id: Q7L5D6
gene_symbol: GET4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: GET4 (TRC35; also known as C7orf20 and conserved edge-expressed protein/CEE) is a cytosolic TPR-like all-alpha helical scaffold protein that functions in the pre-targeting/loading stage of the GET/TRC pathway for post-translational insertion of tail-anchored (TA) membrane proteins into the endoplasmic reticulum (ER). It is a constitutive subunit of the heterotrimeric BAG6/BAT3 (Bag6) complex (BAG6 + UBL4A + GET4/TRC35), which captures the transmembrane domains of newly released TA proteins at the ribosome and bridges their handoff from the cochaperone SGTA onto the cytosolic targeting ATPase GET3/TRC40. GET4/TRC35 directly contacts GET3, and the GET3-GET4 interface forms a composite lid over the GET3 substrate-binding chamber that controls TA loading. Beyond TA targeting, the Bag6 complex acts as a holdase in protein quality control, keeping mislocalized and retrotranslocated hydrophobic substrates soluble en route to the proteasome (ERAD and mislocalized-protein degradation); GET4/TRC35 also retains BAG6 in the cytosol by occluding its nuclear localization signal. GET4 acts in the cytoplasm/cytosol. Biallelic GET4 variants destabilize the TRC complex and cause a congenital disorder of glycosylation with impaired TA-protein targeting.
alternative_products:
- name: '1'
  id: Q7L5D6-1
- name: '2'
  id: Q7L5D6-2
  sequence_note: VSP_017652
existing_annotations:
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Core molecular function; GET4 is the bridging scaffold that loads TA cargo onto GET3, supported by IMP and the Bag6-complex mechanism.
    supported_by:
    - reference_id: PMID:20676083
      supporting_text: facilitates TA protein capture by TRC40
- term:
    id: GO:0045048
    label: protein insertion into ER membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic parent of the specific TA-insertion/targeting terms; GET4's role is upstream loading.
    supported_by:
    - reference_id: PMID:20676083
      supporting_text: facilitates TA protein capture by TRC40
- term:
    id: GO:0071818
    label: BAT3 complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic annotation of GET4/TRC35 as a constitutive subunit of the BAT3/BAG6 complex (BAG6 + UBL4A + GET4/TRC35). Conserved and directly demonstrated.
    action: ACCEPT
    reason: Core cellular component; GET4 is a defining subunit of the Bag6/BAT3 complex.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: Component of the BAG6/BAT3 complex, at least composed of BAG6,
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of the cytosolic localization from the UniProt subcellular location, consistent with multiple experimental IDA annotations.
    action: ACCEPT
    reason: Correct compartment; GET4 is a cytosolic scaffold.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0045048
    label: protein insertion into ER membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment of the parent ER protein-insertion process, consistent with GET4's role in the TA-targeting pathway.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic parent term; GET4 functions at the pre-targeting/loading step.
    supported_by:
    - reference_id: PMID:20676083
      supporting_text: facilitates TA protein capture by TRC40
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: High-throughput interactome dataset capturing GET4 protein interactions. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from a high-throughput screen; uninformative for the core MF.
    supported_by:
    - reference_id: PMID:21516116
      supporting_text: Next-generation sequencing to generate interactome datasets
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24722188
  qualifier: enables
  review:
    summary: Alternatively-spliced isoform interactome (brain) capturing GET4 interactions. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:24722188
      supporting_text: Protein interaction network of alternatively spliced isoforms from brain
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale human interactome map capturing GET4 interactions including the functionally relevant GET3 partner. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions (including GET3) but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: 'Q7L5D6; O43681: GET3'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Human interactome architecture study capturing GET4 interactions including GET3 and BAG6. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: 'Q7L5D6; P46379-2: BAG6'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: HuRI binary interactome (Y2H) capturing GET4 partners. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput Y2H interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Proteome-scale cell-specific interactome capturing GET4 interactions. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell map study capturing GET4 protein interactions. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput cell map; bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Multimodal cell maps as a foundation for structural and functional genomics
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: IMP
  original_reference_id: PMID:21636303
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Real but secondary quality-control/holdase role of the Bag6 complex, distinct from GET4's core TA pre-targeting function.
