Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation of GET1's defining biological process, the insertion of tail-anchored membrane proteins into the ER membrane. Conserved across the WRB/GET1 family and supported by direct experimental evidence. Reason: Core biological process; GET1/WRB is the ER receptor of the GET pathway that inserts TA proteins, supported by IDA/IMP and the UniProt function. Supporting Evidence: file:human/GET1/GET1-uniprot.txt Required for the post-translational delivery of tail-anchored PMID:36640319 the Get1/2 channel functions as an insertase for insertion of TMDs and as a translocase for translocation of C-terminal hydrophilic segments PMID:37963916 the Get3 chaperone captures the TA protein substrate and delivers it to the Get1/Get2 membrane protein complex (GET insertase), which then inserts the substrate via a membrane-embedded hydrophilic groove
GO:0043495 protein-membrane adaptor activity	IBA GO_REF:0000033	ACCEPT	Summary: This is the PAN-GO/GO_Central molecular function used for the GET3 receptor across orthologs, capturing GET1/WRB's role of coupling the soluble GET3/TRC40 chaperone to the ER membrane so that the TA substrate can be inserted. GET1 provides the membrane docking site (its coiled-coil) for the cytosolic targeting factor. Reason: Represents the informative membrane-insertase-receptor molecular function of GET1; the coiled-coil domain docks GET3/TRC40 at the membrane. Supporting Evidence: PMID:21444755 We identify the coiled-coil domain of WRB as the binding site for TRC40/Asna1
GO:0043529 GET complex	IBA GO_REF:0000033	ACCEPT	Summary: GET1/WRB is a constitutive subunit of the GET complex (GET1/WRB + CAMLG/GET2 + GET3/TRC40). Conserved across the family and directly demonstrated structurally. Reason: Core cellular component; GET1 is a defining subunit of the GET insertase complex. Supporting Evidence: file:human/GET1/GET1-uniprot.txt Component of the Golgi to ER traffic (GET) complex, which is composed of GET1/WRB, CAMLG/GET2 and GET3/TRC40
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Electronic transfer of the ER membrane localization from the UniProt subcellular location, consistent with the experimental EXP evidence. Reason: Correct compartment; GET1 is an experimentally established multi-pass ER membrane protein. Supporting Evidence: file:human/GET1/GET1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based electronic assignment of the TA-protein ER insertion process, consistent with the experimental evidence. Reason: Correct core process; redundant with IDA/IMP/IBA evidence. Supporting Evidence: file:human/GET1/GET1-uniprot.txt Required for the post-translational delivery of tail-anchored
GO:0090150 establishment of protein localization to membrane	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA machine-learning electronic annotation of the generic parent process; GET1 establishes localization of TA proteins to the ER membrane. Correct but less specific than GO:0071816. Reason: Correct but generic parent of the specific TA-insertion process that better captures GET1's role. Supporting Evidence: file:human/GET1/GET1-uniprot.txt Required for the post-translational delivery of tail-anchored
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: High-throughput human binary interactome (HuRI/Y2H) capturing many IntAct partners of GET1 (e.g. APOA2, TFRC, CD53, AQP1, HMOX2, SLC7A1); several are themselves TA/membrane proteins and plausible insertase substrates, but the bare protein binding term is uninformative. Reason: Records real Y2H interactions but bare protein binding is uninformative; the informative MF is captured by GO:0043495. Supporting Evidence: file:human/GET1/GET1-uniprot.txt O00258; P02652: APOA2
GO:0005789 endoplasmic reticulum membrane	NAS PMID:32910895 Structural Basis of Tail-Anchored Membrane Protein Biogenesi...	ACCEPT	Summary: ComplexPortal NAS assertion of ER membrane localization from the cryo-EM structural study of the human GET insertase complex. Reason: Correct compartment; consistent with experimental EXP localization. Supporting Evidence: file:human/GET1/GET1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0043529 GET complex	IPI PMID:32910895 Structural Basis of Tail-Anchored Membrane Protein Biogenesi...	ACCEPT	Summary: ComplexPortal IPI assignment of GET complex membership from the cryo-EM structure of the human WRB/CAML/TRC40 insertase complex. Reason: Core cellular component; directly demonstrated structurally. Supporting Evidence: PMID:32910895 Get3 binding to the membrane insertase supports heterotetramer formation
GO:0045048 protein insertion into ER membrane	NAS PMID:23041287 Molecular machinery for insertion of tail-anchored membrane ...	ACCEPT	Summary: ComplexPortal NAS assertion of the (parent) ER protein-insertion process; GET1/WRB with CAML synergistically inserts TA proteins into the ER membrane. Reason: Correct; parent of GO:0071816 and consistent with experimental evidence. Supporting Evidence: PMID:23041287 CAML and WRB synergistically insert TA proteins into the membrane
GO:0005789 endoplasmic reticulum membrane	EXP PMID:21444755 WRB is the receptor for TRC40/Asna1-mediated insertion of ta...	ACCEPT	Summary: Direct experimental evidence that WRB is an ER-resident membrane protein, established in the study that identified WRB as the TRC40 receptor. Reason: Core, experimentally demonstrated localization. Supporting Evidence: PMID:21444755 WRB is an ER-resident membrane protein
GO:0005515 protein binding	IPI PMID:31417168 The WRB Subunit of the Get3 Receptor is Required for the Cor...	KEEP AS NON CORE	Summary: IPI annotation capturing the WRB-CAMLG (P49069) interaction. This reflects the genuine, functionally central GET1-CAMLG association, but the GO term used is the uninformative bare protein binding. Reason: Records the real and important CAMLG interaction, but bare protein binding is uninformative; the functional MF is captured by GO:0043495 and complex membership by GO:0043529. Supporting Evidence: file:human/GET1/GET1-uniprot.txt Interacts with CAMLG (via C-terminus)
GO:0005515 protein binding	IPI PMID:32187542 Differential Modes of Orphan Subunit Recognition for the WRB...	KEEP AS NON CORE	Summary: IPI annotation capturing the WRB-CAMLG (P49069) interaction from the study on orphan subunit recognition by the WRB/CAML complex. Functionally meaningful interaction but the bare protein binding term is uninformative. Reason: Records the real CAMLG interaction; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/GET1/GET1-uniprot.txt Interacts with CAMLG (via C-terminus)
GO:0045048 protein insertion into ER membrane	IMP PMID:31417168 The WRB Subunit of the Get3 Receptor is Required for the Cor...	ACCEPT	Summary: Mutant-phenotype evidence that WRB is required for correct integration of CAML into the ER; WRB acts catalytically to assist CAML topogenesis/insertion. Reason: Correct; supported by IMP. WRB-dependent ER insertion (here of CAML) reflects its insertase-receptor role. Supporting Evidence: PMID:31417168 WRB ... acts catalytically to assist the topogenesis of CAML
GO:0045048 protein insertion into ER membrane	IDA PMID:32187542 Differential Modes of Orphan Subunit Recognition for the WRB...	ACCEPT	Summary: Direct evidence that WRB can correct the topology of (and thereby insert) CAML both in vitro and in cells, supporting GET1's ER protein-insertion role. Reason: Core process; directly demonstrated. Parent of the more specific TA-insertion term. Supporting Evidence: PMID:32187542 When present, WRB can correct the topology of CAML both in vitro and in cells
GO:0050821 protein stabilization	IDA PMID:31417168 The WRB Subunit of the Get3 Receptor is Required for the Cor...	KEEP AS NON CORE	Summary: Without sufficient WRB, CAML fails to adopt its correct topology, generating aberrant topoforms that cluster and are degraded by the proteasome; WRB therefore stabilizes/correctly integrates CAML. This is a real but secondary consequence of GET1's insertase-receptor function. Reason: Supported by IDA but represents WRB-dependent stabilization of one specific partner (CAML), secondary to the core TA-insertion function. Supporting Evidence: PMID:31417168 these congregate in ER-associated clusters and are degraded by the proteasome
GO:0050821 protein stabilization	IDA PMID:32187542 Differential Modes of Orphan Subunit Recognition for the WRB...	KEEP AS NON CORE	Summary: WRB-mediated correction of CAML topology stabilizes CAML; consistent with the partner-stabilization phenotype. Secondary to the core insertase-receptor function. Reason: Real but secondary partner-stabilization effect, not the core function of GET1. Supporting Evidence: PMID:32187542 When present, WRB can correct the topology of CAML both in vitro and in cells
GO:0043529 GET complex	IDA PMID:32910895 Structural Basis of Tail-Anchored Membrane Protein Biogenesi...	ACCEPT	Summary: The cryo-EM structure directly resolves GET1/WRB within the GET insertase complex, forming a heterotetramer with CAML that binds the GET3 homodimer. Reason: Core cellular component, structurally demonstrated. Supporting Evidence: PMID:32910895 Get3 binding to the membrane insertase supports heterotetramer formation
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IDA PMID:27226539 Tail-anchored Protein Insertion in Mammals: FUNCTION AND REC...	ACCEPT	Summary: Direct evidence that in-vitro-synthesized CAML and WRB together are sufficient to confer TA-insertion competence to liposomes, establishing GET1's core role in TA-protein ER insertion. Reason: Core biological process with direct experimental (IDA) support. Supporting Evidence: PMID:27226539 in vitro synthesized CAML and WRB together were sufficient to confer insertion competence to liposomes
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IMP PMID:23041287 Molecular machinery for insertion of tail-anchored membrane ...	ACCEPT	Summary: Mutant-phenotype evidence that CAML and WRB synergistically insert TA proteins into the ER membrane, establishing GET1 as a component of the TRC40 receptor complex driving TA insertion. Reason: Core biological process with IMP support. Supporting Evidence: PMID:23041287 CAML and WRB synergistically insert TA proteins into the membrane
GO:0043529 GET complex	IPI PMID:23041287 Molecular machinery for insertion of tail-anchored membrane ...	ACCEPT	Summary: Mass-spectrometry/IPI identification of GET1/WRB in the TRC40 receptor (GET) complex together with CAMLG and GET3. Reason: Core cellular component; directly demonstrated by complex identification. Supporting Evidence: PMID:23041287 CAML and WRB as components of the TRC40 receptor complex
GO:0005634 nucleus	TAS PMID:9544840 Identification and characterization of a new human cDNA from...	MARK AS OVER ANNOTATED	Summary: The original 1998 cDNA characterization reported predominant nuclear immunofluorescence localization, before the protein's function was known. This was not reproduced and is contradicted by the later function-defining study, which establishes ER membrane residence and could not detect nuclear WRB. GET1/WRB is a multi-pass ER membrane protein with no established nuclear function. Reason: Superseded by experimental ER membrane localization; the early nuclear immunofluorescence result was not reproduced and is inconsistent with GET1's multi-pass ER membrane topology. Supporting Evidence: PMID:21444755 We have not been able to detect WRB in untransfected RPE-1 or HeLa cells using our anti-WRB antibodies
GO:0005634 nucleus	TAS O00258-1 PMID:9544840 Identification and characterization of a new human cDNA from...	MARK AS OVER ANNOTATED	Summary: Duplicate of the early nuclear localization assertion; same provenance and same conclusion. GET1/WRB localizes to the ER membrane, not the nucleus. Reason: Superseded by the experimentally established ER membrane localization; not reproduced. Supporting Evidence: PMID:21444755 WRB is an ER-resident membrane protein

Core Functions

Membrane-insertase receptor of the GET pathway that docks the cytosolic GET3/TRC40 targeting factor at the ER membrane via its coiled-coil domain, enabling post-translational insertion of tail-anchored membrane proteins.

