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,

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.

Molecular Function:

protein carrier chaperone

Directly Involved In:

post-translational protein targeting to endoplasmic reticulum membrane

In Complex:

BAT3 complex

Supporting Evidence:

PMID:20676083
facilitates TA protein capture by TRC40
PMID:34887561
transfer from SGTA to Get3

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:

protein carrier chaperone

Directly Involved In:

tail-anchored membrane protein insertion into ER membrane

Cellular Locations:

cytosol

Supporting Evidence:

PMID:25535373
substrate transfer from small glutamine-rich

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

PMID:20676083

A ribosome-associating factor chaperones tail-anchored membrane proteins.

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.

PMID:21516116

Next-generation sequencing to generate interactome datasets.

PMID:21636303

A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation.

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.

PMID:24722188

Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25535373

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

The minimal Bag6 complex facilitates TA substrate transfer from SGTA to TRC40, the post-translational ER-targeting loading step.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:29042515

Structural basis for regulation of the nucleo-cytoplasmic distribution of Bag6 by TRC35.

TRC35 binding occludes the BAG6 nuclear localization sequence to retain BAG6 in the cytosol and protects TRC35 from RNF126-mediated ubiquitylation/degradation.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32395830

Mutations in GET4 disrupt the transmembrane domain recognition complex pathway.

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.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34887561

Structural insights into metazoan pretargeting GET complexes.

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.

PMID:40205054

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

PMID:37747814

Proteotoxic stresses stimulate dissociation of UBL4A from the tail-anchored protein recognition complex.

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.

PMID:35409131

Targeting of Proteins for Translocation at the Endoplasmic Reticulum.

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.

file:human/GET4/GET4-uniprot.txt

UniProt entry Q7L5D6 (GET4_HUMAN), Golgi to ER traffic protein 4 homolog / TRC35

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.

Suggested Experiments

Experiment: 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.

Experiment: 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.

Deep Research

Falcon

(GET4-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 29 citations 2 artifacts 2026-06-12T02:18:52.419289

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000017 The main figure showing the architecture of the metazoan pre-targeting GET complex (cBUGG) and its interaction with SGTA (cBUGGS) i (image/png)

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

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

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

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

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

Research report: Human GET4 (TRC35) functional annotation (UniProt Q7L5D6)

0) Target verification (critical disambiguation)

The target is human GET4 (synonyms TRC35, C7orf20, CEE, CGI-20), the metazoan homolog of yeast Get4, and a core component of the mammalian TRC/GET tail-anchored (TA) protein targeting pathway. This mapping is explicitly stated in comparative pathway literature that equates metazoan Get4 with TRC35 and cites UniProt Q7L5D6 in this context. (najdrova2022conservedmechanismfor pages 16-20, najdrova2022conservedmechanismfor pages 20-23)

1) Key concepts and definitions (current understanding)

Tail-anchored (TA) proteins

TA proteins are single-pass membrane proteins whose hydrophobic transmembrane domain (TMD) is at the extreme C-terminus, so the targeting signal emerges only after translation terminates; therefore TA proteins are primarily handled by post-translational targeting systems. (najdrova2022conservedmechanismfor pages 88-98)

GET/TRC pathway (guided entry of TA proteins / transmembrane recognition complex)

The GET pathway (yeast terminology) and TRC pathway (mammalian terminology) constitute a conserved cytosolic-to-ER relay that captures TA TMDs in the cytosol, loads them onto a targeting ATPase (Get3 in yeast; TRC40/ASNA1 in mammals), and delivers them to an ER membrane receptor/insertase (Get1/Get2 in yeast; WRB/CAML in mammals) for insertion. (najdrova2022conservedmechanismfor pages 16-20, farkas2021captureanddelivery pages 1-3)

Where GET4/TRC35 fits

GET4/TRC35 is not an enzyme and does not catalyze a chemical reaction. Its primary role is as a scaffold/adaptor in the pre-targeting complex that promotes client handoff to TRC40 and coordinates targeting vs quality-control decisions for hydrophobic clients. (pool2022targetingofproteins pages 7-9, keszei2021structuralinsightsinto pages 6-7)

2) Molecular function and mechanism of GET4/TRC35

2.1 Core molecular function: pretargeting scaffold to load TA substrates onto TRC40

Multiple reviews and structural studies converge on a mechanistic model in which GET4/TRC35 participates in the cytosolic pretargeting complex that connects upstream TA capture factors to the downstream targeting ATPase:

In mammals, the pretargeting machinery is described as a BAG6-containing complex often written as BAG6–UBL4A–TRC35 (GET4) that accepts TA substrates from SGTA and transfers them to TRC40 for delivery to the ER receptor WRB/CAML. (mock2017structuralbasisfor pages 1-2, farkas2021captureanddelivery pages 1-3)
In a mechanistically explicit review of ER targeting, TRC35 is described as ribosome-associated and part of the BAG6 complex, functioning near the ribosomal exit to enhance recruitment of TA-handling factors and promote efficient handover of TA clients to TRC40. (pool2022targetingofproteins pages 7-9)

2.2 Structural and biophysical evidence for GET4’s mechanistic role

A key primary structural study defined the metazoan pretargeting GET complex architecture (cBUGG: cBag6–Ubl4a–Get4–Get3) and how it promotes substrate transfer:

Cryo-EM architecture: Ubl4a and cBag6 assemble with Get4 to form a “recruitment platform” positioned above the Get3 substrate chamber, consistent with a structural role for Get4 in organizing TA substrate loading and transfer. (keszei2021structuralinsightsinto pages 6-7, keszei2021structuralinsightsinto media 33007d62)
Functional interface evidence: Secondary Get3–Get4 interactions were shown to be important for SGTA→Get3 transfer, because a Get3 interface mutation disrupted transfer while not blocking TA capture by Get3 in a reconstituted translation system—supporting a transfer-catalysis/scaffolding function rather than direct substrate binding as the primary role. (keszei2021structuralinsightsinto pages 6-7)

These data support the current view that GET4/TRC35 is a noncatalytic organizational factor that enhances the efficiency and fidelity of TA handoff to TRC40/ASNA1. (keszei2021structuralinsightsinto pages 6-7)