    supported_by:
    - reference_id: PMID:21636303
      supporting_text: improve ERAD efficiency
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IMP
  original_reference_id: PMID:21636303
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Core molecular function; GET4 acts as a carrier/chaperone scaffold in the Bag6 complex.
    supported_by:
    - reference_id: PMID:21636303
      supporting_text: holdase
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34887561
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Records the real and important GET3 interaction, but bare protein binding is uninformative; the informative MF is captured by GO:0140597.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: Interacts with GET3 (PubMed:34887561)
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: NAS
  original_reference_id: PMID:25535373
  qualifier: located_in
  review:
    summary: ComplexPortal NAS assertion of cytosolic localization, consistent with the cytosolic site of the Bag6 pre-targeting complex.
    action: ACCEPT
    reason: Correct compartment; consistent with experimental IDA cytosol annotations.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:20676083
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Real but secondary quality-control/degradation role of the complex; the primary GET4 function is TA pre-targeting/loading.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: ensure their proper delivery to the proteasome
- term:
    id: GO:0006620
    label: post-translational protein targeting to endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:25535373
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Core biological process; GET4 mediates the post-translational ER-targeting (loading) step, demonstrated by IDA.
    supported_by:
    - reference_id: PMID:25535373
      supporting_text: substrate transfer from small glutamine-rich
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: IDA
  original_reference_id: PMID:21636303
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Real but secondary quality-control role, distinct from the core TA pre-targeting function.
    supported_by:
    - reference_id: PMID:21636303
      supporting_text: Trc35, a cofactor that keeps Bag6 outside the nucleus
- term:
    id: GO:0071818
    label: BAT3 complex
  evidence_type: IPI
  original_reference_id: PMID:25535373
  qualifier: part_of
  review:
    summary: IPI assignment of GET4/TRC35 to the minimal Bag6 (BAT3) complex, defined biochemically with BAG6 and UBL4A.
    action: ACCEPT
    reason: Core cellular component; directly demonstrated complex membership.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: Component of the BAG6/BAT3 complex, at least composed of BAG6,
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:21636303
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Real but secondary ERAD/quality-control role of the complex; not GET4's core TA pre-targeting function.
    supported_by:
    - reference_id: PMID:21636303
      supporting_text: improve ERAD efficiency
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IMP
  original_reference_id: PMID:32395830
  qualifier: located_in
  review:
    summary: Cytosolic localization annotation from the disease study; consistent with GET4's site of action.
    action: ACCEPT
    reason: Correct compartment; consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0045048
    label: protein insertion into ER membrane
  evidence_type: IMP
  original_reference_id: PMID:32395830
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:32395830
      supporting_text: poorly targeted to Golgi
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29042515
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Records the real BAG6 interaction; bare protein binding is uninformative per guidelines.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: Interacts with BAG6; the interaction is direct and localizes BAG6 to the cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:29042515
  qualifier: located_in
  review:
    summary: Direct evidence of cytosolic localization; TRC35 retains BAG6 in the cytosol by occluding its nuclear localization signal.
    action: ACCEPT
    reason: Correct compartment; directly demonstrated.
    supported_by:
    - reference_id: PMID:29042515
      supporting_text: retain Bag6 in the cytosol
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:25535373
  qualifier: involved_in
  review:
    summary: 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.
    action: ACCEPT
    reason: Core biological process; IDA demonstrating GET4's role in the TA pre-targeting/loading that commits TA proteins to ER insertion.
    supported_by:
    - reference_id: PMID:25535373
      supporting_text: substrate transfer from small glutamine-rich
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:25535373
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: Interacts with BAG6; the interaction is direct and localizes BAG6 to the cytosol
- term:
    id: GO:0071818
    label: BAT3 complex
  evidence_type: IDA
  original_reference_id: PMID:25535373
  qualifier: part_of
  review:
    summary: Direct evidence placing GET4/TRC35 in the minimal Bag6 (BAT3) complex.
