0140597. Supporting Evidence: file:human/GET4/GET4-uniprot.txt Interacts with GET3 (PubMed:34887561)
GO:0005829 cytosol	NAS PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module...	ACCEPT	Summary: ComplexPortal NAS assertion of cytosolic localization, consistent with the cytosolic site of the Bag6 pre-targeting complex. Reason: Correct compartment; consistent with experimental IDA cytosol annotations. Supporting Evidence: file:human/GET4/GET4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006511 ubiquitin-dependent protein catabolic process	IDA PMID:20676083 A ribosome-associating factor chaperones tail-anchored membr...	KEEP AS NON CORE	Summary: The Bag6 complex routes captured hydrophobic substrates to the proteasome; this ubiquitin-dependent catabolic role is the quality-control branch alternative to productive TA targeting. Secondary to GET4's core pre-targeting function. Reason: Real but secondary quality-control/degradation role of the complex; the primary GET4 function is TA pre-targeting/loading. Supporting Evidence: file:human/GET4/GET4-uniprot.txt ensure their proper delivery to the proteasome
GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane	IDA PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module...	ACCEPT	Summary: Direct evidence that the minimal Bag6 complex facilitates TA substrate transfer from SGTA to TRC40/GET3, i.e. post-translational targeting of TA proteins to the ER. Core biological process for GET4. Reason: Core biological process; GET4 mediates the post-translational ER-targeting (loading) step, demonstrated by IDA. Supporting Evidence: PMID:25535373 substrate transfer from small glutamine-rich
GO:0031647 regulation of protein stability	IDA PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po...	KEEP AS NON CORE	Summary: Direct evidence that TRC35 keeps BAG6 in the cytosol and the complex acts as a holdase maintaining substrates soluble. Secondary stability-regulation/quality-control role. Reason: Real but secondary quality-control role, distinct from the core TA pre-targeting function. Supporting Evidence: PMID:21636303 Trc35, a cofactor that keeps Bag6 outside the nucleus
GO:0071818 BAT3 complex	IPI PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module...	ACCEPT	Summary: IPI assignment of GET4/TRC35 to the minimal Bag6 (BAT3) complex, defined biochemically with BAG6 and UBL4A. Reason: Core cellular component; directly demonstrated complex membership. Supporting Evidence: file:human/GET4/GET4-uniprot.txt Component of the BAG6/BAT3 complex, at least composed of BAG6,
GO:0036503 ERAD pathway	IMP PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po...	KEEP AS NON CORE	Summary: The Bag6/UBL4A/TRC35 complex improves ERAD efficiency by chaperoning retrotranslocated polypeptides to the proteasome; TRC35 keeps BAG6 cytosolic for ERAD engagement. A secondary complex-level quality-control role. Reason: Real but secondary ERAD/quality-control role of the complex; not GET4's core TA pre-targeting function. Supporting Evidence: PMID:21636303 improve ERAD efficiency
GO:0005829 cytosol	IMP PMID:32395830 Mutations in GET4 disrupt the transmembrane domain recogniti...	ACCEPT	Summary: Cytosolic localization annotation from the disease study; consistent with GET4's site of action. Reason: Correct compartment; consistent with experimental evidence. Supporting Evidence: file:human/GET4/GET4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0045048 protein insertion into ER membrane	IMP PMID:32395830 Mutations in GET4 disrupt the transmembrane domain recogniti...	KEEP AS NON CORE	Summary: Mutant-phenotype evidence that biallelic GET4 variants destabilize the TRC complex and impair TA-protein (syntaxin 5) targeting to membranes, linking GET4 to the ER protein-insertion/targeting pathway. This generic parent term is correct but less specific than the TA-targeting terms; GET4 acts at the pre-targeting/loading step. Reason: Supported by IMP, but GO:0045048 is a generic parent of the specific TA-targeting terms that better capture GET4's pre-targeting/loading role. Supporting Evidence: PMID:32395830 poorly targeted to Golgi
GO:0005515 protein binding	IPI PMID:29042515 Structural basis for regulation of the nucleo-cytoplasmic di...	KEEP AS NON CORE	Summary: IPI capturing the GET4(TRC35)-BAG6 interaction from the structural study of BAG6 nucleo-cytoplasmic regulation. Functionally meaningful but the bare protein binding term is uninformative. Reason: Records the real BAG6 interaction; bare protein binding is uninformative per guidelines. Supporting Evidence: file:human/GET4/GET4-uniprot.txt Interacts with BAG6; the interaction is direct and localizes BAG6 to the cytosol