3) Interaction partners and complexes

3.1 The BAG6–UBL4A–GET4/TRC35 complex

In metazoans, yeast Get4/Get5 is replaced/augmented by a heterotrimeric complex containing BAG6, UBL4A (Get5 homolog), and TRC35/GET4. This complex is repeatedly described as central to TA biogenesis and transfer to TRC40. (najdrova2022conservedmechanismfor pages 16-20, mock2017structuralbasisfor pages 1-2)

3.2 Upstream and downstream partners in the TA relay

Upstream capture: SGTA (Sgt2 homolog) captures newly released TA clients and interfaces with the BAG6–UBL4A–TRC35 module. (mock2017structuralbasisfor pages 1-2, qin2023targetingandsurveillance pages 1-2)
Downstream targeting ATPase: TRC40/ASNA1 accepts substrates for delivery to the ER. (mock2017structuralbasisfor pages 1-2)
ER insertion receptor/insertase: WRB/CAML is the downstream ER-resident receptor/insertase for TRC40-delivered TA clients. (najdrova2022conservedmechanismfor pages 16-20, farkas2021captureanddelivery pages 1-3)

4) Subcellular localization: where GET4 acts

4.1 Cytosolic and ribosome-proximal action

GET4/TRC35 functions in the cytosol, early in the pathway, in a ribosome-proximal capture/transfer environment as described in reviews of ER targeting and TA biogenesis. (pool2022targetingofproteins pages 7-9, qin2023targetingandsurveillance pages 1-2)

4.2 Regulation of BAG6 nucleo-cytoplasmic distribution (direct human evidence)

A major human-specific mechanistic finding is that TRC35 directly regulates where BAG6 resides:

TRC35 binds BAG6 in a manner that masks the BAG6 nuclear localization sequence (NLS), preventing BAG6 binding to import machinery and thereby retaining BAG6 in the cytosol. (mock2017structuralbasisfor pages 1-2, mock2017structuralbasisfor pages 2-3)

This provides a concrete mechanistic link between the TA targeting apparatus and cellular compartmentalization of a multifunctional cofactor (BAG6). (mock2017structuralbasisfor pages 1-2)

5) Quality control roles connected to GET4/TRC35 (proteostasis functions)

5.1 Targeting vs degradation decision-making in BAG6-containing complexes

Beyond productive TA targeting, BAG6-containing complexes are described as mediating triage of exposed hydrophobic segments: substrates can be transferred to TRC40 for insertion or directed toward ubiquitin–proteasome degradation when targeting fails or clients are defective/mislocalized. (costa2017intracellulartargetingof pages 25-30, farkas2021captureanddelivery pages 1-3)

This contextualizes GET4/TRC35 as part of a network that couples membrane-protein biogenesis to proteostasis quality control. (pool2022targetingofproteins pages 7-9)

5.2 TRC35 stability is controlled by BAG6 association and ubiquitination

In human TRC35 biology, proper assembly with BAG6 affects TRC35 stability:

Disruption of physiological BAG6–TRC35 association leads to increased ubiquitylated TRC35 and reduced steady-state TRC35 levels; these TRC35 reductions can be rescued by proteasome inhibition (MG132). The BAG6-associated E3 ligase RNF126 is implicated in TRC35 ubiquitylation when TRC35 is unassembled/misassembled. (mock2017structuralbasisfor pages 2-3)

This supports a model in which GET4/TRC35 is itself surveilled by quality-control machinery, and correct complex assembly protects it. (mock2017structuralbasisfor pages 2-3)

6) Recent developments (prioritizing 2023–2024)

Direct GET4/TRC35-focused primary literature in 2024 was limited in the accessible corpus for this run; however, 2023 studies provide meaningful, mechanistically relevant updates on the stress sensitivity and broader proteostasis integration of the BAG6–UBL4A–GET4 module.

6.1 2023 review synthesis: targeting and surveillance mechanisms

A 2023 review summarizes the TRC/GET system as a conserved TA targeting route and reiterates the key role of the Get4/TRC35 pretargeting complex (with UBL4A, BAG6) in TA capture and transfer, emphasizing the integration of targeting with surveillance of mistargeted TA proteins. (qin2023targetingandsurveillance pages 1-2)

Publication: Qin et al. 2023-01, The Innovation Life. URL: https://doi.org/10.59717/j.xinn-life.2023.100013 (qin2023targetingandsurveillance pages 1-2)

6.2 2023 primary study: proteotoxic stress remodels the complex (with quantitative statistics)

A 2023 Biochemical Journal study tested how proteotoxic stresses affect complex integrity:

Disease-associated polyQ inclusions and stresses such as proteasome inhibition and mitochondrial depolarization stimulate dissociation of UBL4A from BAG6 (a core association in the BAG6–UBL4A–GET4 complex), consistent with stress-induced impairment of TA biogenesis machinery and/or reallocation toward aggregate handling. (hagiwara2023proteotoxicstressesstimulate pages 7-10, hagiwara2023proteotoxicstressesstimulate pages 1-3)
Quantitative reporting included: co-IP with 6 biological replicates, statistical testing with Student’s t-test; NanoBiT CCCP time course n=3 with P<0.01; and a CCCP 4-hour assay n=4 with P<0.01 (Welch’s t-test). (hagiwara2023proteotoxicstressesstimulate pages 7-10)

Publication: Hagiwara et al. 2023-10, Biochemical Journal. URL: https://doi.org/10.1042/bcj20230267 (hagiwara2023proteotoxicstressesstimulate pages 7-10)

6.3 2023: broader proteostasis and translation surveillance contexts

A 2023 Nature paper (noncoding translation mitigation) identifies BAG6 pathway components including TRC35/GET4 in a broader proteostasis/surveillance context (as reported in the retrieved snippet), supporting the idea that GET4-containing modules participate not only in TA targeting but also in mitigation of aberrant translation-derived hydrophobic products. (OpenTargets Search: -GET4)

Publication: Kesner et al. 2023-04, Nature. URL: https://doi.org/10.1038/s41586-023-05946-4 (OpenTargets Search: -GET4)

7) Current applications and real-world implementations

7.1 Practical biological applications

In practice, GET4/TRC35 is used as a mechanistic handle to:

Study TA protein biogenesis fidelity (TA clients include key membrane-trafficking proteins such as SNAREs) and how cytosolic chaperone cascades prevent aggregation of hydrophobic TMDs. (farkas2021captureanddelivery pages 1-3)
Probe proteostasis/quality control mechanisms at the interface of targeting and degradation, including how BAG6-centered networks triage hydrophobic clients. (farkas2021captureanddelivery pages 1-3, mock2017structuralbasisfor pages 2-3)

These applications are most mature in mechanistic cell biology and structural biology rather than direct clinical implementation.