Molecular Function:

protein-membrane adaptor activity

Directly Involved In:

tail-anchored membrane protein insertion into ER membrane

Cellular Locations:

endoplasmic reticulum membrane

Supporting Evidence:

PMID:21444755
We identify the coiled-coil domain of WRB as the binding site for TRC40/Asna1

Subunit of the GET (WRB/CAML/TRC40) insertase complex that, together with CAMLG/GET2, forms a heterotetramer accepting GET3-delivered tail-anchored proteins and inserting them into the ER lipid bilayer.

Molecular Function:

protein-membrane adaptor activity

Directly Involved In:

tail-anchored membrane protein insertion into ER membrane

In Complex:

GET complex

Supporting Evidence:

PMID:27226539
in vitro synthesized CAML and WRB together were sufficient to confer insertion competence to liposomes

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

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:21444755

WRB is the receptor for TRC40/Asna1-mediated insertion of tail-anchored proteins into the ER membrane.

Identifies WRB/CHD5 as the ER membrane receptor for TRC40/Asna1 and maps the WRB coiled-coil domain as the TRC40 docking site; WRB is ER-resident, not nuclear.

PMID:23041287

Molecular machinery for insertion of tail-anchored membrane proteins into the endoplasmic reticulum membrane in mammalian cells.

WRB and CAML synergistically insert TA proteins into the ER membrane and together constitute the mammalian TRC40 receptor complex.

PMID:27226539

Tail-anchored Protein Insertion in Mammals: FUNCTION AND RECIPROCAL INTERACTIONS OF THE TWO SUBUNITS OF THE TRC40 RECEPTOR.

In-vitro-synthesized CAML and WRB together are sufficient to confer TA-insertion competence to liposomes; the two subunits are reciprocally dependent.

PMID:31417168

The WRB Subunit of the Get3 Receptor is Required for the Correct Integration of its Partner CAML into the ER.

WRB acts catalytically to assist CAML topogenesis; without sufficient WRB, CAML adopts aberrant topoforms that cluster and are degraded by the proteasome.

PMID:32187542

Differential Modes of Orphan Subunit Recognition for the WRB/CAML Complex.

The WRB/CAML complex is an essential insertase for tail-anchored proteins; WRB can correct the topology of CAML in vitro and in cells.

PMID:32296183

A reference map of the human binary protein interactome.

High-throughput Y2H (HuRI) interactome; source of the IntAct protein binding partners of GET1.

PMID:32910895

Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex.

Cryo-EM of the human WRB/CAML/TRC40 complex; WRB and CAML form a phosphatidylinositol-stabilized heterotetramer that binds the GET3 homodimer, with an insertion mechanism related to YidC and the EMC.

PMID:9544840

Identification and characterization of a new human cDNA from chromosome 21q22.3 encoding a basic nuclear protein.

Original cDNA characterization reporting predominant nuclear immunofluorescence localization; not reproduced and superseded by later ER membrane localization.

PMID:34264263

Capture and delivery of tail-anchored proteins to the endoplasmic reticulum.

Comprehensive review of the GET/TRC pathway; GET1/WRB with CAMLG/GET2 forms the ER membrane receptor-insertase that receives TA substrates from the cytosolic ATPase GET3/TRC40 and mediates their insertion into the ER bilayer.

PMID:36640319

The Get1/2 insertase forms a channel to mediate the insertion of tail-anchored proteins into the ER.

Reconstitution shows the Get1/2 (WRB/CAML) complex forms a dynamic aqueous channel (~2.5 nm, corresponding to two Get1/2 complexes) that is sealed by Get3 and whose channel activity is required to release TA proteins from Get3 for insertion; functions as both insertase and translocase for C-terminal hydrophilic tails.

PMID:37963916

The GET insertase exhibits conformational plasticity and induces membrane thinning.

Structures, simulations and functional data of human and C. thermophilum Get1/Get2/Get3 show the GET insertase fold is conserved, induces local lipid bilayer thinning near the hydrophilic groove to lower the insertion barrier, and that gating between Get2 helix alpha3' and Get3 drives conformational changes across the Get1/Get2 heterotetramer.

file:human/GET1/GET1-uniprot.txt

UniProt entry O00258 (GET1_HUMAN), Guided entry of tail-anchored proteins factor 1

GET1/WRB is the ER membrane receptor for GET3/TRC40 in the GET complex (GET1/WRB + CAMLG/GET2 + GET3/TRC40); multi-pass ER membrane protein required for post-translational delivery of TA proteins to the ER.

Suggested Experiments

Experiment: Reconstitute purified WRB, CAML and GET3/TRC40 into proteoliposomes and measure insertion kinetics for a panel of TA substrates of differing transmembrane-domain hydrophobicity to define GET1's role in substrate handoff and insertion efficiency.

Experiment: Use proximity labeling (BioID/TurboID) from endogenously tagged WRB in human cells to map its in vivo TA-protein client network and distinguish genuine substrates from incidental Y2H hits.

Deep Research

Falcon

(GET1-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 36 citations 2 artifacts 2026-06-12T02:31:41.358782

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000020 The requested information is presented in Figures 1 and 5 of the document. - **Figure 1 (panels B, C, D)** illustrates the conforma (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 GET1 / WRB (UniProt O00258)

0) Target verification (gene/protein identity)

The UniProt accession O00258 corresponds to the human protein commonly called WRB (tryptophan-rich basic protein) and annotated as Guided entry of tail-anchored proteins factor 1 (GET1), also historically referred to as congenital heart disease 5 protein (CHD5). Primary literature identifies WRB as the metazoan homolog of yeast Get1 and an ER-membrane receptor/insertase component for the TRC40/ASNA1 tail-anchored protein targeting pathway, aligning with the provided UniProt identity and family context (WRB/GET1 family). (vilardi2011wrbisthe pages 2-3, farkas2021captureanddelivery pages 5-7)

1) Key concepts and definitions (current understanding)

1.1 Tail-anchored (TA) proteins

Tail-anchored proteins are a class of single-pass membrane proteins in which a single hydrophobic transmembrane domain (TMD) lies near the extreme C-terminus; they are inserted into target membranes post-translationally because the TMD emerges only after translation is nearly complete. Reviews emphasize that organelle-specific insertion pathways exist for TA proteins and that quality-control pathways clear mis-targeted TA proteins. (najdrova2022conservedmechanismfor pages 55-59)

1.2 GET/TRC pathway (ER TA-protein targeting/insertion)

The eukaryotic guided entry of tail-anchored proteins (GET) pathway (and its metazoan counterpart often termed the TRC pathway) comprises: (i) cytosolic capture/shielding of TA TMDs by chaperones and a targeting ATPase (Get3 in yeast; TRC40/ASNA1 in mammals), (ii) delivery of the TA substrate to an ER membrane receptor/insertase (yeast Get1/Get2; mammalian WRB/CAML), and (iii) TA insertion into the ER membrane coupled to ATPase cycling. (farkas2021captureanddelivery pages 1-3, farkas2021captureanddelivery pages 5-7, mateja2018astructuralperspective pages 9-11)

1.3 What GET1/WRB is (molecular function definition)

GET1/WRB is best defined as an ER membrane insertase/receptor subunit that binds the cytosolic targeting factor TRC40/ASNA1 and cooperates with CAML (the Get2 analog) to mediate insertion of TA-protein TMDs into the ER membrane. In early biochemical work, WRB was identified as the ER membrane receptor for TRC40/ASNA1-mediated TA insertion, with a key cytosolic coiled-coil docking domain. (vilardi2011wrbisthe pages 2-3, farkas2021captureanddelivery pages 1-3, farkas2021captureanddelivery pages 5-7)

2) Molecular function, mechanism, and pathway placement

2.1 Subcellular localization

WRB is described as an ER-resident integral membrane protein. Its cytosolic coiled-coil domain provides a binding site for TRC40/ASNA1 and helps recruit TRC40 to ER membranes. (vilardi2011wrbisthe pages 2-3, najdrova2022conservedmechanismfor pages 55-59)

2.2 Core interaction partners

Key partners supported by mechanistic literature include:
- TRC40/ASNA1 (cytosolic ATPase/chaperone that delivers TA substrates to the ER) (farkas2021captureanddelivery pages 1-3, vilardi2011wrbisthe pages 2-3)
- CAML (ER receptor partner; functional analog of Get2; together with WRB forms an obligate ER receptor complex) (farkas2021captureanddelivery pages 5-7, farkas2021captureanddelivery pages 1-3)

Vilardi et al. showed direct interaction between TRC40 and the WRB coiled-coil domain and that soluble coiled-coil fragments can inhibit TRC40-dependent insertion, consistent with a receptor docking role. (vilardi2011wrbisthe pages 2-3)