GO:0005829 cytosol	IDA PMID:29042515 Structural basis for regulation of the nucleo-cytoplasmic di...	ACCEPT	Summary: Direct evidence of cytosolic localization; TRC35 retains BAG6 in the cytosol by occluding its nuclear localization signal. Reason: Correct compartment; directly demonstrated. Supporting Evidence: PMID:29042515 retain Bag6 in the cytosol
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IDA PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module...	ACCEPT	Summary: Direct evidence that the minimal Bag6 complex (with GET4/TRC35) facilitates TA substrate transfer from SGTA to TRC40, the loading step of the TA-insertion pathway. Core biological process. Reason: Core biological process; IDA demonstrating GET4's role in the TA pre-targeting/loading that commits TA proteins to ER insertion. Supporting Evidence: PMID:25535373 substrate transfer from small glutamine-rich
GO:0051087 protein-folding chaperone binding	IPI PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module...	KEEP AS NON CORE	Summary: IPI capturing the direct GET4-BAG6 interaction (BAG6 being the chaperone/holdase of the complex). More informative than bare protein binding but still an interaction term; reflects GET4's scaffold role within the Bag6 complex. Reason: Real direct interaction with the BAG6 chaperone, but an interaction term rather than GET4's core carrier function; complex membership is captured by GO:0071818. Supporting Evidence: file:human/GET4/GET4-uniprot.txt Interacts with BAG6; the interaction is direct and localizes BAG6 to the cytosol
GO:0071818 BAT3 complex	IDA PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module...	ACCEPT	Summary: Direct evidence placing GET4/TRC35 in the minimal Bag6 (BAT3) complex. Reason: Core cellular component; directly demonstrated. Supporting Evidence: file:human/GET4/GET4-uniprot.txt Component of the BAG6/BAT3 complex, at least composed of BAG6,
GO:0005737 cytoplasm	IDA PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po...	ACCEPT	Summary: Direct evidence of cytoplasmic localization; TRC35 keeps BAG6 (and itself) in the cytoplasm. Reason: Correct compartment; directly demonstrated. Supporting Evidence: PMID:21636303 Trc35, a cofactor that keeps Bag6 outside the nucleus
GO:0071818 BAT3 complex	IDA PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po...	ACCEPT	Summary: Direct evidence placing TRC35 in the Bag6/UBL4A/TRC35 complex. Reason: Core cellular component; directly demonstrated. Supporting Evidence: file:human/GET4/GET4-uniprot.txt Component of the BAG6/BAT3 complex, at least composed of BAG6,
GO:0005829 cytosol	IDA PMID:20676083 A ribosome-associating factor chaperones tail-anchored membr...	ACCEPT	Summary: Direct evidence of cytosolic localization from the study that identified the Bat3/TRC35/Ubl4A TA-targeting complex. Reason: Correct compartment; directly demonstrated. Supporting Evidence: file:human/GET4/GET4-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IMP PMID:20676083 A ribosome-associating factor chaperones tail-anchored membr...	ACCEPT	Summary: Mutant-phenotype evidence that the Bat3/TRC35/Ubl4A complex facilitates TA-protein capture by TRC40, the loading step of the TA-insertion pathway. Core biological process for GET4. Reason: Core biological process with IMP support; GET4 (TRC35) is required for efficient TA capture/loading onto GET3. Supporting Evidence: PMID:20676083 facilitates TA protein capture by TRC40
GO:0071818 BAT3 complex	IDA PMID:20676083 A ribosome-associating factor chaperones tail-anchored membr...	ACCEPT	Summary: Direct evidence placing TRC35/C7ORF20 in the Bat3 (Bag6/BAT3) complex with Bat3 and Ubl4A. Reason: Core cellular component; the complex was defined in this study. Supporting Evidence: file:human/GET4/GET4-uniprot.txt Component of the BAG6/BAT3 complex, at least composed of BAG6,

Gene Description

Existing Annotations Review

Core Functions

Scaffold subunit of the Bag6/BAT3 pre-targeting complex that captures tail-anchored protein transmembrane domains and, by directly contacting GET3/TRC40, bridges their handoff from SGTA onto GET3 to load TA cargo for ER targeting.

Mediates the post-translational ER-targeting (loading) step for tail-anchored membrane proteins as part of the cytosolic Bag6 complex, transferring TA substrates from SGTA to the GET3/TRC40 targeting ATPase.

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