7.2 Tooling and experimental platforms

Cryo-EM and crosslinking have enabled structural characterization of the recruitment platform and remodeling by SGTA, providing a framework for mutational/functional studies of substrate transfer. (keszei2021structuralinsightsinto pages 6-7, keszei2021structuralinsightsinto media 33007d62)
NanoBiT complementation assays can quantify complex integrity changes under stress, as in the 2023 UBL4A–BAG6 dissociation study. (hagiwara2023proteotoxicstressesstimulate pages 7-10)

8) Expert opinions and authoritative synthesis

Several authoritative reviews emphasize a consistent expert consensus:

TA targeting is best viewed as a multi-component chaperone cascade in which scaffolding factors (Get4/TRC35 complexes) promote efficient substrate relay to the targeting ATPase and couple targeting decisions to quality control, especially for hydrophobic clients that would otherwise aggregate. (shan2019guidingtailanchoredmembrane pages 2-4, pool2022targetingofproteins pages 7-9)
Modern structural work supports an architecture in which Get4 acts as a platform organizer positioned over Get3/TRC40 to promote transfer rather than as the direct substrate-binding core of the pathway. (keszei2021structuralinsightsinto pages 6-7)

9) Disease associations and phenotypes (evidence strength and caveats)

9.1 Curated association-level links (Open Targets)

Open Targets aggregates evidence connecting GET4 to several disease/phenotype terms, including neurodegenerative disease, atrial fibrillation, atrial flutter, and congenital disorder of glycosylation type IIy. These are associations drawn from specific studies/variants and functional screens, not proof of direct causality or a defined GET4 mechanism in each disease. (OpenTargets Search: -GET4)

9.2 Mechanistic plausibility from proteostasis literature

Given that the BAG6–UBL4A–GET4 module is implicated in:

TA biogenesis (which affects vesicular trafficking and secretory pathway function), (farkas2021captureanddelivery pages 1-3)
quality control and proteotoxic stress responses (including stress-driven complex dissociation), (hagiwara2023proteotoxicstressesstimulate pages 7-10)
stability/ubiquitylation control of TRC35 itself (RNF126, proteasome dependence), (mock2017structuralbasisfor pages 2-3)

it is mechanistically plausible that perturbations could contribute to proteostasis-linked diseases, but the accessible primary clinical genetics evidence for GET4 specifically was limited in this run.

10) Visual evidence (complex architecture)

The cryo-EM figure extracted from Keszei et al. illustrates the cBUGG (cBag6–Ubl4a–Get4–Get3) architecture and how SGTA remodels it, supporting the “recruitment platform” concept for GET4/TRC35 function. (keszei2021structuralinsightsinto media 33007d62, keszei2021structuralinsightsinto media 2e1a5e15)

11) Summary table of functional annotation

The following table consolidates identity, molecular function, partners, localization, QC roles, and key references.

