ELP3 is the catalytic subunit of Elongator, a conserved six-subunit complex (ELP1-ELP6) in which an ELP1-ELP2-ELP3 core associates with an ELP4-ELP5-ELP6 ring. ELP3 combines an N-terminal radical S-adenosyl-L-methionine (SAM) domain, carrying a [4Fe-4S] cluster ligated by three cysteines and SAM, with a C-terminal GNAT-family acetyltransferase domain; the two form a composite active site and tRNA-binding pocket. Using SAM-derived radical chemistry on acetyl-CoA, ELP3 attaches a carboxymethyl group to C5 of uridine 34 in the anticodon of a subset of cytosolic tRNAs (including tRNA-Lys-UUU, tRNA-Gln-UUG and tRNA-Glu-UUC), forming 5-carboxymethyluridine (cm5U34, EC 2.3.1.311). This is the first step toward the wobble modifications ncm5U, mcm5U and mcm5s2U, which are needed for efficient and accurate decoding of A- and G-ending codons. Elongator acts mainly in the cytosol, with a small nuclear pool. Elongator was first described as a histone H3/H4 acetyltransferase that assists RNA polymerase II elongation, and ELP3 has also been linked to acetylation of alpha-tubulin and other proteins; these effects are now largely attributed to altered translation after loss of tRNA modification. Loss of ELP3 function impairs cortical neurogenesis and neuron migration in mouse, and ELP3 variants are associated with amyotrophic lateral sclerosis, where ELP3 acts as a disease modifier.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001764 neuron migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Inferred from mouse Elp3 (Q9CZX0), whose IMP annotation comes from in utero knockdown in developing cortex (PMID:19185337): Elp3 silencing delays radial migration and impairs branching of projection neurons. Ensembl Compara IEA transfer. Reason: The developmental requirement is real and cell-autonomous, but ELP3 does not do the work of neuron migration; its activity is wobble-uridine tRNA modification, and the migration defect is a downstream consequence (originally attributed to alpha-tubulin acetylation, which later work places at the level of codon-dependent translation of the tubulin acetyltransferase). Kept as a non-core, pleiotropic developmental process; not core to ELP3. Supporting Evidence: PMID:19185337 silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons PMID:27847465 Elongator is not a direct tubulin acetytransferase, but it rather regulates the expression of Ξ±-tubulin acetyltransferase at translational level |
| GO:0001764 neuron migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Inferred from mouse Elp3 (Q9CZX0), whose IMP annotation comes from in utero knockdown in developing cortex (PMID:19185337): Elp3 silencing delays radial migration and impairs branching of projection neurons. ISS transfer. Reason: The developmental requirement is real and cell-autonomous, but ELP3 does not do the work of neuron migration; its activity is wobble-uridine tRNA modification, and the migration defect is a downstream consequence (originally attributed to alpha-tubulin acetylation, which later work places at the level of codon-dependent translation of the tubulin acetyltransferase). Kept as a non-core, pleiotropic developmental process; not core to ELP3. Supporting Evidence: PMID:19185337 silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons PMID:27847465 Elongator is not a direct tubulin acetytransferase, but it rather regulates the expression of Ξ±-tubulin acetyltransferase at translational level |
| GO:0002098 tRNA wobble uridine modification | IDA PMID:29415125 Elongator subunit 3 (ELP3) modifies ALS through tRNA modific... | ACCEPT | Summary: ELP3 depletion in human/mouse cells reduces the Elongator-dependent wobble uridine modification mcm5s2U, and ELP3 expression in ALS motor cortex correlates with mcm5s2U levels (PMID:29415125). Reason: ELP3 is the catalytic subunit that installs the cm5 group on U34, the first step of mcm5U, ncm5U and mcm5s2U formation. GO:0002098 is the right level because ELP3 contributes to all three wobble uridine end products, not only mcm5s2U. Core process. Supporting Evidence: PMID:29415125 Depletion of ELP3 in vitro reduced the modified tRNA wobble uridine mcm5s2U PMID:29415125 ELP3, a subunit of the elongator complex that modifies tRNA wobble uridines file:human/ELP3/ELP3-uniprot.txt Catalytic tRNA acetyltransferase subunit of the elongator complex which is required for multiple tRNA modifications |