2.3 Stepwise mechanism (functional annotation narrative)

A synthesis consistent across reviews and primary data is:
1. A TA substrate is captured in the cytosol and delivered by TRC40/ASNA1, which shields the hydrophobic TMD in a protected pocket. (farkas2021captureanddelivery pages 1-3)
2. TRC40 docks at the ER via the receptor/insertase formed by WRB (GET1) and CAML, with WRB’s cytosolic coiled-coil contributing to TRC40 binding. (vilardi2011wrbisthe pages 2-3, farkas2021captureanddelivery pages 5-7)
3. Docking facilitates conformational changes and handoff/release of the TA TMD to the membrane-embedded insertase groove/channel for insertion into the bilayer, followed by TRC40 recycling. (farkas2021captureanddelivery pages 5-7, mcdowell2020structuralbasisof pages 1-3, heo2023theget12insertase pages 1-3)

Structural perspective reviews additionally place WRB/Get1 within an Oxa1/Alb3/YidC-like insertase superfamily, supporting a conserved principle in which a membrane-embedded hydrophilic environment assists TMD insertion. (mateja2018astructuralperspective pages 9-11, farkas2021captureanddelivery pages 5-7)

3) Recent developments (prioritizing 2023–2024)

3.1 2023 structural mechanism: hydrophilic groove and membrane remodeling

A major advance is the 2023 Nature Communications study that reports structures/simulations of human Get1/Get2/Get3 and concludes that the GET insertase is conformationally plastic and induces local membrane thinning near a hydrophilic groove to lower the energetic barrier for insertion. Quantitatively, the paper reports thinning near the insertase from approximately ~4.35 nm to ~2.25 nm in the vicinity of the groove. (mcdowell2023thegetinsertase pages 1-2, mcdowell2023thegetinsertase media b0739839)

This provides direct, modern structural support for annotating WRB/GET1 as a membrane insertase (not merely a static receptor) that actively reshapes the membrane environment during TA insertion. (mcdowell2023thegetinsertase pages 1-2, mcdowell2023thegetinsertase media b0739839)

3.2 2023 channel model for the insertase (mechanistic support)

A 2023 Cell Reports study of the yeast Get1/2 insertase provides complementary mechanistic evidence for a dynamic aqueous channel (reported ~2.5 nm diameter in reconstituted systems) that can be sealed by Get3 and supports substrate release/insertion and translocation of C-terminal hydrophilic tails. While yeast-focused, the mechanistic logic is frequently used to interpret conserved features of the pathway in metazoans. (heo2023theget12insertase pages 1-3)

3.3 2023 proteomics: broader client spectra and pathway “rules of engagement”

A 2023 label-free quantitative proteomics synthesis that compared perturbations across ER targeting/insertase components in human cells reported client-spectrum trends: TRC/GET clients are enriched for proteins with more central or C-terminal TMHs and unexpectedly included many multi-pass membrane proteins. Importantly, the authors reported an “insertase preference” ordering for TA insertion: Wrb >> TRAM1 >> Sec61 > EMC > TRAP > Sec63. (jung2023quantitativemassspectrometry pages 19-22)

3.4 2023 quality control/proteostasis link: BAG6–UBL4A disruption

A 2023 Biochemical Journal study linked proteotoxic stress (including polyglutamine aggregates and other stresses) to dissociation of UBL4A from BAG6, an upstream module required for TA protein biogenesis. This work explicitly situates WRB (Get1)/CAML downstream as the ER-resident receptor and emphasizes that the TA biogenesis machinery interfaces with protein quality control routes that can promote insertion or degradation. (hagiwara2023proteotoxicstressesstimulate pages 1-3)

4) Current applications and real-world implementations

Membrane protein biogenesis research tool / pathway dissection: WRB/GET1 is routinely used as an essential node in experimental perturbations (knockdown/knockout, dominant-negative fragments) to probe the biogenesis of TA proteins and ER membrane protein targeting logic. Its coiled-coil domain can be used experimentally to competitively interfere with TRC40-dependent insertion in vitro. (vilardi2011wrbisthe pages 2-3)
Understanding tissue-selective vulnerability in proteostasis and trafficking: In vivo vertebrate studies indicate that WRB loss yields selective impacts on certain TA substrates (e.g., synaptic or trafficking proteins), which is used as a model to link TA insertion deficits to sensory phenotypes and to selective proteostasis collapse in specific cell types. (riveramonroy2016micelackingwrb pages 1-2, vogl2016tryptophan‐richbasicprotein pages 2-3)
Framework for redundancy among ER insertases: Human proteomics emphasizes overlap and division of labor among TRC/GET, EMC, Sec61-related factors, enabling systems-level modeling of membrane-protein insertion “rules of engagement,” relevant to interpreting phenotypes of membrane biogenesis defects. (jung2023quantitativemassspectrometry pages 19-22)

5) Phenotypes, disease relevance, and expert interpretation

5.1 Congenital heart disease context

Early work noted that the human WRB gene maps to a Down syndrome region on chromosome 21 (21q22.3) within a congenital heart disease region and that WRB shows relatively higher expression in tissues including heart (as well as brain, liver, skeletal muscle, pancreas) in the reported expression surveys. These observations support plausibility for developmental phenotypes but do not by themselves establish monogenic causality. (vilardi2011wrbisthe pages 5-6)

5.2 Strong functional links to sensory synapse biology (hearing/vision) via TA clients

Multiple vertebrate model systems provide mechanistic evidence that WRB-dependent TA insertion is essential in specialized sensory synapses:
- Zebrafish wrb mutants show severe visual behavior defects and synaptic abnormalities; rescue experiments demonstrate that WRB–TRC40 interaction is required (a WRB mutant that cannot bind TRC40 fails to rescue). (daniele2016mutationofwrba pages 1-2)
- Zebrafish wrb mutants also show auditory/vestibular phenotypes with cellular synaptic defects; quantitatively, they exhibit ~50% fewer synaptic ribbons, and certain synaptic TA proteins (e.g., synaptobrevin/VAMP) are reduced to ~40% of wild type while syntaxin 3 is reduced to ~72–84%, consistent with compromised TA processing. (lin2016thezebrafishpinball pages 15-17)
- In hair cells, WRB mediates insertion of the TA protein otoferlin; WRB disruption reduces otoferlin abundance and impairs hair-cell exocytosis and hearing, and manipulations of WRB or otoferlin partially rescue phenotypes—supporting a substrate-level causal mechanism. (vogl2016tryptophan‐richbasicprotein pages 2-3, vogl2016tryptophan‐richbasicprotein pages 1-2, vogl2016tryptophan‐richbasicprotein pages 11-12)

5.3 Proteostasis and selective TA-client dependence in vivo

A mouse study using tissue-specific WRB knockout models concluded that in vitro TRC40-client classification does not always predict in vivo outcomes; some TA proteins (notably the SNARE syntaxin 5) are extremely sensitive to TRC-pathway disruption and can become autophagy targets, underscoring interplay between TA insertion and proteostasis. (riveramonroy2016micelackingwrb pages 1-2)

5.4 Database-level disease association signals (Open Targets)

Open Targets lists low-to-moderate scoring associations between GET1 (ENSG00000182093) and several phenotype/disease terms with PubMed evidence linkage (e.g., “Phenotypic abnormality,” “Esotropia,” “Non-accomodative esotropia,” among others). These should be interpreted as hypothesis-supporting associations rather than definitive causality and should be corroborated with primary genetic/functional studies. (OpenTargets Search: -WRB)

6) Summary evidence map

The following table consolidates key functional-annotation claims, recency highlights, and evidence pointers.

Category	Key points	Key sources (author year journal)	URL	Publication date	Evidence ID(s)
Identity	Human GET1 corresponds to WRB (tryptophan-rich basic protein; also called congenital heart disease 5 protein), the metazoan homolog of yeast Get1, matching UniProt O00258. It is a core component of the ER receptor/insertase for tail-anchored (TA) proteins.	Vilardi 2011 Journal of Cell Science; Farkas & Bohnsack 2021 J Cell Biol	https://doi.org/10.1242/jcs.084277; https://doi.org/10.1083/jcb.202105004	2011-04; 2021-07	(vilardi2011wrbisthe pages 2-3, farkas2021captureanddelivery pages 5-7)
Localization	WRB is an ER-resident integral membrane protein with a cytosol-exposed coiled-coil domain that docks TRC40/ASNA1. Reviews and primary studies consistently place the functional WRB/CAML receptor in the ER membrane.	Vilardi 2011 Journal of Cell Science; Pool 2022 Int J Mol Sci	https://doi.org/10.1242/jcs.084277; https://doi.org/10.3390/ijms23073773	2011-04; 2022-03	(vilardi2011wrbisthe pages 2-3, najdrova2022conservedmechanismfor pages 55-59)
Mechanism	WRB functions as the Get1-like insertase/receptor that receives TA substrates from TRC40/ASNA1 and helps release the substrate TMD for insertion into the ER bilayer. Structural work supports a membrane-embedded hydrophilic groove/channel mechanism analogous to other Oxa1/YidC-family insertases.	McDowell et al. 2020 Molecular Cell; Heo et al. 2023 Cell Reports	https://doi.org/10.1016/j.molcel.2020.08.012; https://doi.org/10.1016/j.celrep.2022.111921	2020-10; 2023-01	(mcdowell2020structuralbasisof pages 1-3, heo2023theget12insertase pages 1-3, mateja2018astructuralperspective pages 9-11)
Partners	The core mammalian receptor is the WRB/CAML complex; WRB directly engages TRC40/ASNA1 through its coiled-coil domain, while CAML acts as the Get2 analog and cooperates in substrate delivery/insertion. WRB and CAML are mutually stabilizing and function as an obligate receptor complex.	Vilardi 2011 Journal of Cell Science; Farkas & Bohnsack 2021 J Cell Biol	https://doi.org/10.1242/jcs.084277; https://doi.org/10.1083/jcb.202105004	2011-04; 2021-07	(vilardi2011wrbisthe pages 2-3, farkas2021captureanddelivery pages 5-7, farkas2021captureanddelivery pages 1-3)
Recent structural findings 2023	2023 work on human GET insertase showed conformational plasticity, a hydrophilic groove in hsGet1/WRB, and membrane thinning near the insertion site. Reported values include local thinning from ~4.35 nm to ~2.25 nm and a ~15° coiled-coil rotation/tilt associated with gating changes.	McDowell et al. 2023 Nature Communications	https://doi.org/10.1038/s41467-023-42867-2	2023-11	(mcdowell2023thegetinsertase pages 1-2, mcdowell2023thegetinsertase media b0739839)
Proteomics client spectra 2023	Quantitative proteomics in human cells found TRC/GET clients enriched for proteins with central or C-terminal TMHs and unexpectedly many multispanning membrane proteins. For insertase preference in TA insertion, the ranking reported was Wrb >> TRAM1 >> Sec61 > EMC > TRAP > Sec63.	Jung & Zimmermann 2023 Int J Mol Sci	https://doi.org/10.3390/ijms241814166	2023-09	(jung2023quantitativemassspectrometry pages 19-22)
Quality control link 2023	Proteotoxic stress and polyQ inclusions disrupt the BAG6–UBL4A pretargeting complex upstream of WRB/CAML, linking TA-protein biogenesis to proteostasis and aggregate-associated pathology. BAG6/UBL4A normally helps shield hydrophobic TMDs and route clients either to WRB/CAML-mediated insertion or degradation.	Hagiwara et al. 2023 Biochemical Journal	https://doi.org/10.1042/bcj20230267	2023-10	(hagiwara2023proteotoxicstressesstimulate pages 1-3)
Phenotypes-Disease	WRB has been linked mechanistically to sensory phenotypes in vertebrate models: defective WRB impairs insertion of TA clients such as otoferlin and disrupts photoreceptor/hair-cell synaptic function, hearing, and vision. The WRB locus also lies in a chromosome 21 congenital heart disease region, but direct human WRB disease causality remains less established than for other TRC-pathway genes.	Rivera-Monroy et al. 2016 Scientific Reports; Vogl et al. 2016 EMBO Journal; Vilardi 2011 Journal of Cell Science	https://doi.org/10.1038/srep39464; https://doi.org/10.15252/embj.201593565; https://doi.org/10.1242/jcs.084277	2016-12; 2016-12; 2011-04	(riveramonroy2016micelackingwrb pages 1-2, vogl2016tryptophan‐richbasicprotein pages 2-3, vogl2016tryptophan‐richbasicprotein pages 1-2, vilardi2011wrbisthe pages 5-6, vogl2016tryptophan‐richbasicprotein pages 11-12)