Entity / aspect	Summary for human GET4 / TRC35	Key evidence / mechanism	Evidence type	Key references
Identity	GET4 encodes the human guided entry of tail-anchored proteins factor 4; common aliases include TRC35, C7orf20, CEE, and CGI-20. It is the metazoan homolog of yeast Get4 and matches the UniProt target Q7L5D6 discussed in the GET/TRC literature (najdrova2022conservedmechanismfor pages 16-20, najdrova2022conservedmechanismfor pages 20-23).	Conserved assignment of metazoan Get4 to TRC35/GET4 in reviews and comparative pathway analyses (najdrova2022conservedmechanismfor pages 16-20, najdrova2022conservedmechanismfor pages 20-23).	Comparative pathway mapping, review	Qin 2023, The Innovation Life, doi: https://doi.org/10.59717/j.xinn-life.2023.100013 ; Pool 2022, IJMS, doi: https://doi.org/10.3390/ijms23073773
Primary molecular function	GET4/TRC35 is a cytosolic pretargeting scaffold/adaptor in the GET/TRC pathway for tail-anchored (TA) membrane proteins. It does not catalyze a chemical reaction; instead, it helps organize factors that capture, shield, and hand off hydrophobic TA transmembrane domains to the targeting ATPase TRC40/ASNA1 for ER delivery (pool2022targetingofproteins pages 7-9, shan2019guidingtailanchoredmembrane pages 2-4, najdrova2022conservedmechanismfor pages 16-20, keszei2021structuralinsightsinto pages 6-7).	Reviews and structural work place Get4/TRC35 in the upstream relay between SGTA/Sgt2 and Get3/TRC40, promoting efficient substrate loading onto the ATPase (pool2022targetingofproteins pages 7-9, shan2019guidingtailanchoredmembrane pages 2-4, keszei2021structuralinsightsinto pages 6-7).	Review, biochemical, cryo-EM	Shan 2019, JBC, doi: https://doi.org/10.1074/jbc.rev119.006197 ; Keszei 2021, Nat Struct Mol Biol, doi: https://doi.org/10.1038/s41594-021-00690-7
Core complex composition	In mammals, GET4/TRC35 is a stable component of the BAG6–UBL4A–GET4 pretargeting complex (often treated as the metazoan counterpart of yeast Get4/Get5). BAG6 binds both GET4/TRC35 and UBL4A/Get5; SGTA acts upstream in TA capture; TRC40/ASNA1 is the downstream targeting ATPase; ER insertion is completed at WRB/CAML (costa2017intracellulartargetingof pages 25-30, najdrova2022conservedmechanismfor pages 16-20, mock2017structuralbasisfor pages 1-2, farkas2021captureanddelivery pages 1-3).	Human/metazoan studies and reviews describe a heterotrimeric BAG6–UBL4A–TRC35 complex that receives TA substrates from SGTA and transfers them to TRC40 for delivery to WRB/CAML (mock2017structuralbasisfor pages 1-2, farkas2021captureanddelivery pages 1-3).	Structural, biochemical, review	Mock 2017, PNAS, doi: https://doi.org/10.1073/pnas.1702940114 ; Farkas & Bohnsack 2021, J Cell Biol, doi: https://doi.org/10.1083/jcb.202105004
Mechanistic role in TA targeting: capture and handoff	Canonical handoff sequence: ribosome / chaperones → SGTA → BAG6–UBL4A–GET4(TRC35) → TRC40/ASNA1 → WRB/CAML at the ER. GET4/TRC35 helps create the recruitment platform that positions upstream factors for TA substrate transfer to Get3/TRC40; in metazoan cryo-EM, UBL4A-cBAG6-GET4 forms a recruitment platform above the Get3 substrate chamber (keszei2021structuralinsightsinto pages 6-7, keszei2021structuralinsightsinto media 33007d62).	Keszei et al. defined a metazoan pretargeting architecture where Get4 helps position Ubl4a/BAG6 to recruit SGTA and promote substrate transfer; mutations affecting the secondary Get3–Get4 interface impaired SGTA→Get3 transfer without blocking Get3 substrate capture per se (keszei2021structuralinsightsinto pages 6-7).	Cryo-EM, crosslinking, biochemical	Keszei 2021, Nat Struct Mol Biol, doi: https://doi.org/10.1038/s41594-021-00690-7 ; Figure context (keszei2021structuralinsightsinto media 33007d62)
Ribosome association / early targeting stage	GET4/TRC35 functions early, close to the site of synthesis. Reviews describe the mammalian pretargeting machinery as ribosome-associated or ribosome-proximal, with TA capture occurring at or near the ribosome before handoff to TRC40; Get4/TRC35 was also identified among ribosome-associated proteins in comparative analyses (pool2022targetingofproteins pages 7-9, qin2023targetingandsurveillance pages 1-2, najdrova2022conservedmechanismfor pages 20-23).	Pool 2022 describes TRC35 within ribosome-associated BAG6 complexes; Qin 2023 discusses ribosome-proximal capture and competition near the tunnel exit; comparative analysis notes Get4 identification in ribosome-associated screens (pool2022targetingofproteins pages 7-9, qin2023targetingandsurveillance pages 1-2, najdrova2022conservedmechanismfor pages 20-23).	Review, proteomic / comparative inference	Pool 2022, IJMS, doi: https://doi.org/10.3390/ijms23073773 ; Qin 2023, The Innovation Life, doi: https://doi.org/10.59717/j.xinn-life.2023.100013
Subcellular localization	Best-supported localization is cytosolic, within the pretargeting complex acting before ER membrane insertion. Functionally, GET4/TRC35 is linked to ER targeting through its interaction network, but it is not itself the ER insertase; ER insertion is mediated by WRB/CAML after TRC40 delivery (najdrova2022conservedmechanismfor pages 16-20, mock2017structuralbasisfor pages 1-2, farkas2021captureanddelivery pages 1-3).	Cytosolic pretargeting role is consistently reported in reviews and structural studies; downstream localization step is ER membrane insertion by WRB/CAML, not by GET4 itself (najdrova2022conservedmechanismfor pages 16-20, mock2017structuralbasisfor pages 1-2, farkas2021captureanddelivery pages 1-3).	Review, structural	Mock 2017, PNAS, doi: https://doi.org/10.1073/pnas.1702940114 ; Farkas & Bohnsack 2021, J Cell Biol, doi: https://doi.org/10.1083/jcb.202105004
Control of BAG6 nucleo-cytoplasmic distribution	A key human-specific mechanistic finding is that TRC35 masks the BAG6 nuclear localization sequence (NLS), thereby retaining BAG6 in the cytosol. Overexpression of TRC35 increases cytosolic retention of BAG6; structural analysis showed TRC35 occludes the first basic cluster of the BAG6 NLS (mock2017structuralbasisfor pages 1-2, mock2017structuralbasisfor pages 2-3).	Human crystal structure and biochemical assays support direct Bag6–TRC35 interfaces; buried surface metrics and mutational effects showed that physiological complex assembly regulates BAG6 localization (mock2017structuralbasisfor pages 1-2, mock2017structuralbasisfor pages 2-3).	Crystal structure, biochemical, cell biology	Mock 2017, PNAS, doi: https://doi.org/10.1073/pnas.1702940114
Quality control role: substrate triage	GET4/TRC35 participates in a module that links TA targeting with cytosolic quality control. BAG6-containing complexes can direct hydrophobic or mislocalized clients either toward productive loading onto TRC40 or toward ubiquitin-proteasome degradation, helping prevent aggregation of exposed transmembrane segments (pool2022targetingofproteins pages 7-9, costa2017intracellulartargetingof pages 25-30, farkas2021captureanddelivery pages 1-3, hagiwara2023proteotoxicstressesstimulate pages 1-3).	Reviews emphasize the dual targeting-versus-degradation role of BAG6 complexes; Hagiwara 2023 further links this machinery to aggregate/proteotoxic stress responses (farkas2021captureanddelivery pages 1-3, hagiwara2023proteotoxicstressesstimulate pages 1-3).	Review, biochemical	Farkas & Bohnsack 2021, J Cell Biol, doi: https://doi.org/10.1083/jcb.202105004 ; Hagiwara 2023, Biochem J, doi: https://doi.org/10.1042/bcj20230267
Quality control role: RNF126 and TRC35 stability	Human studies indicate that unassembled or mutant TRC35 can become a target of RNF126-mediated ubiquitylation in the BAG6-associated quality-control network. Proper Bag6 association protects TRC35; Bag6-disrupting mutants increased Ub-conjugated TRC35 and lowered steady-state TRC35 levels, reversible by proteasome inhibition (MG132) (mock2017structuralbasisfor pages 2-3).	Mock et al. identified RNF126 as a Bag6-associated E3 ligase implicated in TRC35 ubiquitylation and showed that disrupted physiological Bag6–TRC35 interaction destabilizes TRC35 (mock2017structuralbasisfor pages 2-3).	Structural, biochemical, ubiquitination assay	Mock 2017, PNAS, doi: https://doi.org/10.1073/pnas.1702940114
Proteotoxic stress effects (2023)	In 2023, proteotoxic stress studies showed that the TA recognition complex is stress-sensitive: polyQ aggregates, proteasome inhibition, and CCCP-induced mitochondrial depolarization promoted dissociation of UBL4A from BAG6, implying that the BAG6–UBL4A–GET4 module is remodeled under proteotoxic conditions and may shift away from normal TA biogenesis (hagiwara2023proteotoxicstressesstimulate pages 7-10, hagiwara2023proteotoxicstressesstimulate pages 1-3).	Hagiwara et al. reported quantitative assays: co-IP with n = 6 biological replicates analyzed by Student’s t-test; NanoBiT CCCP time-course n = 3, P < 0.01; CCCP 4 h assay n = 4, Welch’s t-test, P < 0.01 (hagiwara2023proteotoxicstressesstimulate pages 7-10).	Biochemical, cell assay, quantitative stress biology	Hagiwara 2023, Biochem J, doi: https://doi.org/10.1042/bcj20230267
Related nuclear / DNA-damage context	The strongest direct evidence concerns BAG6, not GET4 as an autonomous nuclear factor. Because TRC35 controls BAG6 cytosolic retention, it indirectly interfaces with BAG6’s reported nuclear functions in p300 acetylation, histone methylation, and DNA-damage signaling-mediated cell death; however, direct GET4-specific nuclear signaling functions remain less established than its pretargeting role (mock2017structuralbasisfor pages 1-2).	Mock 2017 explicitly ties TRC35 to BAG6 localization control while noting BAG6 nuclear functions; evidence is indirect for GET4 beyond localization control (mock2017structuralbasisfor pages 1-2).	Structural, cell biology, literature synthesis	Mock 2017, PNAS, doi: https://doi.org/10.1073/pnas.1702940114
2023–2024 broader relevance / applications	Recent literature places GET4/TRC35-containing BAG6 complexes in broader proteostasis surveillance, including mitigation of aberrant noncoding translation products and maintenance of membrane protein biogenesis fidelity. One 2023 Nature study identified BAG6, TRC35/GET4, RNF126, SGTA, and UBL4A in this surveillance axis (OpenTargets Search: -GET4). Disease links in Open Targets are currently association-level rather than definitive mechanism-level annotations for GET4 itself (OpenTargets Search: -GET4).	Evidence supports translational quality control relevance but not yet a mature clinical application directly targeting GET4; Open Targets associations include neurodegenerative disease and congenital disorder of glycosylation type IIy, but these should be interpreted cautiously as evidence aggregation rather than causal proof (OpenTargets Search: -GET4).	Genetics / CRISPRi association, database aggregation	Kesner 2023, Nature, doi: https://doi.org/10.1038/s41586-023-05946-4 ; Open Targets context (OpenTargets Search: -GET4)

