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).