Table: This table summarizes the main functional annotation evidence for human GET1/WRB (UniProt O00258), including identity, localization, molecular mechanism, partners, and recent 2023 developments. It is useful as a compact evidence map linking core biological claims to specific sources and context IDs.

7) Conclusions (functional annotation)

GET1/WRB (UniProt O00258) is best annotated as an endoplasmic reticulum membrane insertase/receptor that functions with CAML to receive TA protein substrates delivered by TRC40/ASNA1 and to catalyze/enable their insertion into the ER bilayer through a membrane-embedded hydrophilic groove/channel mechanism. 2023 structures directly support WRB/GET1 as an active insertase that can remodel the membrane (thinning) and undergo conformational changes during insertion, and 2023 proteomics indicates broader client spectra and overlap with other ER insertion systems. (vilardi2011wrbisthe pages 2-3, farkas2021captureanddelivery pages 5-7, mcdowell2023thegetinsertase pages 1-2, jung2023quantitativemassspectrometry pages 19-22)

URLs and publication dates (key sources cited)

Vilardi et al. “WRB is the receptor for TRC40/Asna1-mediated insertion…” Journal of Cell Science (2011-04). https://doi.org/10.1242/jcs.084277 (vilardi2011wrbisthe pages 2-3, vilardi2011wrbisthe pages 5-6)
McDowell et al. “The GET insertase exhibits conformational plasticity and induces membrane thinning” Nature Communications (2023-11). https://doi.org/10.1038/s41467-023-42867-2 (mcdowell2023thegetinsertase pages 1-2, mcdowell2023thegetinsertase media b0739839)
Jung & Zimmermann “Quantitative Mass Spectrometry Characterizes Client Spectra…” Int J Mol Sci (2023-09). https://doi.org/10.3390/ijms241814166 (jung2023quantitativemassspectrometry pages 19-22)
Hagiwara et al. “Proteotoxic stresses stimulate dissociation of UBL4A…” Biochemical Journal (2023-10). https://doi.org/10.1042/bcj20230267 (hagiwara2023proteotoxicstressesstimulate pages 1-3)
Heo et al. “The Get1/2 insertase forms a channel…” Cell Reports (2023-01). https://doi.org/10.1016/j.celrep.2022.111921 (heo2023theget12insertase pages 1-3)

References

(vilardi2011wrbisthe pages 2-3): Fabio Vilardi, Holger Lorenz, and Bernhard Dobberstein. Wrb is the receptor for trc40/asna1-mediated insertion of tail-anchored proteins into the er membrane. Journal of Cell Science, 124:1301-1307, Apr 2011. URL: https://doi.org/10.1242/jcs.084277, doi:10.1242/jcs.084277. This article has 154 citations and is from a domain leading peer-reviewed journal.
(farkas2021captureanddelivery pages 5-7): 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.
(najdrova2022conservedmechanismfor pages 55-59): V Najdrová. Conserved mechanism for targeting of tail-anchored proteins in eukaryotes. Unknown journal, 2022.
(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.
(mateja2018astructuralperspective pages 9-11): Agnieszka Mateja and Robert J Keenan. A structural perspective on tail-anchored protein biogenesis by the get pathway. Current opinion in structural biology, 51:195-202, Aug 2018. URL: https://doi.org/10.1016/j.sbi.2018.07.009, doi:10.1016/j.sbi.2018.07.009. This article has 56 citations and is from a peer-reviewed journal.
(mcdowell2020structuralbasisof pages 1-3): Melanie A. McDowell, Michael Heimes, Francesco Fiorentino, Shahid Mehmood, Ákos Farkas, Javier Coy-Vergara, Di Wu, Jani Reddy Bolla, Volker Schmid, Roger Heinze, Klemens Wild, Dirk Flemming, Stefan Pfeffer, Blanche Schwappach, Carol V. Robinson, and Irmgard Sinning. Structural basis of tail-anchored membrane protein biogenesis by the get insertase complex. Molecular Cell, 80:72-86.e7, Oct 2020. URL: https://doi.org/10.1016/j.molcel.2020.08.012, doi:10.1016/j.molcel.2020.08.012. This article has 115 citations and is from a highest quality peer-reviewed journal.
(heo2023theget12insertase pages 1-3): Paul Heo, Jacob A. Culver, Jennifer Miao, Frederic Pincet, and Malaiyalam Mariappan. The get1/2 insertase forms a channel to mediate the insertion of tail-anchored proteins into the er. Cell Reports, 42:111921, Jan 2023. URL: https://doi.org/10.1016/j.celrep.2022.111921, doi:10.1016/j.celrep.2022.111921. This article has 8 citations and is from a highest quality peer-reviewed journal.
(mcdowell2023thegetinsertase pages 1-2): Melanie A. McDowell, Michael Heimes, Giray Enkavi, Ákos Farkas, Daniel Saar, Klemens Wild, Blanche Schwappach, Ilpo Vattulainen, and Irmgard Sinning. The get insertase exhibits conformational plasticity and induces membrane thinning. Nature Communications, Nov 2023. URL: https://doi.org/10.1038/s41467-023-42867-2, doi:10.1038/s41467-023-42867-2. This article has 16 citations and is from a highest quality peer-reviewed journal.
(mcdowell2023thegetinsertase media b0739839): Melanie A. McDowell, Michael Heimes, Giray Enkavi, Ákos Farkas, Daniel Saar, Klemens Wild, Blanche Schwappach, Ilpo Vattulainen, and Irmgard Sinning. The get insertase exhibits conformational plasticity and induces membrane thinning. Nature Communications, Nov 2023. URL: https://doi.org/10.1038/s41467-023-42867-2, doi:10.1038/s41467-023-42867-2. This article has 16 citations and is from a highest quality peer-reviewed journal.
(jung2023quantitativemassspectrometry pages 19-22): Martin Jung and Richard Zimmermann. Quantitative mass spectrometry characterizes client spectra of components for targeting of membrane proteins to and their insertion into the membrane of the human er. International Journal of Molecular Sciences, 24:14166, Sep 2023. URL: https://doi.org/10.3390/ijms241814166, doi:10.3390/ijms241814166. This article has 10 citations.
(hagiwara2023proteotoxicstressesstimulate pages 1-3): 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.
(riveramonroy2016micelackingwrb pages 1-2): Jhon Rivera-Monroy, Lena Musiol, Kirsten Unthan-Fechner, Ákos Farkas, Anne Clancy, Javier Coy-Vergara, Uri Weill, Sarah Gockel, Shuh-Yow Lin, David P. Corey, Tobias Kohl, Philipp Ströbel, Maya Schuldiner, Blanche Schwappach, and Fabio Vilardi. Mice lacking wrb reveal differential biogenesis requirements of tail-anchored proteins in vivo. Scientific Reports, Dec 2016. URL: https://doi.org/10.1038/srep39464, doi:10.1038/srep39464. This article has 50 citations and is from a peer-reviewed journal.
(vogl2016tryptophan‐richbasicprotein pages 2-3): Christian Vogl, Iliana Panou, Gulnara Yamanbaeva, Carolin Wichmann, Sara J Mangosing, Fabio Vilardi, Artur A Indzhykulian, Tina Pangršič, Rosamaria Santarelli, Montserrat Rodriguez‐Ballesteros, Thomas Weber, Sangyong Jung, Elena Cardenas, Xudong Wu, Sonja M Wojcik, Kelvin Y Kwan, Ignacio del Castillo, Blanche Schwappach, Nicola Strenzke, David P Corey, Shuh‐Yow Lin, and Tobias Moser. Tryptophan‐rich basic protein (wrb) mediates insertion of the tail‐anchored protein otoferlin and is required for hair cell exocytosis and hearing. The EMBO Journal, 35:2536-2552, Dec 2016. URL: https://doi.org/10.15252/embj.201593565, doi:10.15252/embj.201593565. This article has 82 citations.
(vilardi2011wrbisthe pages 5-6): Fabio Vilardi, Holger Lorenz, and Bernhard Dobberstein. Wrb is the receptor for trc40/asna1-mediated insertion of tail-anchored proteins into the er membrane. Journal of Cell Science, 124:1301-1307, Apr 2011. URL: https://doi.org/10.1242/jcs.084277, doi:10.1242/jcs.084277. This article has 154 citations and is from a domain leading peer-reviewed journal.
(daniele2016mutationofwrba pages 1-2): Lauren L. Daniele, Farida Emran, Glenn P. Lobo, Robert J. Gaivin, and Brian D. Perkins. Mutation ofwrb, a component of the guided entry of tail-anchored protein pathway, disrupts photoreceptor synapse structure and function. Investigative Opthalmology & Visual Science, 57:2942, Jun 2016. URL: https://doi.org/10.1167/iovs.15-18996, doi:10.1167/iovs.15-18996. This article has 35 citations.
(lin2016thezebrafishpinball pages 15-17): Shuh‐Yow Lin, Melissa A. Vollrath, Sara Mangosing, Jun Shen, Elena Cardenas, and David P. Corey. The zebrafish pinball wizard gene encodes wrb, a tail‐anchored‐protein receptor essential for inner‐ear hair cells and retinal photoreceptors. The Journal of Physiology, 594:895-914, Feb 2016. URL: https://doi.org/10.1113/jp271437, doi:10.1113/jp271437. This article has 34 citations.
(vogl2016tryptophan‐richbasicprotein pages 1-2): Christian Vogl, Iliana Panou, Gulnara Yamanbaeva, Carolin Wichmann, Sara J Mangosing, Fabio Vilardi, Artur A Indzhykulian, Tina Pangršič, Rosamaria Santarelli, Montserrat Rodriguez‐Ballesteros, Thomas Weber, Sangyong Jung, Elena Cardenas, Xudong Wu, Sonja M Wojcik, Kelvin Y Kwan, Ignacio del Castillo, Blanche Schwappach, Nicola Strenzke, David P Corey, Shuh‐Yow Lin, and Tobias Moser. Tryptophan‐rich basic protein (wrb) mediates insertion of the tail‐anchored protein otoferlin and is required for hair cell exocytosis and hearing. The EMBO Journal, 35:2536-2552, Dec 2016. URL: https://doi.org/10.15252/embj.201593565, doi:10.15252/embj.201593565. This article has 82 citations.
(vogl2016tryptophan‐richbasicprotein pages 11-12): Christian Vogl, Iliana Panou, Gulnara Yamanbaeva, Carolin Wichmann, Sara J Mangosing, Fabio Vilardi, Artur A Indzhykulian, Tina Pangršič, Rosamaria Santarelli, Montserrat Rodriguez‐Ballesteros, Thomas Weber, Sangyong Jung, Elena Cardenas, Xudong Wu, Sonja M Wojcik, Kelvin Y Kwan, Ignacio del Castillo, Blanche Schwappach, Nicola Strenzke, David P Corey, Shuh‐Yow Lin, and Tobias Moser. Tryptophan‐rich basic protein (wrb) mediates insertion of the tail‐anchored protein otoferlin and is required for hair cell exocytosis and hearing. The EMBO Journal, 35:2536-2552, Dec 2016. URL: https://doi.org/10.15252/embj.201593565, doi:10.15252/embj.201593565. This article has 82 citations.
(OpenTargets Search: -WRB): Open Targets Query (-WRB, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Artifacts