| GO:0002098 tRNA wobble uridine modification | NAS PMID:27847465 The Many Faces of Elongator in Neurodevelopment and Disease. | ACCEPT | Summary: Review of Elongator in neurodevelopment, stating that Elongator modifies U34 in tRNAs to ncm5U, mcm5U and mcm5s2U, with ELP3 as the enzymatic core. Reason: Consistent with the IDA row and with the biochemistry of the ELP3 family (PMID:25151136, PMID:30733442). Core process. Supporting Evidence: PMID:27847465 In eukaryotes, U34 in the anticodons of tRNALysUUU, tRNAGluUUC and tRNAGlnUUG are modified to 5-carbamoyl-methyl-uridine (ncm5U), 5-methoxy-carbonyl-methyl-uridine (mcm5U), or 5-methoxy-carbonyl-methyl-2-thio-uridine (mcm5s2U) PMID:27847465 Elp3 functions as the enzymatic core of Elongator, harboring two domains essential for Elongator function PMID:27847465 there is accumulating evidence in the last decade to indicate that the main role of this complex is to maintain translational fidelity via regulation of tRNA modifications |
| GO:0002926 tRNA wobble base 5-methoxycarbonylmethyl-2-thiouridinylation | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for the PTN000123913 node, seeded by S. cerevisiae Elp3 and S. pombe Elp3, for mcm5s2U34 formation. Reason: ELP3 performs the first, Elongator-dependent step (cm5U formation) of the mcm5s2U pathway; the methyl ester and 2-thio groups are added by other enzymes. The term describes the multi-step modification process, and ELP3 does catalytic work within it. Human ELP3 depletion reduces mcm5s2U (PMID:29415125). The node placement is sound for this deeply conserved eukaryotic subunit. Supporting Evidence: PMID:15769872 the Elp1 and Elp3 proteins specifically coprecipitate a tRNA susceptible to formation of an mcm5 side chain PMID:29415125 Depletion of ELP3 in vitro reduced the modified tRNA wobble uridine mcm5s2U |
| GO:0002926 tRNA wobble base 5-methoxycarbonylmethyl-2-thiouridinylation | TAS PMID:29332244 Structural insights into the function of Elongator. | ACCEPT | Summary: Structural review of Elongator (abstract-only cache) describing Elp3 as the catalytic subunit with radical SAM and acetyltransferase domains, acting in tRNA modification. Reason: Consistent with the IBA and experimental data for the same claim; ELP3 performs the first step of mcm5s2U formation. Supporting Evidence: PMID:29332244 Although the catalytic subunit of Elongator is Elp3, which contains a radical S-adenosyl-L-methionine (SAM) domain and a putative histone acetyltransferase domain PMID:29415125 Depletion of ELP3 in vitro reduced the modified tRNA wobble uridine mcm5s2U |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping of the radical SAM signatures (IPR006638, IPR007197) to catalytic activity. Reason: Per the RADICAL_SAM project treatment rule, the generic catalytic activity term is replaced by the specific reaction ELP3 catalyses: tRNA uridine(34) acetyltransferase activity (EC 2.3.1.311), which the gene already carries (IEA, ISS). The reaction is demonstrated for the archaeal Elp3 ortholog and ELP3 is the catalytic subunit of human Elongator. Proposed replacements: tRNA uridine(34) acetyltransferase activity Supporting Evidence: file:human/ELP3/ELP3-uniprot.txt acts as a tRNA uridine(34) acetyltransferase by mediating formation of carboxymethyluridine in the wobble base at position 34 in tRNAs PMID:25151136 a single archaeal protein, the homolog of the third subunit of the eukaryotic Elongator complex (Elp3), is able to catalyze the same reaction PMID:30733442 our results establish the clinically relevant Elongator subunit as a non-canonical acetyltransferase and genuine tRNA modification enzyme |
| GO:0005515 protein binding | IPI PMID:11714725 Purification and characterization of the human elongator com... | REMOVE | Summary: IPI protein binding with ELP1 (O95163). Co-purification of human Elongator subunits from HeLa cells. Reason: Generic protein binding is uninformative. The reported partner is ELP1 (O95163), another subunit of the Elongator holoenzyme; this interaction is fully captured by the part_of elongator holoenzyme complex (GO:0033588) annotations accepted in this review. No more informative molecular function is supported by a subunit-subunit interaction. Removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:19185337 Elongator controls the migration and differentiation of cort... | REMOVE | Summary: IPI protein binding with ELP1 (O95163). Co-immunoprecipitation within Elongator in the cortical neuron study. Reason: Generic protein binding is uninformative. The reported partner is ELP1 (O95163), another subunit of the Elongator holoenzyme; this interaction is fully captured by the part_of elongator holoenzyme complex (GO:0033588) annotations