    action: ACCEPT
    reason: Core cellular component; directly demonstrated.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: Component of the BAG6/BAT3 complex, at least composed of BAG6,
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21636303
  qualifier: located_in
  review:
    summary: Direct evidence of cytoplasmic localization; TRC35 keeps BAG6 (and itself) in the cytoplasm.
    action: ACCEPT
    reason: Correct compartment; directly demonstrated.
    supported_by:
    - reference_id: PMID:21636303
      supporting_text: Trc35, a cofactor that keeps Bag6 outside the nucleus
- term:
    id: GO:0071818
    label: BAT3 complex
  evidence_type: IDA
  original_reference_id: PMID:21636303
  qualifier: part_of
  review:
    summary: Direct evidence placing TRC35 in the Bag6/UBL4A/TRC35 complex.
    action: ACCEPT
    reason: Core cellular component; directly demonstrated.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: Component of the BAG6/BAT3 complex, at least composed of BAG6,
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:20676083
  qualifier: located_in
  review:
    summary: Direct evidence of cytosolic localization from the study that identified the Bat3/TRC35/Ubl4A TA-targeting complex.
    action: ACCEPT
    reason: Correct compartment; directly demonstrated.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IMP
  original_reference_id: PMID:20676083
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Core biological process with IMP support; GET4 (TRC35) is required for efficient TA capture/loading onto GET3.
    supported_by:
    - reference_id: PMID:20676083
      supporting_text: facilitates TA protein capture by TRC40
- term:
    id: GO:0071818
    label: BAT3 complex
  evidence_type: IDA
  original_reference_id: PMID:20676083
  qualifier: part_of
  review:
    summary: Direct evidence placing TRC35/C7ORF20 in the Bat3 (Bag6/BAT3) complex with Bat3 and Ubl4A.
    action: ACCEPT
    reason: Core cellular component; the complex was defined in this study.
    supported_by:
    - reference_id: file:human/GET4/GET4-uniprot.txt
      supporting_text: Component of the BAG6/BAT3 complex, at least composed of BAG6,
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: PMID:20676083
  title: A ribosome-associating factor chaperones tail-anchored membrane proteins.
  findings:
  - statement: Identifies the Bat3/TRC35(C7ORF20)/Ubl4A complex that is recruited to ribosomes, binds TA-protein TMDs, and facilitates TA protein capture by TRC40 for targeting.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding study defining the Bag6/BAT3 (TRC35-containing) TA pre-targeting complex.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; bare protein binding source.
- id: PMID:21636303
  title: A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation.
  findings:
  - statement: The Bag6/Ubl4A/Trc35 complex acts as a holdase that chaperones retrotranslocated polypeptides to the proteasome to improve ERAD efficiency; Trc35 keeps Bag6 outside the nucleus for ERAD engagement.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the holdase/ERAD and BAG6 cytosolic-retention roles of the TRC35-containing complex.
- id: PMID:24722188
  title: Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput isoform interactome; bare protein binding source.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; bare protein binding, includes GET3.
- id: PMID:25535373
  title: Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain.
  findings:
  - statement: The minimal Bag6 complex facilitates TA substrate transfer from SGTA to TRC40, the post-translational ER-targeting loading step.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines the minimal Bag6 module and its TA-loading (SGTA->TRC40) function.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; bare protein binding, includes BAG6/GET3.
- id: PMID:29042515
  title: Structural basis for regulation of the nucleo-cytoplasmic distribution of Bag6 by TRC35.
  findings:
  - statement: TRC35 binding occludes the BAG6 nuclear localization sequence to retain BAG6 in the cytosol and protects TRC35 from RNF126-mediated ubiquitylation/degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the GET4/TRC35-mediated cytoplasmic retention of BAG6.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI Y2H interactome; bare protein binding source.