Edison artifact artifact-00

Citations

najdrova2022conservedmechanismfor pages 55-59
vilardi2011wrbisthe pages 2-3
farkas2021captureanddelivery pages 1-3
jung2023quantitativemassspectrometry pages 19-22
hagiwara2023proteotoxicstressesstimulate pages 1-3
vilardi2011wrbisthe pages 5-6
daniele2016mutationofwrba pages 1-2
lin2016thezebrafishpinball pages 15-17
riveramonroy2016micelackingwrb pages 1-2
farkas2021captureanddelivery pages 5-7
mateja2018astructuralperspective pages 9-11
mcdowell2020structuralbasisof pages 1-3
mcdowell2023thegetinsertase pages 1-2
https://doi.org/10.1242/jcs.084277;
https://doi.org/10.1083/jcb.202105004
https://doi.org/10.3390/ijms23073773
https://doi.org/10.1016/j.molcel.2020.08.012;
https://doi.org/10.1016/j.celrep.2022.111921
https://doi.org/10.1038/s41467-023-42867-2
https://doi.org/10.3390/ijms241814166
https://doi.org/10.1042/bcj20230267
https://doi.org/10.1038/srep39464;
https://doi.org/10.15252/embj.201593565;
https://doi.org/10.1242/jcs.084277
https://doi.org/10.1242/jcs.084277,
https://doi.org/10.1083/jcb.202105004,
https://doi.org/10.1016/j.sbi.2018.07.009,
https://doi.org/10.1016/j.molcel.2020.08.012,
https://doi.org/10.1016/j.celrep.2022.111921,
https://doi.org/10.1038/s41467-023-42867-2,
https://doi.org/10.3390/ijms241814166,
https://doi.org/10.1042/bcj20230267,
https://doi.org/10.1038/srep39464,
https://doi.org/10.15252/embj.201593565,
https://doi.org/10.1167/iovs.15-18996,
https://doi.org/10.1113/jp271437,

📚 Additional Documentation

Notes

(GET1-notes.md)

GET1 (WRB) gene review notes

Identity

UniProt O00258, GET1_HUMAN, 174 aa. Gene symbol GET1 (HGNC:12790); synonyms WRB, CHD5 (congenital heart disease 5 protein), tryptophan-rich basic protein. [file:human/GET1/GET1-uniprot.txt "RecName: Full=Guided entry of tail-anchored proteins factor 1"]
ER membrane protein with three predicted transmembrane helices and a cytosolic coiled-coil domain. [file:human/GET1/GET1-uniprot.txt "Multi-pass membrane protein"]; [file:human/GET1/GET1-uniprot.txt "REGION 39..97" / "Interaction with GET3/TRC40"]; [file:human/GET1/GET1-uniprot.txt "COILED 39..94"]
Belongs to the WRB/GET1 family; structurally related to the Oxa1 superfamily of insertases. [file:human/GET1/GET1-uniprot.txt "Belongs to the WRB/GET1 family"]; PMID:31417168

Core function: ER membrane insertase receptor for GET3/TRC40

GET1/WRB is the ER-membrane receptor for the cytosolic ATPase GET3/TRC40 (Get3 in yeast), which delivers tail-anchored (TA) proteins. PMID:21444755
The coiled-coil domain (cytosolic, between TMD1 and TMD2) is the docking site for TRC40/GET3. PMID:21444755; PMID:21444755
A soluble coiled-coil domain competes with endogenous WRB and blocks TRC40-mediated TA insertion in vitro (dose-dependent, up to 92% reduction). PMID:21444755
GET1/WRB acts together with CAMLG/GET2 as the mammalian receptor; the two are necessary and synergistic for insertion. PMID:23041287; PMID:23041287
WRB + CAML reconstituted into liposomes are sufficient to confer TA insertion competence. PMID:27226539
WRB/CAML is described directly as "an essential insertase for tail-anchored proteins in the endoplasmic reticulum." PMID:32187542

GET complex / structure

Component of the GET complex: GET1/WRB + CAMLG/GET2 + GET3/TRC40. [file:human/GET1/GET1-uniprot.txt "Component of the Golgi to ER traffic (GET) complex, which is composed of GET1/WRB, CAMLG/GET2 and GET3/TRC40"]
Cryo-EM of human WRB/CAML/TRC40: WRB and CAML form a heterotetramer stabilized by phosphatidylinositol; GET3 binding supports heterotetramer formation. PMID:32910895; [file:human/GET1/GET1-uniprot.txt "GET1 and CAMLG form a heterotetramer which is stabilized by phosphatidylinositol binding and which binds to the GET3 homodimer"]
Structural homology with YidC and the EMC implies a conserved insertion mechanism via a hydrophilic groove. PMID:32910895
PDB structures: 6SO5 (EM 4.2 A), 8CQZ (X-ray 2.8 A, residues 38-97), 8CR1/8CR2 (EM). [file:human/GET1/GET1-uniprot.txt "PDB; 6SO5; EM"]

Role in CAMLG topogenesis / protein stabilization

WRB is required for correct topology and integration of its partner CAML into the ER; without WRB, CAML adopts aberrant topoforms that cluster and are degraded by the proteasome. PMID:31417168; PMID:31417168
WRB can correct the topology of CAML in vitro and in cells. PMID:32187542
This is the basis for the "protein stabilization" (GO:0050821) IDA annotations (PMID:31417168, PMID:32187542): WRB stabilizes/correctly integrates CAML. WRB and CAML are mutually dependent for expression. PMID:31417168
Note GO term scoping: GO:0050821 "protein stabilization" is about preventing degradation/maintaining native conformation; WRB preventing CAML mis-folding/degradation is a reasonable but secondary (non-core) consequence of its insertase activity. Keep as non-core.

Subcellular location

ER membrane (experimental). [file:human/GET1/GET1-uniprot.txt "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"]; PMID:21444755
The original 1998 paper reported a predominantly NUCLEAR localization by immunofluorescence (source of GO:0005634 nucleus TAS, PMID:9544840). PMID:9544840
This nuclear localization was NOT reproduced and is contradicted by the later, function-defining study, which establishes ER residence and could not detect nuclear WRB. PMID:21444755
Conclusion: GO:0005634 nucleus is superseded/incorrect. WRB is a multi-pass ER membrane protein with no established nuclear function; the 1998 result predates knowledge of the protein and is best treated as an over-annotation. Mark as over-annotated (do not retain as a real location).

Interactions (IPI / protein binding)

PMID:32296183 (Luck et al., human binary interactome / HuRI Y2H map): source of a large list of IntAct GO:0005515 partners (APOA2, TFRC, CD53, COMT, AQP1, HMOX2, SLC7A1, STX2-2, etc.). These are high-throughput Y2H hits; many are themselves TA/membrane proteins (plausible insertase substrates) but the bare "protein binding" term is uninformative. Keep as non-core.
CAMLG (P49069) IPI interactions (PMID:31417168, PMID:32187542) reflect the genuine, functionally central WRB-CAML association, but the GO term used is the uninformative GO:0005515. Keep as non-core (the informative MF is captured by GO:0043495 / GET3-receptor activity, and complex membership by GO:0043529).