Table: This table summarizes the best-supported functions, interactions, localization, quality-control roles, and recent developments for human GET4/TRC35 (UniProt Q7L5D6). It emphasizes experimentally grounded mechanisms in tail-anchored protein targeting and distinguishes direct evidence from broader association-level disease links.

12) Key takeaways (functional annotation statement)

Human GET4/TRC35 (UniProt Q7L5D6) is a conserved, cytosolic, ribosome-proximal pretargeting scaffold in the TRC/GET pathway that promotes handoff of nascent tail-anchored membrane proteins from SGTA to the targeting ATPase TRC40/ASNA1, enabling delivery to the ER insertase WRB/CAML. Its best-supported additional roles are in proteostasis-linked triage (via the BAG6 module), including regulation of BAG6 localization through NLS masking and stabilization of TRC35 by preventing inappropriate RNF126/proteasome-mediated degradation of unassembled TRC35; and the complex is stress-sensitive, with proteotoxic insults promoting dissociation of UBL4A–BAG6 interactions. (mock2017structuralbasisfor pages 1-2, keszei2021structuralinsightsinto pages 6-7, pool2022targetingofproteins pages 7-9, mock2017structuralbasisfor pages 2-3, hagiwara2023proteotoxicstressesstimulate pages 7-10)

References

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(farkas2021captureanddelivery pages 1-3): Ákos Farkas and Katherine E. Bohnsack. Capture and delivery of tail-anchored proteins to the endoplasmic reticulum. The Journal of Cell Biology, Jul 2021. URL: https://doi.org/10.1083/jcb.202105004, doi:10.1083/jcb.202105004. This article has 49 citations.
(pool2022targetingofproteins pages 7-9): Martin R. Pool. Targeting of proteins for translocation at the endoplasmic reticulum. International Journal of Molecular Sciences, 23:3773, Mar 2022. URL: https://doi.org/10.3390/ijms23073773, doi:10.3390/ijms23073773. This article has 41 citations.
(keszei2021structuralinsightsinto pages 6-7): Alexander F. A. Keszei, Matthew C. J. Yip, Ta-Chien Hsieh, and Sichen Shao. Structural insights into metazoan pretargeting get complexes. Nature Structural & Molecular Biology, 28:1029-1037, Dec 2021. URL: https://doi.org/10.1038/s41594-021-00690-7, doi:10.1038/s41594-021-00690-7. This article has 16 citations and is from a highest quality peer-reviewed journal.
(mock2017structuralbasisfor pages 1-2): Jee-Young Mock, Yue Xu, Yihong Ye, and William M. Clemons. Structural basis for regulation of the nucleo-cytoplasmic distribution of bag6 by trc35. Proceedings of the National Academy of Sciences, 114:11679-11684, Oct 2017. URL: https://doi.org/10.1073/pnas.1702940114, doi:10.1073/pnas.1702940114. This article has 29 citations and is from a highest quality peer-reviewed journal.
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(qin2023targetingandsurveillance pages 1-2): Qing Qin, Kang Shen, and Xiangming Wang. Targeting and surveillance mechanisms for tail-anchored proteins. The Innovation Life, 1:100013, Jan 2023. URL: https://doi.org/10.59717/j.xinn-life.2023.100013, doi:10.59717/j.xinn-life.2023.100013. This article has 2 citations.
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(costa2017intracellulartargetingof pages 25-30): B. F. Costa, S. Colombo, P. Cassella, and N. Borgese. 'intracellular targeting of tail-anchored proteins'. Text, Jan 2017. URL: https://doi.org/10.13130/b-g-figueiredo-costa_phd2017-01-27, doi:10.13130/b-g-figueiredo-costa_phd2017-01-27. This article has 0 citations and is from a peer-reviewed journal.
(hagiwara2023proteotoxicstressesstimulate pages 7-10): Takumi Hagiwara, Ryosuke Minami, Chizuru Ushio, Naoto Yokota, and Hiroyuki Kawahara. Proteotoxic stresses stimulate dissociation of ubl4a from the tail-anchored protein recognition complex. Biochemical Journal, 480:1583-1598, Oct 2023. URL: https://doi.org/10.1042/bcj20230267, doi:10.1042/bcj20230267. This article has 0 citations and is from a domain leading peer-reviewed journal.
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(OpenTargets Search: -GET4): Open Targets Query (-GET4, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
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Artifacts