accepted in this review. No more informative molecular function is supported by a subunit-subunit interaction. Removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:22854966 DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and ... | REMOVE | Summary: IPI protein binding with ELP1 (O95163). Interaction mapping within human Elongator (ELP5/ELP6 paper). Reason: Generic protein binding is uninformative. The reported partner is ELP1 (O95163), another subunit of the Elongator holoenzyme; this interaction is fully captured by the part_of elongator holoenzyme complex (GO:0033588) annotations accepted in this review. No more informative molecular function is supported by a subunit-subunit interaction. Removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI protein binding with ELP1 (O95163). High-throughput binary interactome (HuRI-related dual proteome-scale network) detecting ELP3-ELP1. Reason: Generic protein binding is uninformative. The reported partner is ELP1 (O95163), another subunit of the Elongator holoenzyme; this interaction is fully captured by the part_of elongator holoenzyme complex (GO:0033588) annotations accepted in this review. No more informative molecular function is supported by a subunit-subunit interaction. Removal does not dispute the interaction. |
| GO:0005634 nucleus | EXP PMID:11714725 Purification and characterization of the human elongator com... | KEEP AS NON CORE | Summary: Nuclear localization of human ELP3 in HeLa nuclear-extract purification of Elongator (PMID:11714725). Reason: ELP3 has been detected in the nucleus in several studies, and a nuclear isoform/pool exists, so the location is not wrong. However, the Elongator tRNA modification activity acts in the cytosol, nuclear Elongator functions (histone acetylation, Pol II elongation) are no longer considered physiologically primary, and only a small fraction is nuclear. Kept as non-core. Supporting Evidence: PMID:11714725 Elongator is a component of early elongation complexes formed in HeLa nuclear extracts PMID:15769872 implying that a small fraction of Elongator localizes to the nucleus |
| GO:0005634 nucleus | EXP PMID:11818576 Human Elongator facilitates RNA polymerase II transcription ... | KEEP AS NON CORE | Summary: Nuclear Elongator from HeLa cells in the RNA polymerase II chromatin transcription study (PMID:11818576). Reason: ELP3 has been detected in the nucleus in several studies, and a nuclear isoform/pool exists, so the location is not wrong. However, the Elongator tRNA modification activity acts in the cytosol, nuclear Elongator functions (histone acetylation, Pol II elongation) are no longer considered physiologically primary, and only a small fraction is nuclear. Kept as non-core. Supporting Evidence: PMID:11818576 human Elongator facilitates transcription by RNA polymerase II PMID:15769872 implying that a small fraction of Elongator localizes to the nucleus |
| GO:0005634 nucleus | EXP PMID:22002106 Systematic analysis of protein pools, isoforms, and modifica... | KEEP AS NON CORE | Summary: Proteome-wide subcellular fractionation (PMID:22002106) detected a larger ELP3 isoform specifically in the nucleus and both isoforms in the nuclear fraction. Reason: ELP3 has been detected in the nucleus in several studies, and a nuclear isoform/pool exists, so the location is not wrong. However, the Elongator tRNA modification activity acts in the cytosol, nuclear Elongator functions (histone acetylation, Pol II elongation) are no longer considered physiologically primary, and only a small fraction is nuclear. Kept as non-core. Supporting Evidence: PMID:22002106 In the case of ELP3, the larger (A) isoform has a turnover value of βΌ5 h and is detected specifically in the nucleus PMID:22002106 only one isoform is present in the Cytoplasm (Aβ²), whereas both isoforms are detected in the Nucleus (A and Aβ²) |
| GO:0005634 nucleus | EXP PMID:22854966 DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and ... | KEEP AS NON CORE | Summary: Nuclear ELP3 reported in the ELP5/ELP6 characterisation (PMID:22854966; abstract-only cache). Reason: ELP3 has been detected in the nucleus in several studies, and a nuclear isoform/pool exists, so the location is not wrong. However, the Elongator tRNA modification activity acts in the cytosol, nuclear Elongator functions (histone acetylation, Pol II elongation) are no longer considered physiologically primary, and only a small fraction is nuclear. Kept as non-core. Supporting Evidence: PMID:22854966 The Elongator complex is composed of 6 subunits (Elp1-Elp6) PMID:15769872 implying that a small fraction of Elongator localizes to the nucleus |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT IBA (is_active_in nucleus) from the PTN000123915 node, with yeast, fly, plant, trypanosome and human ELP3 as donors. Reason: ELP3 has been detected in the nucleus in several studies, and a nuclear isoform/pool exists, so the location is not wrong. However, the Elongator tRNA modification activity acts in the cytosol, nuclear Elongator functions (histone acetylation, Pol II elongation) are no longer considered physiologically primary, and only a small fraction is nuclear. Kept as non-core. The IBA reflects the historical nuclear (transcription) assignments of Elongator; the conserved site of the tRNA modification activity is the cytoplasm. Supporting Evidence: PMID:15769872 implying that a small fraction of Elongator localizes to the nucleus PMID:17018299 Our results indicate that the physiologically relevant function of the evolutionary-conserved Elongator complex is in formation of modified nucleosides in tRNAs |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping (SL-0191 Nucleus). Reason: ELP3 has been detected in the nucleus in several studies, and a nuclear isoform/pool exists, so the location is not wrong. However, the Elongator tRNA modification activity acts in the cytosol, nuclear Elongator functions (histone acetylation, Pol II elongation) are no longer considered physiologically primary, and only a small fraction is nuclear. Kept as non-core. Supporting Evidence: PMID:22002106 In the case of ELP3, the larger (A) isoform has a turnover value of βΌ5 h and is detected specifically in the nucleus |
| GO:0005730 nucleolus | IDA PMID:11714725 Purification and characterization of the human elongator com... | UNDECIDED | Summary: Nucleolar localization attributed to the human Elongator purification paper (PMID:11714725). Reason: The cached abstract does not mention nucleolar localization and full text is not available, so the underlying observation cannot be checked. Nucleolar localization is not reported elsewhere for ELP3 in the sources reviewed and is not obviously connected to cytosolic tRNA modification. Deferred rather than removed, because the curator saw the full text. Supporting Evidence: PMID:11714725 Elongator is a component of early elongation complexes formed in HeLa nuclear extracts |
| GO:0005737 cytoplasm | EXP PMID:19185337 Elongator controls the migration and differentiation of cort... | MODIFY | Summary: Cytoplasmic ELP3 in mouse cortical neurons and cultured cells (PMID:19185337). Reason: ELP3 and the Elongator holoenzyme are predominantly cytoplasmic, where they modify tRNA U34. The location is correct but general; the more specific supported term is cytosol (GO:0005829), which the gene already carries by IDA (HPA, GO_REF:0000052). Elongator is a soluble complex acting on cytosolic tRNAs, so MODIFY to cytosol. Proposed replacements: cytosol Supporting Evidence: PMID:19185337 Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro PMID:17018299 Our results indicate that the physiologically relevant function of the evolutionary-conserved Elongator complex is in formation of modified nucleosides in tRNAs |
| GO:0005737 cytoplasm | EXP PMID:22002106 Systematic analysis of protein pools, isoforms, and modifica... | MODIFY | Summary: Proteome-wide fractionation detecting one ELP3 isoform in the cytoplasmic fraction (PMID:22002106). Reason: ELP3 and the Elongator holoenzyme are predominantly cytoplasmic, where they modify tRNA U34. The location is correct but general; the more specific supported term is cytosol (GO:0005829), which the gene already carries by IDA (HPA, GO_REF:0000052). Elongator is a soluble complex acting on cytosolic tRNAs, so MODIFY to cytosol. Proposed replacements: cytosol Supporting Evidence: PMID:22002106 only one isoform is present in the Cytoplasm (Aβ²), whereas both isoforms are detected in the Nucleus (A and Aβ²) |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBA (is_active_in cytoplasm) from the PTN000123913 node. Reason: ELP3 and the Elongator holoenzyme are predominantly cytoplasmic, where they modify tRNA U34. The location is correct but general; the more specific supported term is cytosol (GO:0005829), which the gene already carries by IDA (HPA, GO_REF:0000052). Elongator is a soluble complex acting on cytosolic tRNAs, so MODIFY to cytosol. The IBA itself is sound; the refinement is to the soluble compartment. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000123913 SUPPORTS TRANSFER The ELP3 node correctly places conserved cytoplasmic Elongator activity; cytoplasm is true but broader than the supported cytosol. Proposed replacements: cytosol Supporting Evidence: PMID:15769872 the Elp1 and Elp3 proteins specifically coprecipitate a tRNA susceptible to formation of an mcm5 side chain PMID:17018299 Our results indicate that the physiologically relevant function of the evolutionary-conserved Elongator complex is in formation of modified nucleosides in tRNAs |