Disease / development context (background, not core MF/BP)

WRB/CHD5 maps to chromosome 21q22.3 within the Down syndrome congenital heart disease region. PMID:9544840; PMID:21444755
Loss in model organisms causes cardiac and eye/retinal phenotypes (medaka, zebrafish pwi photoreceptor degeneration), consistent with pleiotropic effects of impaired TA-protein insertion. PMID:21444755

Annotation review decisions (summary)

GO:0071816 tail-anchored membrane protein insertion into ER membrane (IDA/IMP/IBA/IEA): ACCEPT — core BP.
GO:0043495 protein-membrane adaptor activity (IBA): MODIFY is tempting but this is the standard PAN-GO MF for the GET3 receptor; keep as ACCEPT representing the membrane-insertase-receptor MF (this is the term GO_Central uses for GET1 orthologs). Core MF.
GO:0043529 GET complex (IDA/IPI/IBA): ACCEPT — core CC.
GO:0005789 ER membrane (EXP/NAS/IEA): ACCEPT — core CC.
GO:0045048 protein insertion into ER membrane (IDA/IMP/NAS): ACCEPT (parent of GO:0071816; correct, slightly less specific). Core BP.
GO:0090150 establishment of protein localization to membrane (IEA/ARBA): ACCEPT as correct generic parent (non-core).
GO:0050821 protein stabilization (IDA x2): KEEP_AS_NON_CORE — refers to WRB-dependent correct integration/stabilization of CAML; real but secondary to insertase function.
GO:0005515 protein binding (IPI x3 refs): KEEP_AS_NON_CORE — uninformative; includes functionally important CAMLG binding and HuRI Y2H hits.
GO:0005634 nucleus (TAS, PMID:9544840): MARK_AS_OVER_ANNOTATED — superseded by ER localization; not reproduced.

Falcon deep-research findings (incorporated 2026-06)

GET1/WRB is an active insertase, not merely a receptor: reconstituted Get1/2 (WRB/CAML) forms a dynamic aqueous channel (~2.5 nm, ≈ two Get1/2 complexes) sealed by Get3, and channel activity is required to release TA proteins from Get3 for membrane insertion; it acts as both insertase (TMD insertion) and translocase (C-terminal hydrophilic tail). PMID:36640319. Strengthens GO:0071816 (added to supported_by).
2023 human GET insertase structures: the Get1/Get2/Get3 fold is conserved across eukaryotes and the insertase induces local lipid-bilayer thinning near the hydrophilic groove to lower the energetic barrier for TA insertion. PMID:37963916. Supports GET1/WRB's active, membrane-remodeling insertase role (added to supported_by for GO:0071816).
Gating mechanism: the interaction between Get2 helix α3' and Get3 drives conformational changes in both Get3 and the Get1/Get2 membrane heterotetramer, providing a structural basis for how Get1 (WRB) coiled-coil engagement promotes Get3 opening and substrate handoff. PMID:37963916.
Pathway review (Farkas & Bohnsack 2021) frames GET1/WRB + CAMLG/GET2 as the obligate ER receptor-insertase that receives TA cargo from cytosolic GET3/TRC40; corroborates existing core-function calls. PMID:34264263 (added as HIGH-relevance reference).
Falcon also cites Jung & Zimmermann 2023 (IJMS) reporting a TA-insertase preference ordering "Wrb >> TRAM1 >> Sec61 > EMC > TRAP > Sec63" (proteomics, indirect) and Hagiwara 2023 (Biochem J) on upstream BAG6-UBL4A dissociation under proteotoxic stress; these are pathway-context/quality-control and were not added as GET1-specific structured references (no GET1-specific functional finding).

Pn Notes

(GET1-pn-notes.md)

GET1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: O00258
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-11
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/GET1/GET1-ai-review.yaml
AIGR review HTML: missing - genes/human/GET1/GET1-ai-review.html
Gene notes: present - genes/human/GET1/GET1-notes.md
GOA TSV: present - genes/human/GET1/GET1-goa.tsv
UniProt record: present - genes/human/GET1/GET1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/GET1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/GET1.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/GET1/GET1-deep-research-falcon.md

AIGR Review Snapshot

Description: GET1 (WRB; also known as congenital heart disease 5 protein/CHD5 and tryptophan-rich basic protein) is a multi-pass endoplasmic reticulum (ER) membrane protein that is the membrane receptor for the cytosolic ATPase GET3/TRC40 in the GET (guided entry of tail-anchored proteins) pathway. This pathway delivers tail-anchored (TA) membrane proteins, which carry a single C-terminal transmembrane domain, to the ER for post-translational insertion. GET1/WRB has three transmembrane helices and a cytosolic coiled-coil domain (residues ~39-97) that docks the TA-loaded GET3/TRC40 homodimer at the membrane. Together with CAMLG/GET2, GET1 forms a heterotetrameric insertase that, with bound GET3, accepts the TA substrate and catalyzes its insertion into the ER lipid bilayer through a hydrophilic groove, mechanistically related to the YidC/Oxa1 insertase superfamily and the ER membrane protein complex (EMC). GET1 and CAMLG are mutually dependent for stable expression and correct topology, and GET1 is required for the proper integration of its partner CAMLG into the ER membrane. The protein is broadly expressed and resides in the ER membrane.
Existing/core annotation action counts: ACCEPT: 15; KEEP_AS_NON_CORE: 6; MARK_AS_OVER_ANNOTATED: 2

PN Consistency Summary

Consistency: Deep research (notes + falcon), review YAML, and PN annotation are consistent: GET1/WRB is the ER membrane receptor-insertase subunit of the GET pathway, with CAMLG/GET2 forming the heterotetramer that accepts GET3-delivered TA proteins. Distinction "receptor/insertase (GET1) vs ATPase targeting factor (GET3)" is honored. The review correctly MARK_AS_OVER_ANNOTATED the legacy nucleus TAS (PMID:9544840), not reproduced.
PN story / NEW pressure: PN asserts post-translational ER-membrane targeting/insertion of TA proteins — already captured by review's core terms GO:0071816 (TA insertion into ER membrane), GO:0045048 (protein insertion into ER membrane), GO:0043495 (protein-membrane adaptor activity, the PAN-GO MF), GO:0043529 (GET complex). No NEW GO term warranted; already captured.
Evidence alignment: Strong overlap — review's GET-pathway PMIDs (21444755, 23041287, 27226539, 32910895, 36640319, 37963916) fully support the PN targeting/insertion claim.
Verdict: Consistent; well-reviewed. Flag the GO:0006620 goa_status inconsistency between GET1 (more_specific_than_existing_goa) and GET3 (new_to_goa) dossiers and that GO:0006620 (targeting) fits GET3 better than the receptor-insertase GET1.

Full Consistency Review

UniProt: O00258 (WRB) · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE
PN placement: ER proteostasis|Protein transport|GET pathway component ; PN-node mapping: group → GO:0006620 (post-translational protein targeting to ER membrane), scope=ok_for_propagation, goa_status=more_specific_than_existing_goa; class → GO:0015031 (protein transport); branch=no_mapping.
Consistency: Deep research (notes + falcon), review YAML, and PN annotation are consistent: GET1/WRB is the ER membrane receptor-insertase subunit of the GET pathway, with CAMLG/GET2 forming the heterotetramer that accepts GET3-delivered TA proteins. Distinction "receptor/insertase (GET1) vs ATPase targeting factor (GET3)" is honored. The review correctly MARK_AS_OVER_ANNOTATED the legacy nucleus TAS (PMID:9544840), not reproduced.
PN story / NEW pressure: PN asserts post-translational ER-membrane targeting/insertion of TA proteins — already captured by review's core terms GO:0071816 (TA insertion into ER membrane), GO:0045048 (protein insertion into ER membrane), GO:0043495 (protein-membrane adaptor activity, the PAN-GO MF), GO:0043529 (GET complex). No NEW GO term warranted; already captured.
Mapping strategy: GET1 does not alter the GET-node mapping. Discrepancy flag: GET1 dossier labels GO:0006620 more_specific_than_existing_goa whereas the identical GET3 mapping labels it new_to_goa — one is wrong (GET1's GOA carries the insertion terms but not GO:0006620 specifically; both genes should share the same goa_status for the same projected term). GO:0006620 is verified-real and a defensible group term, but is a targeting (not insertion) term; GET1's role is the membrane receptor-insertase, so GO:0006620 is slightly off-target for GET1 specifically (better fits GET3). Acceptable as a group/pathway-level term, but narrower-fit for GET3 than GET1.
Evidence alignment: Strong overlap — review's GET-pathway PMIDs (21444755, 23041287, 27226539, 32910895, 36640319, 37963916) fully support the PN targeting/insertion claim.
Verdict: Consistent; well-reviewed. Flag the GO:0006620 goa_status inconsistency between GET1 (more_specific_than_existing_goa) and GET3 (new_to_goa) dossiers and that GO:0006620 (targeting) fits GET3 better than the receptor-insertase GET1.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-11
review_yaml: genes/human/GET1/GET1-ai-review.yaml
PN workbook rows: 1