Edison artifact artifact-00

Citations

najdrova2022conservedmechanismfor pages 88-98
pool2022targetingofproteins pages 7-9
keszei2021structuralinsightsinto pages 6-7
mock2017structuralbasisfor pages 1-2
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qin2023targetingandsurveillance pages 1-2
hagiwara2023proteotoxicstressesstimulate pages 7-10
farkas2021captureanddelivery pages 1-3
najdrova2022conservedmechanismfor pages 16-20
najdrova2022conservedmechanismfor pages 20-23
costa2017intracellulartargetingof pages 25-30
hagiwara2023proteotoxicstressesstimulate pages 1-3
shan2019guidingtailanchoredmembrane pages 2-4
https://doi.org/10.59717/j.xinn-life.2023.100013
https://doi.org/10.1042/bcj20230267
https://doi.org/10.1038/s41586-023-05946-4
https://doi.org/10.3390/ijms23073773
https://doi.org/10.1074/jbc.rev119.006197
https://doi.org/10.1038/s41594-021-00690-7
https://doi.org/10.1073/pnas.1702940114
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📚 Additional Documentation

Notes

(GET4-notes.md)

GET4 (TRC35, C7orf20) review notes

UniProt: Q7L5D6 (GET4_HUMAN), 327 aa. HGNC:21690. Gene names: GET4; synonyms C7orf20, CEE, TRC35; ORF CGI-20.

Identity / nomenclature

"Golgi to ER traffic protein 4 homolog"; AltNames: Conserved edge-expressed protein (CEE); Transmembrane domain recognition complex 35 kDa subunit (TRC35) [file:human/GET4/GET4-uniprot.txt "Short=TRC35"].
Yeast ortholog is Get4 (Yor164C); GET4 belongs to the GET4 family [file:human/GET4/GET4-uniprot.txt "Belongs to the GET4 family"].
Fold: TPR-like all-α helical solenoid (Gene3D 1.25.40.10; FunFam; PANTHER PTHR12875; Pfam PF04190 GET4; InterPro IPR007317). Crystal structure 6AU8 (res 23-305) is essentially all helices.

Core biology: pre-targeting / bridging complex of the GET/TRC pathway

GET4/TRC35 is a scaffold subunit of the heterotrimeric BAG6/BAT3 (a.k.a. "Bag6 complex" / TRC pretargeting bridging complex) composed of BAG6, UBL4A and GET4/TRC35 [file:human/GET4/GET4-uniprot.txt "Component of the BAG6/BAT3 complex, at least composed of BAG6, UBL4A and GET4/TRC35"]. It functions in the post-translational targeting of tail-anchored (TA) membrane proteins to the ER:

The Bag6 complex (Bat3+TRC35+Ubl4A) facilitates TA-protein capture by TRC40/GET3 PMID:20676083.
TRC35 = C7ORF20, identified as a 35 kD component co-purifying with Bat3 PMID:20676083.
The complex is recruited to ribosomes, interacts with TMDs of newly released TA proteins, and transfers them to TRC40 PMID:20676083.
The minimal Bag6 complex facilitates TA substrate transfer from SGTA to TRC40 PMID:25535373; D84 mutagenesis reduces TA-protein delivery [file:human/GET4/GET4-uniprot.txt "D->K: Reduces tail-anchored protein delivery."].
Cryo-EM of the metazoan pretargeting GET complex: Get4 (TRC35) directly contacts the Get3/TRC40 ATPase; the Get3 helix-8/Get4 C-terminus form a composite lid over the substrate chamber, and Get4-Get3 secondary interactions facilitate TA transfer from SGTA to Get3 [PMID:34887561 "Get3 helix 8 and the Get4 C terminus form a composite lid over the Get3 substrate-binding chamber that is opened by SGTA"; "Both interactions facilitate TA protein transfer from SGTA to Get3"].
Get4 R25D/K29D loses Get3 interaction and impairs TA delivery [file:human/GET4/GET4-uniprot.txt "R->D: Loss of interaction with GET3"]; direct GET3 interaction documented [file:human/GET4/GET4-uniprot.txt "Interacts with GET3 (PubMed:34887561)"].

So the CORE molecular role is a pre-targeting/bridging scaffold (protein carrier chaperone) that loads TA cargo onto GET3/TRC40 — process = post-translational TA protein insertion into the ER membrane.

Secondary / quality-control roles of the complex

The BAG6 complex also acts as a holdase / sorting platform in protein quality control: maintaining mislocalized/retrotranslocated hydrophobic substrates soluble and sorting them to the proteasome or ER (ERAD, mislocalized-protein degradation) PMID:21636303.
TRC35 keeps BAG6 in the cytosol so BAG6 can engage in ERAD PMID:21636303.

Distinct (regulatory) function: cytoplasmic retention of BAG6

TRC35 binding occludes the BAG6 nuclear localization sequence, retaining BAG6 in the cytosol, and protects TRC35 from RNF126-mediated ubiquitination/degradation PMID:29042515. BAG6-binding region maps to residues 195-271 [file:human/GET4/GET4-uniprot.txt "REGION 195..271 /note=\"Interacts with BAG6\""].

Localization

Cytoplasm, cytosol [file:human/GET4/GET4-uniprot.txt "SUBCELLULAR LOCATION: Cytoplasm, cytosol"]. Multiple IDA cytosol annotations (PMID:20676083, 29042515) and IDA cytoplasm (PMID:21636303).

