Affinage

ELP6

Elongator complex protein 6 · UniProt Q0PNE2

Length
266 aa
Mass
29.8 kDa
Annotated
2026-04-28
41 papers in source corpus 16 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ELP6 is a core subunit of the evolutionarily conserved Elongator complex, where it serves as a structural bridge within the Elp4/5/6 heterohexameric ring that adopts a RecA-like ATPase fold and mediates ATP-regulated tRNA binding required for mcm5/ncm5 wobble uridine modifications (PMID:22343726, PMID:22556426, PMID:15769872). The intact Elp456 ring is essential for holo-Elongator histone acetyltransferase activity toward histones H3 and H4, and loss of ELP6 disrupts association of the Elp456 subcomplex with the catalytic Elp123 subcomplex (PMID:11904415, PMID:12424236). The tRNA modification function of Elongator accounts for its roles in translational fidelity, polarized exocytosis, and cell migration, as tRNA overexpression suppresses phenotypes of Elongator-deficient cells (PMID:17018299, PMID:22854966). Patient-derived missense mutations in human ELP6 impair tRNA modification and cause a neurodevelopmental disorder with epilepsy and motor dysfunction, as demonstrated by structural analysis of mutant Elp456 and recapitulation in mouse models (PMID:35698786).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2001 High

    Establishing that ELP6 is part of a distinct three-subunit subcomplex (Elp4/5/6) within a six-subunit Elongator resolved the modular architecture of the complex and placed ELP6 as a separable functional unit.

    Evidence Tandem affinity purification and biochemical fractionation in yeast, replicated across two independent labs

    PMID:11435442 PMID:11689709

    Open questions at the time
    • No structural information on ELP6 or the Elp456 subcomplex
    • Enzymatic activity of each subcomplex undefined
  2. 2001 High

    Demonstrating that ELP6 deletion phenocopied all other Elongator subunit deletions (zymocin resistance, thermosensitivity, slow growth) established it as functionally integral rather than peripheral.

    Evidence Gene deletion and phenotypic analysis in yeast across multiple labs

    PMID:11689709 PMID:11737649

    Open questions at the time
    • Molecular function of ELP6 within the complex unknown
    • Whether phenotypes reflect tRNA modification, HAT activity, or other functions unresolved
  3. 2002 High

    Showing that Elp4/5/6 subunits are required for the HAT activity of holo-Elongator identified the subcomplex as an essential regulatory or structural cofactor for catalysis, and revealed that ELP6 deletion disrupts the Elp456–Elp123 interaction.

    Evidence In vitro HAT assays on free and nucleosomal histones with subunit deletion strains; co-immunoprecipitation mapping

    PMID:11904415 PMID:12424236

    Open questions at the time
    • Whether Elp456 directly contacts substrate or allosterically activates Elp3 unknown
    • Structural basis for ELP6's bridging role undefined
  4. 2005 High

    Identifying ELP6 as required for mcm5/ncm5 wobble uridine tRNA modification established a direct molecular function for Elongator beyond chromatin, with tRNA immunoprecipitation showing Elongator–tRNA association.

    Evidence HPLC analysis of modified nucleosides in individual tRNAs from elp mutants; tRNA immunoprecipitation

    PMID:15769872

    Open questions at the time
    • Whether ELP6 directly contacts tRNA unknown
    • Relative contributions of tRNA modification vs. HAT activity to cellular phenotypes unresolved
  5. 2006 High

    Genetic suppression of Elongator-deficient phenotypes by tRNA overexpression demonstrated that tRNA modification is the primary cellular function underlying transcriptional elongation and exocytosis phenotypes, unifying disparate roles.

    Evidence tRNA overexpression rescue of multiple elp mutant phenotypes in yeast

    PMID:17018299

    Open questions at the time
    • Whether HAT activity has any tRNA-independent role remains unresolved
    • Mechanism by which specific tRNA modifications affect exocytosis not defined
  6. 2012 High

    Crystal structures of yeast Elp456 revealed a heterohexameric ring with RecA-like ATPase folds, showed ELP6 acts as the structural bridge connecting ELP4 and ELP5, and demonstrated ATP-regulated tRNA binding by the ring, providing the first mechanistic framework for substrate engagement.