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

UniProt: O00258
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=more_specific_than_existing_goa | 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: O00258
gene_symbol: GET1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: GET1 (WRB; also known as congenital heart disease 5 protein/CHD5 and tryptophan-rich basic protein) is a multi-pass endoplasmic reticulum (ER) membrane protein that is the membrane receptor for the cytosolic ATPase GET3/TRC40 in the GET (guided entry of tail-anchored proteins) pathway. This pathway delivers tail-anchored (TA) membrane proteins, which carry a single C-terminal transmembrane domain, to the ER for post-translational insertion. GET1/WRB has three transmembrane helices and a cytosolic coiled-coil domain (residues ~39-97) that docks the TA-loaded GET3/TRC40 homodimer at the membrane. Together with CAMLG/GET2, GET1 forms a heterotetrameric insertase that, with bound GET3, accepts the TA substrate and catalyzes its insertion into the ER lipid bilayer through a hydrophilic groove, mechanistically related to the YidC/Oxa1 insertase superfamily and the ER membrane protein complex (EMC). GET1 and CAMLG are mutually dependent for stable expression and correct topology, and GET1 is required for the proper integration of its partner CAMLG into the ER membrane. The protein is broadly expressed and resides in the ER membrane.
alternative_products:
- name: '1'
  id: O00258-1
- name: '2'
  id: O00258-2
  sequence_note: VSP_043081
existing_annotations:
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) annotation of GET1's defining biological process, the insertion of tail-anchored membrane proteins into the ER membrane. Conserved across the WRB/GET1 family and supported by direct experimental evidence.
    action: ACCEPT
    reason: Core biological process; GET1/WRB is the ER receptor of the GET pathway that inserts TA proteins, supported by IDA/IMP and the UniProt function.
    supported_by:
    - reference_id: file:human/GET1/GET1-uniprot.txt
      supporting_text: Required for the post-translational delivery of tail-anchored
    - reference_id: PMID:36640319
      supporting_text: the Get1/2 channel functions as an insertase for insertion of TMDs and as a translocase for translocation of C-terminal hydrophilic segments
    - reference_id: PMID:37963916
      supporting_text: the Get3 chaperone captures the TA protein substrate and delivers it to the Get1/Get2 membrane protein complex (GET insertase), which then inserts the substrate via a membrane-embedded hydrophilic groove
- term:
    id: GO:0043495
    label: protein-membrane adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: This is the PAN-GO/GO_Central molecular function used for the GET3 receptor across orthologs, capturing GET1/WRB's role of coupling the soluble GET3/TRC40 chaperone to the ER membrane so that the TA substrate can be inserted. GET1 provides the membrane docking site (its coiled-coil) for the cytosolic targeting factor.
    action: ACCEPT
    reason: Represents the informative membrane-insertase-receptor molecular function of GET1; the coiled-coil domain docks GET3/TRC40 at the membrane.
    supported_by:
    - reference_id: PMID:21444755
      supporting_text: We identify the coiled-coil domain of WRB as the binding site for TRC40/Asna1
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: GET1/WRB is a constitutive subunit of the GET complex (GET1/WRB + CAMLG/GET2 + GET3/TRC40). Conserved across the family and directly demonstrated structurally.
    action: ACCEPT
    reason: Core cellular component; GET1 is a defining subunit of the GET insertase complex.
    supported_by:
    - reference_id: file:human/GET1/GET1-uniprot.txt
      supporting_text: Component of the Golgi to ER traffic (GET) complex, which is
        composed of GET1/WRB, CAMLG/GET2 and GET3/TRC40
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of the ER membrane localization from the UniProt subcellular location, consistent with the experimental EXP evidence.
    action: ACCEPT
    reason: Correct compartment; GET1 is an experimentally established multi-pass ER membrane protein.
    supported_by:
    - reference_id: file:human/GET1/GET1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0071816
    label: tail-anchored membrane 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 TA-protein ER insertion process, consistent with the experimental evidence.
    action: ACCEPT
    reason: Correct core process; redundant with IDA/IMP/IBA evidence.
    supported_by:
    - reference_id: file:human/GET1/GET1-uniprot.txt
      supporting_text: Required for the post-translational delivery of tail-anchored
- term:
    id: GO:0090150
    label: establishment of protein localization to membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning electronic annotation of the generic parent process; GET1 establishes localization of TA proteins to the ER membrane. Correct but less specific than GO:0071816.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic parent of the specific TA-insertion process that better captures GET1's role.
    supported_by:
    - reference_id: file:human/GET1/GET1-uniprot.txt
      supporting_text: Required for the post-translational delivery of tail-anchored
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput human binary interactome (HuRI/Y2H) capturing many IntAct partners of GET1 (e.g. APOA2, TFRC, CD53, AQP1, HMOX2, SLC7A1); several are themselves TA/membrane proteins and plausible insertase substrates, but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real Y2H interactions but bare protein binding is uninformative; the informative MF is captured by GO:0043495.
    supported_by:
    - reference_id: file:human/GET1/GET1-uniprot.txt
      supporting_text: 'O00258; P02652: APOA2'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:32910895
  qualifier: located_in
  review:
    summary: ComplexPortal NAS assertion of ER membrane localization from the cryo-EM structural study of the human GET insertase complex.
    action: ACCEPT
    reason: Correct compartment; consistent with experimental EXP localization.
    supported_by:
    - reference_id: file:human/GET1/GET1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IPI
  original_reference_id: PMID:32910895
  qualifier: part_of
  review:
    summary: ComplexPortal IPI assignment of GET complex membership from the cryo-EM structure of the human WRB/CAML/TRC40 insertase complex.
    action: ACCEPT
    reason: Core cellular component; directly demonstrated structurally.
    supported_by:
    - reference_id: PMID:32910895
      supporting_text: Get3 binding to the membrane insertase supports heterotetramer formation
- term:
    id: GO:0045048
    label: protein insertion into ER membrane
  evidence_type: NAS
  original_reference_id: PMID:23041287
  qualifier: involved_in
  review:
    summary: ComplexPortal NAS assertion of the (parent) ER protein-insertion process; GET1/WRB with CAML synergistically inserts TA proteins into the ER membrane.
    action: ACCEPT
    reason: Correct; parent of GO:0071816 and consistent with experimental evidence.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: CAML and WRB synergistically insert TA proteins into the membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:21444755
  qualifier: located_in
  review:
    summary: Direct experimental evidence that WRB is an ER-resident membrane protein, established in the study that identified WRB as the TRC40 receptor.
    action: ACCEPT
    reason: Core, experimentally demonstrated localization.
    supported_by:
    - reference_id: PMID:21444755
      supporting_text: WRB is an ER-resident membrane protein
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31417168
  qualifier: enables
  review:
    summary: IPI annotation capturing the WRB-CAMLG (P49069) interaction. This reflects the genuine, functionally central GET1-CAMLG association, but the GO term used is the uninformative bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Records the real and important CAMLG interaction, but bare protein binding is uninformative; the functional MF is captured by GO:0043495 and complex membership by GO:0043529.
    supported_by:
    - reference_id: file:human/GET1/GET1-uniprot.txt
      supporting_text: Interacts with CAMLG (via C-terminus)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32187542
  qualifier: enables
  review:
    summary: IPI annotation capturing the WRB-CAMLG (P49069) interaction from the study on orphan subunit recognition by the WRB/CAML complex. Functionally meaningful interaction but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real CAMLG interaction; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/GET1/GET1-uniprot.txt
      supporting_text: Interacts with CAMLG (via C-terminus)
- term:
    id: GO:0045048
    label: protein insertion into ER membrane
  evidence_type: IMP
  original_reference_id: PMID:31417168
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that WRB is required for correct integration of CAML into the ER; WRB acts catalytically to assist CAML topogenesis/insertion.
    action: ACCEPT
    reason: Correct; supported by IMP. WRB-dependent ER insertion (here of CAML) reflects its insertase-receptor role.
    supported_by:
    - reference_id: PMID:31417168
      supporting_text: WRB ... acts catalytically to assist the topogenesis of CAML
- term:
    id: GO:0045048
    label: protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:32187542
  qualifier: involved_in
  review:
    summary: Direct evidence that WRB can correct the topology of (and thereby insert) CAML both in vitro and in cells, supporting GET1's ER protein-insertion role.
    action: ACCEPT
    reason: Core process; directly demonstrated. Parent of the more specific TA-insertion term.
    supported_by:
    - reference_id: PMID:32187542
      supporting_text: When present, WRB can correct the topology of CAML both in vitro and in cells
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:31417168
  qualifier: involved_in
  review:
    summary: Without sufficient WRB, CAML fails to adopt its correct topology, generating aberrant topoforms that cluster and are degraded by the proteasome; WRB therefore stabilizes/correctly integrates CAML. This is a real but secondary consequence of GET1's insertase-receptor function.
    action: KEEP_AS_NON_CORE
    reason: Supported by IDA but represents WRB-dependent stabilization of one specific partner (CAML), secondary to the core TA-insertion function.
    supported_by:
    - reference_id: PMID:31417168
      supporting_text: these congregate in ER-associated clusters and are degraded by the proteasome
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:32187542
  qualifier: involved_in
  review:
    summary: WRB-mediated correction of CAML topology stabilizes CAML; consistent with the partner-stabilization phenotype. Secondary to the core insertase-receptor function.
    action: KEEP_AS_NON_CORE
    reason: Real but secondary partner-stabilization effect, not the core function of GET1.
    supported_by:
    - reference_id: PMID:32187542
      supporting_text: When present, WRB can correct the topology of CAML both in vitro and in cells
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IDA
  original_reference_id: PMID:32910895
  qualifier: part_of
  review:
    summary: The cryo-EM structure directly resolves GET1/WRB within the GET insertase complex, forming a heterotetramer with CAML that binds the GET3 homodimer.
    action: ACCEPT
    reason: Core cellular component, structurally demonstrated.
    supported_by:
    - reference_id: PMID:32910895
      supporting_text: Get3 binding to the membrane insertase supports heterotetramer formation
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:27226539
  qualifier: involved_in
  review:
    summary: Direct evidence that in-vitro-synthesized CAML and WRB together are sufficient to confer TA-insertion competence to liposomes, establishing GET1's core role in TA-protein ER insertion.
    action: ACCEPT
    reason: Core biological process with direct experimental (IDA) support.
    supported_by:
    - reference_id: PMID:27226539
      supporting_text: in vitro synthesized CAML and WRB together were sufficient to confer insertion competence to liposomes
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IMP
  original_reference_id: PMID:23041287
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that CAML and WRB synergistically insert TA proteins into the ER membrane, establishing GET1 as a component of the TRC40 receptor complex driving TA insertion.
    action: ACCEPT
    reason: Core biological process with IMP support.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: CAML and WRB synergistically insert TA proteins into the membrane
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IPI
  original_reference_id: PMID:23041287
  qualifier: part_of
  review:
    summary: Mass-spectrometry/IPI identification of GET1/WRB in the TRC40 receptor (GET) complex together with CAMLG and GET3.
    action: ACCEPT
    reason: Core cellular component; directly demonstrated by complex identification.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: CAML and WRB as components of the TRC40 receptor complex
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:9544840
  qualifier: located_in
  review:
    summary: The original 1998 cDNA characterization reported predominant nuclear immunofluorescence localization, before the protein's function was known. This was not reproduced and is contradicted by the later function-defining study, which establishes ER membrane residence and could not detect nuclear WRB. GET1/WRB is a multi-pass ER membrane protein with no established nuclear function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Superseded by experimental ER membrane localization; the early nuclear immunofluorescence result was not reproduced and is inconsistent with GET1's multi-pass ER membrane topology.
    supported_by:
    - reference_id: PMID:21444755
      supporting_text: We have not been able to detect WRB in untransfected RPE-1 or HeLa cells using our anti-WRB antibodies
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:9544840
  qualifier: located_in
  isoform: O00258-1
  review:
    summary: Duplicate of the early nuclear localization assertion; same provenance and same conclusion. GET1/WRB localizes to the ER membrane, not the nucleus.
    action: MARK_AS_OVER_ANNOTATED
    reason: Superseded by the experimentally established ER membrane localization; not reproduced.
    supported_by:
    - reference_id: PMID:21444755
      supporting_text: WRB is an ER-resident membrane protein
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: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:21444755
  title: WRB is the receptor for TRC40/Asna1-mediated insertion of tail-anchored proteins into the ER membrane.
  findings:
  - statement: Identifies WRB/CHD5 as the ER membrane receptor for TRC40/Asna1 and maps the WRB coiled-coil domain as the TRC40 docking site; WRB is ER-resident, not nuclear.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Function-defining study identifying GET1/WRB as the GET3/TRC40 ER receptor and establishing ER (not nuclear) localization.
- id: PMID:23041287
  title: Molecular machinery for insertion of tail-anchored membrane proteins into the endoplasmic reticulum membrane in mammalian cells.
  findings:
  - statement: WRB and CAML synergistically insert TA proteins into the ER membrane and together constitute the mammalian TRC40 receptor complex.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the WRB/CAML receptor complex and its synergistic TA-insertion activity.
- id: PMID:27226539
  title: 'Tail-anchored Protein Insertion in Mammals: FUNCTION AND RECIPROCAL INTERACTIONS OF THE TWO SUBUNITS OF THE TRC40 RECEPTOR.'
  findings:
  - statement: In-vitro-synthesized CAML and WRB together are sufficient to confer TA-insertion competence to liposomes; the two subunits are reciprocally dependent.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Demonstrates sufficiency of WRB+CAML for TA insertion in a reconstituted system.
- id: PMID:31417168
  title: The WRB Subunit of the Get3 Receptor is Required for the Correct Integration of its Partner CAML into the ER.
  findings:
  - statement: WRB acts catalytically to assist CAML topogenesis; without sufficient WRB, CAML adopts aberrant topoforms that cluster and are degraded by the proteasome.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the protein insertion (of CAML) and protein stabilization annotations; WRB and CAML are mutually dependent.
- id: PMID:32187542
  title: Differential Modes of Orphan Subunit Recognition for the WRB/CAML Complex.
  findings:
  - statement: The WRB/CAML complex is an essential insertase for tail-anchored proteins; WRB can correct the topology of CAML in vitro and in cells.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Describes WRB/CAML as an essential TA insertase and WRB-mediated CAML topology correction.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: High-throughput Y2H (HuRI) interactome; source of the IntAct protein binding partners of GET1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Bare protein binding Y2H hits; many partners are membrane/TA proteins but the term is uninformative.
- id: PMID:32910895
  title: Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex.
  findings:
  - statement: Cryo-EM of the human WRB/CAML/TRC40 complex; WRB and CAML form a phosphatidylinositol-stabilized heterotetramer that binds the GET3 homodimer, with an insertion mechanism related to YidC and the EMC.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive structure of the human GET insertase complex.
- id: PMID:9544840
  title: Identification and characterization of a new human cDNA from chromosome 21q22.3 encoding a basic nuclear protein.
  findings:
  - statement: Original cDNA characterization reporting predominant nuclear immunofluorescence localization; not reproduced and superseded by later ER membrane localization.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: DISPUTED
    review_notes: Source of the nucleus annotation; the nuclear localization was not reproduced and is contradicted by later work establishing ER membrane residence.
- id: PMID:34264263
  title: Capture and delivery of tail-anchored proteins to the endoplasmic reticulum.
  findings:
  - statement: Comprehensive review of the GET/TRC pathway; GET1/WRB with CAMLG/GET2 forms the ER membrane receptor-insertase that receives TA substrates from the cytosolic ATPase GET3/TRC40 and mediates their insertion into the ER bilayer.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (J Cell Biol 2021, 220:8). Authoritative pathway review framing GET1/WRB as the ER receptor-insertase subnit of the GET pathway.
- id: PMID:36640319
  title: The Get1/2 insertase forms a channel to mediate the insertion of tail-anchored proteins into the ER.
  findings:
  - statement: Reconstitution shows the Get1/2 (WRB/CAML) complex forms a dynamic aqueous channel (~2.5 nm, corresponding to two Get1/2 complexes) that is sealed by Get3 and whose channel activity is required to release TA proteins from Get3 for insertion; functions as both insertase and translocase for C-terminal hydrophilic tails.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Cell Rep 2022, 42:111921). Mechanistic evidence that the GET1/2 insertase acts as a channel-forming insertase/translocase; directly supports GET1's TA-insertion role (yeast Get1/2, conserved in mammalian WRB/CAML).
- id: PMID:37963916
  title: The GET insertase exhibits conformational plasticity and induces membrane thinning.
  findings:
  - statement: Structures, simulations and functional data of human and C. thermophilum Get1/Get2/Get3 show the GET insertase fold is conserved, induces local lipid bilayer thinning near the hydrophilic groove to lower the insertion barrier, and that gating between Get2 helix alpha3' and Get3 drives conformational changes across the Get1/Get2 heterotetramer.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Commun 2023, 14:7355). Modern structural support for GET1/WRB as an active membrane insertase (not a static receptor) that remodels the bilayer; includes human Get1/Get2/Get3.
- id: file:human/GET1/GET1-uniprot.txt
  title: UniProt entry O00258 (GET1_HUMAN), Guided entry of tail-anchored proteins factor 1
  findings:
  - statement: GET1/WRB is the ER membrane receptor for GET3/TRC40 in the GET complex (GET1/WRB + CAMLG/GET2 + GET3/TRC40); multi-pass ER membrane protein required for post-translational delivery of TA proteins to the ER.
    reference_section_type: OTHER
core_functions:
- description: Membrane-insertase receptor of the GET pathway that docks the cytosolic GET3/TRC40 targeting factor at the ER membrane via its coiled-coil domain, enabling post-translational insertion of tail-anchored membrane proteins.
  molecular_function:
    id: GO:0043495
    label: protein-membrane adaptor activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:21444755
    supporting_text: We identify the coiled-coil domain of WRB as the binding site for TRC40/Asna1
  directly_involved_in:
  - id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
- description: Subunit of the GET (WRB/CAML/TRC40) insertase complex that, together with CAMLG/GET2, forms a heterotetramer accepting GET3-delivered tail-anchored proteins and inserting them into the ER lipid bilayer.
  molecular_function:
    id: GO:0043495
    label: protein-membrane adaptor activity
  in_complex:
    id: GO:0043529
    label: GET complex
  supported_by:
  - reference_id: PMID:27226539
    supporting_text: in vitro synthesized CAML and WRB together were sufficient to confer insertion competence to liposomes
  directly_involved_in:
  - id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
proposed_new_terms: []
suggested_questions:
- question: Does GET1/WRB contribute substrate selectivity for particular tail-anchored proteins, or is selectivity entirely determined upstream by GET3/TRC40?
- question: Are the many HuRI Y2H interactors of GET1 (membrane/TA proteins such as TFRC, AQP1, SLC7A1) genuine insertase substrates, and could GET1 interactomics be used to define its physiological client repertoire?
suggested_experiments:
- description: Reconstitute purified WRB, CAML and GET3/TRC40 into proteoliposomes and measure insertion kinetics for a panel of TA substrates of differing transmembrane-domain hydrophobicity to define GET1's role in substrate handoff and insertion efficiency.
- description: Use proximity labeling (BioID/TurboID) from endogenously tagged WRB in human cells to map its in vivo TA-protein client network and distinguish genuine substrates from incidental Y2H hits.

