EFR3A (protein EFR3 homolog A; KIAA0143) is a non-enzymatic, all-alpha-helical ARM/HEAT-repeat scaffold that sits on the cytoplasmic face of the plasma membrane. It is anchored there by palmitoylation of an N-terminal cysteine cluster (Cys6-Cys9), assisted by a conserved basic patch that binds acidic phospholipids. Its disordered C terminus folds into a three-helix element on binding the TTC7-FAM126 subcomplex of the phosphatidylinositol 4-kinase type III alpha (PI4KA) complex, so EFR3A tethers the PI4KA-TTC7-FAM126 assembly to the plasma membrane, where PI4KA generates the plasma-membrane pool of phosphatidylinositol 4-phosphate, the precursor of PI(4,5)P2. EFR3A does not contact PI4KA directly and has no catalytic activity of its own. It is partly redundant with its paralog EFR3B. Depletion of EFR3A and EFR3B together alters desensitization of G protein-coupled receptors such as AGTR1, probably as an indirect consequence of altered plasma-membrane phosphoinositide homeostasis. Rare missense variants have been reported in autism spectrum disorder cohorts.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence detects a cytosolic signal; UniProt records that a small amount of EFR3A is cytosolic, while palmitoylated EFR3A is predominantly at the plasma membrane. Reason: A minor cytosolic pool is consistent with a palmitoylated peripheral membrane protein (newly synthesized or depalmitoylated protein; the palmitoylation-deficient C6S-C9S mutant is entirely cytosolic). The functional site of EFR3A is the plasma membrane, so cytosol is a true but peripheral location. Supporting Evidence: file:human/EFR3A/EFR3A-uniprot.txt A small amount is observed in the cytosol PMID:23229899 Importantly, palmitoylation-deficient mutants (C6S/C7S/C8S/C9S for EFR3A and C5S/C7S/C8S for EFR3B) were localized in the cytosol |
| GO:0005829 cytosol | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: SubCell keyword mapping of the curated UniProt statement that a small fraction of EFR3A is cytosolic. Reason: Same claim as the HPA IDA cytosol row and handled consistently; a minor, non-functional pool relative to the plasma-membrane-anchored protein. Supporting Evidence: file:human/EFR3A/EFR3A-uniprot.txt A small amount is observed in the cytosol |
| GO:0005886 plasma membrane | EXP PMID:25380825 EFR3s are palmitoylated plasma membrane proteins that contro... | ACCEPT | Summary: Bojjireddy et al. show that EFR3s are palmitoylated plasma-membrane proteins; this matches independent localization and mutagenesis data from Nakatsu et al. Reason: Plasma membrane is the core functional location of EFR3A. The cached record for PMID:25380825 is abstract-only but its title states the finding directly, and the same result is reproduced in full-text papers (PMID:23229899, PMID:24360784). Supporting Evidence: PMID:25380825 EFR3s are palmitoylated plasma membrane proteins that control responsiveness to G-protein-coupled receptors. PMID:23229899 These data suggest that EFR3 is a peripheral membrane protein whose posttranslational lipidation enables its localization to membranes and its function in PI4KIIIΞ±-mediated PtdIns4P synthesis at the plasma membrane. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT places plasma-membrane activity at PTN000278197, the PTHR12444 node that includes EFR3A and EFR3B (human and mouse donors); Q14156 is a descendant (PTHR12444:SF1) with its own experimental plasma-membrane evidence. Reason: The target sits inside the clade carrying the IBD, and nothing suggests loss of the palmitoylation motif or membrane binding in human EFR3A. Its appearance among the donors is expected, because its own IDA/EXP data were evidence for the node. Supporting Evidence: PMID:23229899 we show that PI4KIIIΞ± was targeted to the plasma membrane as part of an evolutionarily conserved complex containing Efr3/rolling blackout, which we found was a palmitoylated peripheral membrane protein. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence places EFR3A at the plasma membrane, in agreement with tagged-protein studies. Reason: Consistent with the experimental literature on palmitoylation-dependent plasma-membrane anchoring. Supporting Evidence: file:human/EFR3A/EFR3A-uniprot.txt Palmitoylated at its N-terminus, anchoring the protein to the |
| GO:0005886 plasma membrane | IDA PMID:23229899 PtdIns4P synthesis by PI4KIIIΞ± at the plasma membrane and it... | ACCEPT | Summary: Tagged EFR3A localizes to the plasma membrane; mutation of the palmitoylated N-terminal cysteines (C6S/C7S/C8S/C9S) makes it cytosolic. Reason: Direct localization and loss-of-localization mutagenesis in the cited paper. Supporting Evidence: PMID:23229899 Importantly, palmitoylation-deficient mutants (C6S/C7S/C8S/C9S for EFR3A and C5S/C7S/C8S for EFR3B) were localized in the cytosol PMID:24360784 Whereas wild-type EFR3A-GFP localized to the plasma membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined electronic plasma-membrane annotation; agrees with the experimental rows. Reason: Same claim as the experimental plasma-membrane rows, which establish it for this protein. Supporting Evidence: PMID:23229899 These data suggest that EFR3 is a peripheral membrane protein whose posttranslational lipidation enables its localization to membranes and its function in PI4KIIIΞ±-mediated PtdIns4P synthesis at the plasma membrane. |
