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.
| 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 |
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Download this section (compressed HTML)Q: Does GET1/WRB contribute substrate selectivity for particular tail-anchored proteins, or is selectivity entirely determined upstream by GET3/TRC40?
Q: 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?
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.
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