GET1

Gene Description

Existing Annotations Review

Core Functions

Membrane-insertase receptor of the GET pathway that docks the cytosolic GET3/TRC40 targeting factor at the ER membrane via its coiled-coil domain, enabling post-translational insertion of tail-anchored membrane proteins.

Subunit of the GET (WRB/CAML/TRC40) insertase complex that, together with CAMLG/GET2, forms a heterotetramer accepting GET3-delivered tail-anchored proteins and inserting them into the ER lipid bilayer.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human GET1 / WRB (UniProt O00258)

0) Target verification (gene/protein identity)

1) Key concepts and definitions (current understanding)

1.1 Tail-anchored (TA) proteins

1.2 GET/TRC pathway (ER TA-protein targeting/insertion)

1.3 What GET1/WRB is (molecular function definition)

2) Molecular function, mechanism, and pathway placement

2.1 Subcellular localization

2.2 Core interaction partners

2.3 Stepwise mechanism (functional annotation narrative)

3) Recent developments (prioritizing 2023–2024)

3.1 2023 structural mechanism: hydrophilic groove and membrane remodeling

3.2 2023 channel model for the insertase (mechanistic support)

3.3 2023 proteomics: broader client spectra and pathway “rules of engagement”

3.4 2023 quality control/proteostasis link: BAG6–UBL4A disruption

4) Current applications and real-world implementations

5) Phenotypes, disease relevance, and expert interpretation

5.1 Congenital heart disease context

5.2 Strong functional links to sensory synapse biology (hearing/vision) via TA clients

5.3 Proteostasis and selective TA-client dependence in vivo

5.4 Database-level disease association signals (Open Targets)

6) Summary evidence map

7) Conclusions (functional annotation)

URLs and publication dates (key sources cited)

Artifacts

Citations

📚 Additional Documentation

Notes

GET1 (WRB) gene review notes

Identity

Core function: ER membrane insertase receptor for GET3/TRC40

GET complex / structure

Role in CAMLG topogenesis / protein stabilization

Subcellular location

Interactions (IPI / protein binding)

Disease / development context (background, not core MF/BP)

Annotation review decisions (summary)

Falcon deep-research findings (incorporated 2026-06)

Pn Notes

GET1 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