| GO:0005737 cytoplasm | IDA GO_REF:0000054 | MODIFY | Summary: Localization of a tagged ELP3 fusion protein in living cells (GO_REF:0000054). Reason: ELP3 and the Elongator holoenzyme are predominantly cytoplasmic, where they modify tRNA U34. The location is correct but general; the more specific supported term is cytosol (GO:0005829), which the gene already carries by IDA (HPA, GO_REF:0000052). Elongator is a soluble complex acting on cytosolic tRNAs, so MODIFY to cytosol. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | IDA PMID:11714725 Purification and characterization of the human elongator com... | MODIFY | Summary: Cytoplasmic ELP3 reported in the human Elongator purification paper (PMID:11714725). Reason: ELP3 and the Elongator holoenzyme are predominantly cytoplasmic, where they modify tRNA U34. The location is correct but general; the more specific supported term is cytosol (GO:0005829), which the gene already carries by IDA (HPA, GO_REF:0000052). Elongator is a soluble complex acting on cytosolic tRNAs, so MODIFY to cytosol. Proposed replacements: cytosol Supporting Evidence: PMID:11714725 a six-subunit complex, holo-Elongator, which has histone acetyltransferase activity directed against histone H3 and H4 |
| GO:0005737 cytoplasm | IDA PMID:11818576 Human Elongator facilitates RNA polymerase II transcription ... | MODIFY | Summary: Cytoplasmic ELP3 reported in the HeLa Elongator study (PMID:11818576). Reason: ELP3 and the Elongator holoenzyme are predominantly cytoplasmic, where they modify tRNA U34. The location is correct but general; the more specific supported term is cytosol (GO:0005829), which the gene already carries by IDA (HPA, GO_REF:0000052). Elongator is a soluble complex acting on cytosolic tRNAs, so MODIFY to cytosol. Proposed replacements: cytosol Supporting Evidence: PMID:11818576 Human Elongator contains histone acetyltransferase activity with specificity to histone H3 |
| GO:0005737 cytoplasm | IDA PMID:22854966 DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and ... | MODIFY | Summary: Cytoplasmic ELP3 reported in the ELP5/ELP6 characterisation (PMID:22854966). Reason: ELP3 and the Elongator holoenzyme are predominantly cytoplasmic, where they modify tRNA U34. The location is correct but general; the more specific supported term is cytosol (GO:0005829), which the gene already carries by IDA (HPA, GO_REF:0000052). Elongator is a soluble complex acting on cytosolic tRNAs, so MODIFY to cytosol. Proposed replacements: cytosol Supporting Evidence: PMID:22854966 The Elongator complex is composed of 6 subunits (Elp1-Elp6) |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: UniProt subcellular location mapping (SL-0086 Cytoplasm). Reason: ELP3 and the Elongator holoenzyme are predominantly cytoplasmic, where they modify tRNA U34. The location is correct but general; the more specific supported term is cytosol (GO:0005829), which the gene already carries by IDA (HPA, GO_REF:0000052). Elongator is a soluble complex acting on cytosolic tRNAs, so MODIFY to cytosol. Proposed replacements: cytosol Supporting Evidence: file:human/ELP3/ELP3-uniprot.txt Catalytic tRNA acetyltransferase subunit of the elongator complex which is required for multiple tRNA modifications |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence (GO_REF:0000052) localizing ELP3 to the cytosol. Reason: Cytosol is where Elongator modifies tRNA U34 and is the most specific supported compartment for the core activity. Supporting Evidence: PMID:17018299 Our results indicate that the physiologically relevant function of the evolutionary-conserved Elongator complex is in formation of modified nucleosides in tRNAs PMID:27847465 there is accumulating evidence in the last decade to indicate that the main role of this complex is to maintain translational fidelity via regulation of tRNA modifications |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:11818576 Human Elongator facilitates RNA polymerase II transcription ... | MARK AS OVER ANNOTATED | Summary: Purified three-subunit human Elongator stimulated