Disease

Biallelic missense GET4 variants (p.Arg122His, p.Ile279Met) cause CDG2Y; they destabilize all three TRC proteins (BAG6/UBL4A/GET4) by 70-90% and impair TA-protein (syntaxin 5) targeting [PMID:32395830 "We identified an individual with compound heterozygous missense variants (p.Arg122His, p.Ile279Met) in GET4 that reduced all three TRC proteins by 70% to 90%"; "the TA protein, syntaxin 5, is poorly targeted to Golgi membranes"].

PTM

N-terminal Met removed, N-acetyl-Ala at position 2; phospho-Ser12. Ubiquitinated by RNF126 (when unassembled from BAG6) leading to proteasomal degradation [file:human/GET4/GET4-uniprot.txt "Ubiquitinated by RNF12, leading to proteasomal degradation"].

GO annotation assessment summary

CORE MF: GO:0140597 protein carrier activity ("protein carrier chaperone") — loads TA cargo onto GET3 (IMP PMID:21636303, IBA). ACCEPT.
CORE BP: GO:0071816 tail-anchored membrane protein insertion into ER membrane (IDA/IMP), GO:0006620 post-translational protein targeting to ER membrane (IDA, ComplexPortal). ACCEPT.
GO:0045048 protein insertion into ER membrane (more general parent of 0071816) — ACCEPT but more general; keep as supporting.
CC: GO:0071818 BAT3 complex (multiple IDA/IPI/IBA) — ACCEPT core. GO:0005829 cytosol / GO:0005737 cytoplasm — ACCEPT.
GO:0031647 regulation of protein stability (IMP/IDA PMID:21636303): the holdase/cofactor role; KEEP_AS_NON_CORE (secondary QC role; also relates to TRC35 stabilizing BAG6).
GO:0036503 ERAD pathway (IMP PMID:21636303): complex-level QC role; KEEP_AS_NON_CORE.
GO:0036506 maintenance of unfolded protein: in UniProt GO list (IMP ParkinsonsUK-UCL) but NOT in goa.tsv; not reviewed (not in GOA).
GO:0006511 ubiquitin-dependent protein catabolic process (IDA PMID:20676083, ComplexPortal): the complex routes substrates to proteasome; KEEP_AS_NON_CORE (PMID:20676083 is primarily the TA-targeting/capture paper; catabolic role is the alternative QC branch).
GO:0051087 protein-folding chaperone binding (IPI PMID:25535373, partner BAG6/P46379): real direct interaction with BAG6; more informative than bare protein binding but is an interaction term; KEEP_AS_NON_CORE.
GO:0005515 protein binding (IPI, many): bare/uninformative; KEEP_AS_NON_CORE. Includes the functionally meaningful GET3 (O43681) and BAG6 (P46379) interactions but the term itself is uninformative.
The interactome-screen IPIs (PMID:21516116, 24722188, 25416956, 28514442, 32296183, 33961781, 40205054) are high-throughput protein-binding; KEEP_AS_NON_CORE. Among these the GET3 (O43681) and BAG6 (P46379-2) captures are biologically meaningful; FBN1/NUP85/KRTAP9-3/DUSP21/etc. are likely incidental.

No REMOVE warranted: all experimental annotations are consistent with established GET4 biology; the IEA/IBA are also consistent. No MODIFY strictly required, though GO:0045048 is a more general parent — I keep it ACCEPT as a valid (if general) term rather than MODIFY, since 0071816/0006620 already capture the specific function and both are present.

Falcon deep-research findings (incorporated 2026-06)

Proteotoxic stress remodels the GET4-containing complex: polyQ inclusions, proteasome inhibition, and CCCP-induced mitochondrial depolarization stimulate dissociation of UBL4A from BAG6 within the BAG6/UBL4A/GET4(TRC35) complex PMID:37747814. Added as a MEDIUM-relevance reference (complex-level stress sensitivity, not a direct GET4-specific assay).
Review framing of GET4/TRC35 as ribosome-associated within BAG6 complexes near the ribosomal exit, enhancing recruitment of TA-handling factors and handover to TRC40 [PMID:35409131 "Targeting of Proteins for Translocation at the Endoplasmic Reticulum" (Pool 2022)]. Consistent with the existing ribosome-recruitment picture (PMID:20676083); added as MEDIUM review support.
The Falcon cryo-EM "metazoan pretargeting GET complex" source (Keszei et al. 2021, DOI 10.1038/s41594-021-00690-7) is ALREADY in the review as PMID:34887561 (GET4-GET3 composite lid / SGTA->Get3 transfer); not re-added.
The Falcon "structural basis ... BAG6 by TRC35" source (Mock et al. 2017 PNAS, DOI 10.1073/pnas.1702940114) is ALREADY in the review as PMID:29042515 (NLS masking, RNF126 stabilization); not re-added.
Open Targets disease associations (neurodegenerative disease, atrial fibrillation/flutter, CDG type IIy) reported by Falcon are association-level only; the curated CDG link is already captured by PMID:32395830. No new disease reference added.
Kesner 2023 Nature (noncoding-translation surveillance, DOI 10.1038/s41586-023-05946-4) mentions GET4/BAG6-pathway components only in passing per Falcon's OpenTargets snippet; not a GET4-specific assay, so notes-only (not added).

Pn Notes

(GET4-pn-notes.md)

GET4 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q7L5D6
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-11
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/GET4/GET4-ai-review.yaml
AIGR review HTML: missing - genes/human/GET4/GET4-ai-review.html
Gene notes: present - genes/human/GET4/GET4-notes.md
GOA TSV: present - genes/human/GET4/GET4-goa.tsv
UniProt record: present - genes/human/GET4/GET4-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/GET4.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/GET4.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/GET4/GET4-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 16; KEEP_AS_NON_CORE: 17

PN Consistency Summary

Consistency: Strong and mutually consistent. Deep research (falcon, incorporated into notes), the review YAML, and the PN annotation all describe GET4/TRC35 as the scaffold subunit of the BAG6/BAT3 pre-targeting complex that loads tail-anchored (TA) cargo onto GET3/TRC40 for post-translational ER insertion. The PN "GET pathway component" label and its GO:0006620 mapping match the review's core BP annotation (GO:0006620 IDA, ACCEPT). No contradictions.
PN story / NEW pressure: PN asserts only the canonical post-translational ER-targeting role, which the review already captures as core (GO:0006620, GO:0071816 TA-insertion, GO:0140597 carrier activity). The secondary holdase/ERAD/quality-control branch (GO:0031647, GO:0036503, GO:0006511) is in the review but not the PN story. No new GO term needed. Conclusion: already captured (no NEW pressure).
Evidence alignment: PN dossier lists no reference titles, so alignment is via projected-term provenance. Review's core support (PMID:20676083 founding Bag6/TRC complex; PMID:25535373 minimal Bag6 module SGTA→TRC40; PMID:34887561 cryo-EM GET4-GET3 lid; PMID:32395830 disease IMP) all encode the same post-translational TA-targeting biology the PN node maps to. No divergence.
Verdict: Fully consistent; PN already captured by the review, which is more granular (adds TA-specific GO:0071816 and the QC branch). No edits warranted.