- id: PMID:32395830
  title: Mutations in GET4 disrupt the transmembrane domain recognition complex pathway.
  findings:
  - statement: Biallelic GET4 missense variants reduce all three TRC proteins by 70-90% and impair targeting of the TA protein syntaxin 5, causing a congenital disorder of glycosylation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Disease study; IMP evidence that GET4 loss disrupts the TRC/GET pathway and TA targeting.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; bare protein binding source.
- id: PMID:34887561
  title: Structural insights into metazoan pretargeting GET complexes.
  findings:
  - statement: Cryo-EM of the metazoan pretargeting GET complex; Get4(TRC35) directly contacts Get3/TRC40 and the Get3 helix-8/Get4 C-terminus form a composite lid over the substrate chamber, facilitating TA transfer from SGTA to Get3.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural basis of the GET4-GET3 interaction and TA-loading mechanism.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput cell map; bare protein binding source.
- id: PMID:37747814
  title: Proteotoxic stresses stimulate dissociation of UBL4A from the tail-anchored protein recognition complex.
  findings:
  - statement: Disease-associated polyQ inclusions, proteasome inhibition, and CCCP-induced mitochondrial depolarization stimulate dissociation of UBL4A from BAG6 within the BAG6/UBL4A/GET4(TRC35) complex, indicating the TA-recognition complex is remodeled under proteotoxic stress.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Hagiwara et al., Biochem J 2023). Adds stress-sensitivity of the GET4-containing BAG6/UBL4A complex; relevant to GET4 via its complex, not a direct GET4-specific assay.
- id: PMID:35409131
  title: Targeting of Proteins for Translocation at the Endoplasmic Reticulum.
  findings:
  - statement: Reviews the mammalian TRC/GET pre-targeting machinery, describing TRC35(GET4) within ribosome-associated BAG6 complexes that enhance recruitment of TA-handling factors and promote handover of TA clients to TRC40.
    reference_section_type: OTHER
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Pool 2022, Int J Mol Sci review (DOI 10.3390/ijms23073773); supports the ribosome-proximal pre-targeting role of GET4/TRC35.
- id: file:human/GET4/GET4-uniprot.txt
  title: UniProt entry Q7L5D6 (GET4_HUMAN), Golgi to ER traffic protein 4 homolog / TRC35
  findings:
  - statement: Component of the BAG6/BAT3 complex (BAG6 + UBL4A + GET4/TRC35); interacts directly with BAG6 (retaining it in the cytosol) and with GET3; cytosolic scaffold of the TA pre-targeting pathway.
    reference_section_type: OTHER
core_functions:
- description: 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.
  molecular_function:
    id: GO:0140597
    label: protein carrier chaperone
  in_complex:
    id: GO:0071818
    label: BAT3 complex
  supported_by:
  - reference_id: PMID:20676083
    supporting_text: facilitates TA protein capture by TRC40
  - reference_id: PMID:34887561
    supporting_text: transfer from SGTA to Get3
  directly_involved_in:
  - id: GO:0006620
    label: post-translational protein targeting to endoplasmic reticulum membrane
- description: 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.
  molecular_function:
    id: GO:0140597
    label: protein carrier chaperone
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:25535373
    supporting_text: substrate transfer from small glutamine-rich
  directly_involved_in:
  - id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
proposed_new_terms: []
suggested_questions:
- question: How is GET4/TRC35 partitioned between the productive TA-targeting branch (loading onto GET3) and the quality-control/ERAD holdase branch of the Bag6 complex, and what determines the choice?
- question: Do the disease-causing GET4 variants impair TA targeting primarily through loss of complex stability, or also through specific disruption of the GET4-GET3 loading interface?
suggested_experiments:
- description: Reconstitute the SGTA -> BAG6/UBL4A/GET4 -> GET3 handoff with purified wild-type and interface-mutant GET4 to quantify how the GET4-GET3 composite lid controls TA loading kinetics and fidelity.
- description: Compare the cytosolic interactome and substrate flux of cells expressing wild-type versus CDG-associated GET4 variants to distinguish complex-destabilization from loading-interface defects.