RNA polymerase II transcription on chromatin templates in vitro in an acetyl-CoA-dependent manner and bound Pol II (PMID:11818576). Reason: The in vitro observation is not disputed, but it does not establish that ELP3 regulates Pol II transcription in cells. In yeast the transcription (and exocytosis) phenotypes of Elongator mutants are suppressed by overexpressing two tRNA species, showing they are secondary to loss of wobble uridine modification, and UniProt now records that Elongator is no longer thought to act directly in transcription. Retained as an over-annotation rather than removed because the experimental result itself stands. Supporting Evidence: PMID:11818576 human Elongator facilitates transcription by RNA polymerase II PMID:17018299 Our results indicate that the physiologically relevant function of the evolutionary-conserved Elongator complex is in formation of modified nucleosides in tRNAs file:human/ELP3/ELP3-uniprot.txt it is no longer thought to play a direct role in this process and its primary function is thought to be in tRNA modification |
| GO:0006417 regulation of translation | NAS PMID:22854966 DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and ... | KEEP AS NON CORE | Summary: Author statement in the ELP5/ELP6 paper (PMID:22854966) linking Elongator to translation. Reason: U34 modifications installed via ELP3 tune codon-specific decoding (e.g. AAA/GAA/CAA codons), so Elongator loss changes translation of codon-biased transcripts. This is a genuine but downstream consequence of the tRNA modification activity rather than a regulatory activity of ELP3 itself; kept as non-core. Supporting Evidence: PMID:27847465 there is accumulating evidence in the last decade to indicate that the main role of this complex is to maintain translational fidelity via regulation of tRNA modifications PMID:27847465 Elongator is not a direct tubulin acetytransferase, but it rather regulates the expression of Ξ±-tubulin acetyltransferase at translational level |
| GO:0007417 central nervous system development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Inferred from mouse Elp3 (Q9CZX0) IMP (PMID:19185337, cortical projection neuron maturation). Ensembl Compara IEA transfer. Reason: Broad developmental process term reflecting a requirement for Elongator-dependent tRNA modification in the developing cortex. True as a phenotype-level association, but pleiotropic and indirect; kept as non-core. Supporting Evidence: PMID:19185337 silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons |
| GO:0007417 central nervous system development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Inferred from mouse Elp3 (Q9CZX0) IMP (PMID:19185337, cortical projection neuron maturation). ISS transfer. Reason: Broad developmental process term reflecting a requirement for Elongator-dependent tRNA modification in the developing cortex. True as a phenotype-level association, but pleiotropic and indirect; kept as non-core. Supporting Evidence: PMID:19185337 silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons |
| GO:0016407 acetyltransferase activity | IDA PMID:11714725 Purification and characterization of the human elongator com... | MODIFY | Summary: Purified six-subunit human holo-Elongator showed histone H3/H4 acetyltransferase activity; the three-subunit core containing ELP3 did not (PMID:11714725). Reason: ELP3 is an acetyltransferase, so the term is correct, but it is general. The specific, physiologically established acetyltransferase activity of ELP3 is tRNA uridine(34) acetyltransferase (EC 2.3.1.311), a descendant of GO:0016407 that the gene already carries. The histone acetylation measured in this paper is the historical activity whose in vivo relevance is now doubted; it is not proposed here as a separate MF. Proposed replacements: tRNA uridine(34) acetyltransferase activity Supporting Evidence: PMID:11714725 a six-subunit complex, holo-Elongator, which has histone acetyltransferase activity directed against histone H3 and H4 file:human/ELP3/ELP3-uniprot.txt such activity is however unclear in vivo and recent evidence suggests that ELP3 primarily acts as a tRNA acetyltransferase PMID:30733442 our results establish the clinically relevant Elongator subunit as a non-canonical acetyltransferase and genuine tRNA modification enzyme |
| GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping of the GNAT domain (IPR000182). Reason: Correct but general: the GNAT (KAT-like) domain of ELP3 forms a composite active site with the radical SAM domain and transfers the acetyl-CoA-derived carbon to tRNA U34. Replace with the specific descendant tRNA uridine(34) acetyltransferase activity, already carried by the gene. Proposed replacements: tRNA uridine(34) acetyltransferase activity Supporting Evidence: PMID:27455459 form a composite active site and tRNA-binding pocket, with an iron-sulfur cluster located in the dimerization interface of two DmcElp3 molecules PMID:30733442 our results establish the clinically relevant Elongator subunit as a non-canonical acetyltransferase and genuine tRNA modification enzyme |
| GO:0030335 positive regulation of cell migration | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Inferred from mouse Elp3 (Q9CZX0), whose IMP is itself sourced from PMID:22854966 (human melanoma cells): ELP3 depletion reduces melanoma cell migration and tumorigenicity. Ensembl Compara IEA transfer. Reason: A knockdown phenotype in a tumour cell line does not show that ELP3 regulates cell migration; ELP3 modifies tRNA wobble uridines, and loss of that modification alters translation of many proteins, so reduced motility is an indirect, downstream effect. A 'positive regulation' process term over-states the role. Not false as a phenotype, hence over-annotation rather than removal. Supporting Evidence: PMID:22854966 the migration and tumorigenicity of melanoma-derived cells are significantly decreased upon Elongator depletion through ELP1 or ELP3 |
| GO:0030335 positive regulation of cell migration | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Inferred from mouse Elp3 (Q9CZX0), whose IMP is itself sourced from PMID:22854966 (human melanoma cells): ELP3 depletion reduces melanoma cell migration and tumorigenicity. ISS transfer. Reason: A knockdown phenotype in a tumour cell line does not show that ELP3 regulates cell migration; ELP3 modifies tRNA wobble uridines, and loss of that modification alters translation of many proteins, so reduced motility is an indirect, downstream effect. A 'positive regulation' process term over-states the role. Not false as a phenotype, hence over-annotation rather than removal. Supporting Evidence: PMID:22854966 the migration and tumorigenicity of melanoma-derived cells are significantly decreased upon Elongator depletion through ELP1 or ELP3 |
| GO:0033588 elongator holoenzyme complex | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for Elongator holoenzyme complex membership, PTN000123915 node. Reason: ELP3 is the catalytic subunit of Elongator (ELP1-6) in all eukaryotes; deeply conserved. Supporting Evidence: file:human/ELP3/ELP3-uniprot.txt Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6. PMID:27847465 Elp3 functions as the enzymatic core of Elongator, harboring two domains essential for Elongator function |
| GO:0033588 elongator holoenzyme complex | IDA PMID:22854966 DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and ... | ACCEPT | Summary: Human Elongator subunit composition defined by purification (PMID:22854966). Reason: Direct evidence that ELP3 is part of the six-subunit human Elongator, bridged to ELP4 via ELP5. Supporting Evidence: PMID:22854966 DERP6/ELP5 is required for the integrity of Elongator and directly connects ELP3 to ELP4 PMID:22854966 The Elongator complex is composed of 6 subunits (Elp1-Elp6) |
| GO:0033588 elongator holoenzyme complex | IPI PMID:22854966 DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and ... | ACCEPT | Summary: Interaction evidence placing ELP3 in human Elongator (PMID:22854966). Reason: Same claim as the IDA row; ELP3 is an integral Elongator subunit. Supporting Evidence: PMID:22854966 DERP6/ELP5 is required for the integrity of Elongator and directly connects ELP3 to ELP4 file:human/ELP3/ELP3-uniprot.txt Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6. |
| GO:0051536 iron-sulfur cluster binding | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping of radical SAM signatures to iron-sulfur cluster binding. Reason: Per the RADICAL_SAM treatment rule: correct but general. The radical SAM cluster of ELP3 is a [4Fe-4S] cluster ligated by three cysteines and SAM, so the specific descendant is 4 iron, 4 sulfur cluster binding (GO:0051539). Proposed replacements: 4 iron, 4 sulfur cluster binding Supporting Evidence: file:human/ELP3/ELP3-uniprot.txt Binds 1 [4Fe-4S] cluster. The cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine. PMID:27455459 form a composite active site and tRNA-binding pocket, with an iron-sulfur cluster located in the dimerization interface of two DmcElp3 molecules |