Full Consistency Review

UniProt: Q7L5D6 · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE
PN placement: ER proteostasis|Protein transport|GET pathway component ; PN-node mapping: group=mapped scope=ok_for_propagation_to_go→GO:0006620 (post-translational protein targeting to ER membrane); class Protein transport=mapped→GO:0015031 (protein transport); branch=no_mapping.
Consistency: Strong and mutually consistent. Deep research (falcon, incorporated into notes), the review YAML, and the PN annotation all describe GET4/TRC35 as the scaffold subunit of the BAG6/BAT3 pre-targeting complex that loads tail-anchored (TA) cargo onto GET3/TRC40 for post-translational ER insertion. The PN "GET pathway component" label and its GO:0006620 mapping match the review's core BP annotation (GO:0006620 IDA, ACCEPT). No contradictions.
PN story / NEW pressure: PN asserts only the canonical post-translational ER-targeting role, which the review already captures as core (GO:0006620, GO:0071816 TA-insertion, GO:0140597 carrier activity). The secondary holdase/ERAD/quality-control branch (GO:0031647, GO:0036503, GO:0006511) is in the review but not the PN story. No new GO term needed. Conclusion: already captured (no NEW pressure).
Mapping strategy: No change needed. GO:0006620 (goa_status already_in_goa_exact) is present and ACCEPTed in the review — the projection is exact, not broader (unlike the TOMM20/HSPA8/RAB7A "too broad" precedent). The class-level GO:0015031 is correctly flagged as a broad propagation target for the ER Protein-transport class, not for GET4 specifically.
Evidence alignment: PN dossier lists no reference titles, so alignment is via projected-term provenance. Review's core support (PMID:20676083 founding Bag6/TRC complex; PMID:25535373 minimal Bag6 module SGTA→TRC40; PMID:34887561 cryo-EM GET4-GET3 lid; PMID:32395830 disease IMP) all encode the same post-translational TA-targeting biology the PN node maps to. No divergence.
Verdict: Fully consistent; PN already captured by the review, which is more granular (adds TA-specific GO:0071816 and the QC branch). No edits warranted.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-11
review_yaml: genes/human/GET4/GET4-ai-review.yaml
PN workbook rows: 1

PN row 1: ER proteostasis | Protein transport | GET pathway component

UniProt: Q7L5D6
In branches: ER
PN-node mapping records (path + ancestors):
- [group] ER proteostasis|Protein transport|GET pathway component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane]
  rationale: The PN GET-pathway group covers machinery for post-translational delivery of tail-anchored membrane proteins to the ER. GO does not model the GET pathway directly in the local cache, and the closest supported process term is post-translational targeting to the ER membrane.
- [class] ER proteostasis|Protein transport
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0015031 protein transport]
  rationale: The PN ER Protein transport class groups ER-targeting and ER-insertion pathways. GO protein transport is the appropriate propagation target, while the source class remains ER-specific and broader than any single GO transport subtype.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (2)

GO:0015031 protein transport | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Protein transport
GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Protein transport|GET pathway component

Note

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

📄 View Raw YAML

id: 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.

GET4

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human GET4 (TRC35) functional annotation (UniProt Q7L5D6)

0) Target verification (critical disambiguation)

1) Key concepts and definitions (current understanding)

Tail-anchored (TA) proteins

GET/TRC pathway (guided entry of TA proteins / transmembrane recognition complex)

Where GET4/TRC35 fits

2) Molecular function and mechanism of GET4/TRC35

2.1 Core molecular function: pretargeting scaffold to load TA substrates onto TRC40

2.2 Structural and biophysical evidence for GET4’s mechanistic role

3) Interaction partners and complexes

3.1 The BAG6–UBL4A–GET4/TRC35 complex

3.2 Upstream and downstream partners in the TA relay

4) Subcellular localization: where GET4 acts

4.1 Cytosolic and ribosome-proximal action

4.2 Regulation of BAG6 nucleo-cytoplasmic distribution (direct human evidence)

5) Quality control roles connected to GET4/TRC35 (proteostasis functions)

5.1 Targeting vs degradation decision-making in BAG6-containing complexes

5.2 TRC35 stability is controlled by BAG6 association and ubiquitination

6) Recent developments (prioritizing 2023–2024)

6.1 2023 review synthesis: targeting and surveillance mechanisms

6.2 2023 primary study: proteotoxic stress remodels the complex (with quantitative statistics)

6.3 2023: broader proteostasis and translation surveillance contexts

7) Current applications and real-world implementations

7.1 Practical biological applications

7.2 Tooling and experimental platforms

8) Expert opinions and authoritative synthesis

9) Disease associations and phenotypes (evidence strength and caveats)

9.1 Curated association-level links (Open Targets)

9.2 Mechanistic plausibility from proteostasis literature

10) Visual evidence (complex architecture)

11) Summary table of functional annotation

12) Key takeaways (functional annotation statement)

Artifacts

Citations

📚 Additional Documentation

Notes

GET4 (TRC35, C7orf20) review notes

Identity / nomenclature

Core biology: pre-targeting / bridging complex of the GET/TRC pathway

Secondary / quality-control roles of the complex

Distinct (regulatory) function: cytoplasmic retention of BAG6

Localization

Disease

PTM

GO annotation assessment summary

Falcon deep-research findings (incorporated 2026-06)

Pn Notes

GET4 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: ER proteostasis | Protein transport | GET pathway component

Projected GO annotations (2)

Note

📄 View Raw YAML