| GO:0016082 synaptic vesicle priming | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl Compara transfer of a SynGO annotation of mouse Efr3a (PMID:30867420). In that study, halving or presynaptically deleting Efr3a prevented amyloid-beta oligomers from depleting presynaptic PI(4,5)P2 and lowering release probability; Efr3a was used as a tool to dampen Gq-coupled GPCR (mGluR5) responsiveness. Reason: I read the full text of PMID:30867420. It shows that Efr3a dosage modifies a pathology-induced loss of release probability, through the GPCR/PIP2 axis, in APP/PS1 mice and Abeta-treated slices. It does not show that EFR3A does any step of synaptic vesicle priming (e.g. Munc13/Munc18-dependent SNARE assembly), nor does it report a baseline priming defect. EFR3A's molecular role is to tether PI4KA at the plasma membrane in all cell types, so any effect on priming acts several steps away, via lipid supply. PAINT propagated plasma membrane and protein localization to plasma membrane at PTN000278197 but not this term. A process this indirect should not be propagated to the human protein. The mouse SynGO source annotation would need a separate donor-side review. Supporting Evidence: PMID:30867420 One way to control the PIP2 level is to manipulate the responsiveness of GΞ±q-coupled GPCRs. The mammalian pho eighty-five requiring 3 (Efr3) proteins can control GPCR responsiveness PMID:30867420 Taken together, these results indicate that reducing Efr3a is an effective method to inhibit AΞ²-induced PIP2 depletion. PMID:30867420 It has long been known that Efr3a functions as an adaptor in the type IIIΙ phosphatidylinositol 4-kinase (PI4KIIIΞ±) complex |
| GO:0046854 phosphatidylinositol phosphate biosynthetic process | TAS PMID:23229899 PtdIns4P synthesis by PI4KIIIΞ± at the plasma membrane and it... | MODIFY | Summary: EFR3A tethers the PI4KA complex to the plasma membrane and so supports PI4KA-mediated synthesis of the plasma-membrane PI4P pool. Reason: EFR3A takes part in PI4P synthesis in the scaffold sense of CLAUDE.md. It has no catalytic activity, but it supplies the membrane anchorage that the PI4KA step needs, and interface-disrupting EFR3 mutations reduce PI4KA recruitment. The phosphoinositide that depends on EFR3 is specifically PI4P (PI4KA makes PI4P; PI(4,5)P2 is made by PIP5Ks), so the precise child term GO:0180048 phosphatidylinositol 4-phosphate biosynthetic process (is_a GO:0046854) is supported and preferred. Proposed replacements: phosphatidylinositol 4-phosphate biosynthetic process Supporting Evidence: PMID:23229899 These data suggest that EFR3 is a peripheral membrane protein whose posttranslational lipidation enables its localization to membranes and its function in PI4KIIIΞ±-mediated PtdIns4P synthesis at the plasma membrane. PMID:25608530 The majority of this PI4P pool is synthesized by an evolutionarily conserved complex, which has as its core the PI 4-kinase PI4KIIIΞ± (Stt4 in yeast) and also comprises TTC7 (Ypp1 in yeast) and the peripheral plasma membrane protein EFR3. |
| GO:0072659 protein localization to plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBD at PTN000278197 (EFR3A/EFR3B clade of PTHR12444), seeded by human EFR3A and EFR3B experimental data, both of which recruit TTC7B/PI4KA to the plasma membrane. Reason: The node placement is sound and human EFR3A is inside it. Recruiting the PI4KA complex to the plasma membrane is the core process EFR3A performs; EFR3A provides the membrane anchor itself. Supporting Evidence: PMID:39705356 Complex disrupting mutations in TTC7B, FAM126A, and EFR3 decrease PI4KA recruitment to the plasma membrane. |
| GO:0072659 protein localization to plasma membrane | IMP PMID:23229899 PtdIns4P synthesis by PI4KIIIΞ± at the plasma membrane and it... | ACCEPT | Summary: EFR3 knockdown and palmitoylation-deficient mutants show that EFR3 is required to bring TTC7B and PI4KIIIalpha to the plasma membrane. Reason: Core process, backed by mutagenesis and by later structural and BRET recruitment assays (PMID:39705356). The palmitoylation-mutant recruitment assay in the quoted sentence was done with EFR3B; the curators annotated EFR3A from the full paper's knockdown data, and the structural work confirms the same mechanism for the EFR3A C terminus. Supporting Evidence: PMID:23229899 Importantly, palmitoylation-deficient mutants (C6S/C7S/C8S/C9S for EFR3A and C5S/C7S/C8S for EFR3B) were localized in the cytosol (Fig. 4 C), and the EFR3B palmitoylation-deficient mutant was unable to recruit tagged TTC7B and M1-PI4KIIIΞ± to the plasma membrane PMID:39705356 Fundamental to PI4KA activity is its targeted recruitment to the plasma membrane by the lipidated proteins EFR3A and EFR3B. |