| GO:0106261 tRNA uridine(34) acetyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation from Rhea (RHEA:61020) and EC 2.3.1.311. Reason: This is the core catalytic activity of ELP3: radical-SAM-dependent transfer of a carboxymethyl group from acetyl-CoA to C5 of tRNA U34 to form cm5U34. Supporting Evidence: file:human/ELP3/ELP3-uniprot.txt acts as a tRNA uridine(34) acetyltransferase by mediating formation of carboxymethyluridine in the wobble base at position 34 in tRNAs PMID:25151136 a single archaeal protein, the homolog of the third subunit of the eukaryotic Elongator complex (Elp3), is able to catalyze the same reaction PMID:30733442 our results establish the clinically relevant Elongator subunit as a non-canonical acetyltransferase and genuine tRNA modification enzyme |
| GO:0106261 tRNA uridine(34) acetyltransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from Methanocaldococcus infernus Elp3 (D5VRB9), which alone catalyses cm5U34 formation in vitro (PMID:25151136). Reason: The archaeal ortholog's activity is biochemically demonstrated, the active-site architecture is conserved (PMID:27455459, PMID:30733442), and ELP3 is the catalytic subunit of human Elongator. Core MF. Supporting Evidence: PMID:25151136 a single archaeal protein, the homolog of the third subunit of the eukaryotic Elongator complex (Elp3), is able to catalyze the same reaction PMID:25151136 abstracts a hydrogen atom from acetyl-CoA, rather than from tRNA as we initially envisioned PMID:30733442 our results establish the clinically relevant Elongator subunit as a non-canonical acetyltransferase and genuine tRNA modification enzyme |
| GO:1904047 S-adenosyl-L-methionine binding | ISS PMID:25151136 Archaeal Elp3 catalyzes tRNA wobble uridine modification at ... | NEW | Summary: ELP3 is a radical SAM enzyme: SAM binds the unique iron of the [4Fe-4S] cluster and is reductively cleaved to a 5'-deoxyadenosyl radical that initiates the U34 carboxymethylation. Reason: Not in GOA. SAM cosubstrate binding is intrinsic to the ELP3 reaction (EC 2.3.1.311 consumes SAM) and is shown biochemically for archaeal Elp3; UniProt records the cluster as coordinated by an exchangeable SAM. Comparator check, against GOA rather than against this project's own proposals: GOA does annotate GO:1904047 to radical SAM enzymes in exactly this role, by UniRule -- ECOLI/queE (UR000100349), ECOLI/moaA and PSEPK/moaA (UR000101305), METEA/pqqE and PSEPK/pqqE (UR000098303). So the absence here is patchy UniRule coverage, which rules happen to carry the term, not a GO convention against annotating a radical SAM enzyme's own cosubstrate. That is also why those five genes have an existing row to ACCEPT or MODIFY while this one needs a NEW row. Supporting Evidence: PMID:25151136 Association of tRNA with Elp3 allows 5β²-dAβ’ to be generated from SAM in the radical SAM domain of Elp3 file:human/ELP3/ELP3-uniprot.txt Binds 1 [4Fe-4S] cluster. The cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Does human ELP3 have any direct protein lysine acetyltransferase activity in vivo (alpha-tubulin, connexin-43, Bruchpilot homologues, histones), or are all reported protein-acetylation changes secondary to altered codon-dependent translation after loss of U34 modification?
Q: Does the nuclear pool of ELP3 (including the nuclear-specific larger isoform) have a distinct function, or is it inactive storage of the complex?
Q: Is DPH3 (the KTI11 orthologue) the physiological electron donor that reduces the ELP3 [4Fe-4S] cluster in human Elongator, as in yeast?
Q: Should the historic GO:0006357 and GO:0005730 assignments to human ELP3 be revisited by the contributing group in light of the tRNA-bypass evidence?
Experiment: Reconstitute recombinant human Elongator with chemically reconstituted [4Fe-4S] ELP3, a reductant (DPH3 or dithionite), SAM, labelled acetyl-CoA and unmodified tRNA-Lys-UUU; detect cm5U34 and 5'-deoxyadenosine by LC-MS, and test radical SAM cysteine and GNAT active-site mutants.
Hypothesis: Human ELP3, within the reconstituted ELP1-ELP6 holoenzyme, directly catalyses cm5U34 formation from acetyl-CoA and SAM.
Experiment: In ELP3-depleted human neural progenitors, test whether overexpression of hypomodified tRNA-Lys-UUU and tRNA-Gln-UUG rescues alpha-tubulin K40 acetylation, ATAT1 protein level and migration, compared with re-expression of catalytically inactive ELP3.
Hypothesis: Reduced alpha-tubulin acetylation and neuron-migration defects after ELP3 loss are caused by loss of U34 modification rather than direct protein acetylation.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)