| GO:0098793 presynapse | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Inferred logically from the synaptic vesicle priming annotation, which this review removes. Reason: The row exists only because of GO:0016082, which is removed above. EFR3A is a plasma membrane protein in essentially all cells, and the presynaptic Efr3a cKO data in mouse (PMID:30867420) are consistent with its presence at axonal plasma membrane. No study shows synaptic localization or enrichment of EFR3A, so presynapse adds nothing informative beyond plasma membrane. Supporting Evidence: PMID:30867420 These results demonstrate that selectively deleting Efr3a at the presynaptic site of the SC-CA1 synapse effectively rescues the reduced Pr in APP/PS1 mice. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of the mouse SynGO glutamatergic-synapse annotation from PMID:30867420, which is based on genetic manipulation of Efr3a at the SC-CA1 synapse, not on localization. Reason: The source study modulated Efr3a dosage and measured transmission at a glutamatergic synapse; it did not localize the protein to synapses. EFR3A acts at the plasma membrane of many cell types, so the synapse type of the recording reflects the experimental system, not a property of EFR3A. Supporting Evidence: PMID:30867420 Taken together, these results indicate that reducing Efr3a is an effective method to inhibit AΞ²-induced PIP2 depletion. |
| GO:0043495 protein-membrane adaptor activity | IDA PMID:39705356 Molecular basis for plasma membrane recruitment of PI4KA by ... | NEW | Summary: EFR3A binds the plasma membrane through its palmitoylated N terminus and conserved basic patch, and binds the TTC7B-FAM126A subcomplex through its C terminus (Kd about 23.5 nM), tethering the PI4KA complex to the membrane. This is exactly protein-membrane adaptor activity. Reason: GOA has no molecular function for EFR3A beyond generic protein binding. The cryo-EM/HDX-MS structure plus interface mutagenesis (PMID:39705356) shows a direct EFR3A-TTC7B/FAM126A interface needed for PI4KA plasma-membrane recruitment. Membrane anchoring has been shown by palmitoylation-site mutagenesis in human EFR3A (PMID:23229899) and by basic-patch mutagenesis of mouse EFR3A (PMID:24360784; mouse Efr3a is in the same PANTHER subfamily, PTHR12444:SF1). This activity is what links the existing process rows (protein localization to plasma membrane, PI4P synthesis) to a mechanism. As a comparator check, the PomBase GO-CAM gomodel:663d668500002178 gives S. pombe efr3 GO:0043495 in the same role (noted in modules/phosphoinositide_biosynthesis.yaml), so the term is the established convention for this scaffold role. Yeast Efr3 is placed by PANTHER in a separate family (PTHR47766), so that precedent is about curation convention, not phylogenetic transfer; the human evidence is direct. Supporting Evidence: PMID:39705356 The EFR3A C terminus undergoes a disorder-order transition upon binding to the PI4KA complex, with an unexpected direct interaction with both TTC7B and FAM126A. PMID:39705356 Complex disrupting mutations in TTC7B, FAM126A, and EFR3 decrease PI4KA recruitment to the plasma membrane. PMID:24360784 A conserved basic patch in Efr3, which binds acidic phospholipids, anchors the complex to the plasma membrane. |
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Download this section (compressed HTML)Q: Does EFR3A have functions distinct from EFR3B (tissue distribution, palmitoylation dynamics, TTC7A versus TTC7B preference), or are the paralogs fully interchangeable in PI4KA recruitment?
Q: Is the reported EFR3A-flotillin-2 association and effect on membrane order (PMID:37880612) independent of PI4KA-dependent PI4P supply?
Q: Isoform 2 (Q14156-2) lacks residues 1-36, which contain the palmitoylated Cys6-Cys9 cluster. Is this isoform expressed as protein, and if so is it cytosolic and unable to recruit PI4KA, acting as a dominant-negative or as a cytosolic pool?
Q: Should the mouse SynGO synaptic vesicle priming and glutamatergic synapse annotations for Efr3a (PMID:30867420) be revisited, given that the data show a disease-model modifier effect rather than participation in priming?
Experiment: Single EFR3A knockout (with EFR3B intact) versus double knockout in neurons, measuring plasma-membrane PI4P and PI(4,5)P2 with biosensors and baseline readily-releasable pool size, to test whether EFR3A has a direct, non-redundant presynaptic role.
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