    Evidence X-ray crystallography; in vitro tRNA-binding and ATP-regulation assays; site-directed mutagenesis; GST pulldown for histone H3 binding

    PMID:22343726 PMID:22556426

    Open questions at the time
    • Whether ATP is hydrolyzed or only bound is unclear
    • How tRNA is handed off from Elp456 to the catalytic Elp3 active site unknown
  7. 2012 High

    Identification of human ELP6 (C3ORF75) as a bona fide human Elongator subunit extended findings to mammalian biology and showed ELP6 depletion impairs melanoma cell migration and tumorigenicity.

    Evidence Biochemical co-purification of human subunits; RNAi knockdown with migration, invasion, and tumorigenicity assays in melanoma cells

    PMID:22854966

    Open questions at the time
    • Whether migration defects are tRNA-modification-dependent or reflect an independent function not tested
    • Signaling pathways downstream of ELP6 in cancer cells uncharacterized
  8. 2016 High

    Single-particle EM of full yeast Elongator placed the Elp456 hexamer on one of the two Elp123 lobes within a bilobal ~850 kDa asymmetric architecture, establishing the spatial relationship between the regulatory and catalytic subcomplexes.

    Evidence Single-particle electron microscopy with cross-linking mass spectrometry restraints

    PMID:27872205

    Open questions at the time
    • Resolution insufficient for atomic-level subunit interfaces
    • How asymmetry relates to catalytic mechanism unknown
  9. 2022 High

    Patient-derived ELP6 missense mutations were shown to impair tRNA modification both in vitro and in patient cells, and mouse modeling recapitulated a neurodevelopmental syndrome with epilepsy and motor defects, establishing ELP6 as a disease gene with a mechanism distinct from Elp123 mutations.

    Evidence Cryo-EM/crystal structure of human/murine Elp456; in vitro tRNA modification assay; HPLC-MS in patient cells; mouse modeling

    PMID:35698786

    Open questions at the time
    • Whether all pathogenic ELP6 variants act through the same mechanism unknown
    • Neuronal cell-type-specific consequences of tRNA hypomodification not resolved
  10. 2025 Medium

    ELP6 knockdown in melanoma cells was linked to G1 cell cycle arrest and reduced p42 MAPK expression, placing ELP6 upstream of ERK1/2 signaling in this context.

    Evidence shRNA knockdown with flow cytometry cell cycle analysis and western blot for ERK pathway components

    PMID:40177137

    Open questions at the time
    • Whether ERK pathway effects are direct or secondary to tRNA modification defects untested
    • Single lab, no rescue experiment reported
    • Mechanism connecting tRNA modification to MAPK pathway not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the atomic-resolution structure of holo-human Elongator with tRNA substrate bound, the mechanism of tRNA handoff from the Elp456 ring to the Elp3 catalytic site, whether ELP6 possesses ATPase activity or only binds ATP, and the precise neuronal cell types whose dysfunction underlies ELP6-associated disease.
  • No structure of holo-Elongator with tRNA substrate
  • ATPase activity of ELP6 not biochemically confirmed
  • Cell-type-specific disease mechanism in neurons undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0003723 RNA binding 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 3
Partners
ELP1ELP2ELP3ELP4ELP5
Complex memberships
Elongator complexElp4/5/6 subcomplex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 ELP6 (TOT6) is one of three subunits forming the Elp4/5/6 subcomplex (HAP) of the six-subunit holo-Elongator complex; the full complex can be separated into two subcomplexes: Elp1/2/3 and Elp4/5/6, each purified by TAP of any individual subunit. Tandem affinity purification (TAP), biochemical fractionation, genetic disruption with phenotypic analysis Molecular and cellular biology High 11435442 11689709
2001 Disruption of ELP6 (TOT6) confers resistance to K. lactis zymocin, thermosensitivity, slow growth, and hypersensitivity to drugs, phenotypes identical to other elp mutants, establishing ELP6 as functionally integral to the Elongator/TOT complex. Gene deletion, phenotypic analysis (zymocin resistance, growth assays) Molecular microbiology High 11435442 11689709 11737649
2002 The three smallest Elongator subunits Elp4, Elp5, and Elp6 are required for the histone acetyltransferase (HAT) activity of the intact Elongator complex toward histone H3 (K14) and H4 (K8), including nucleosomal substrates. In vitro HAT assay with purified complex from elp4, elp5, elp6 deletion strains; chromatin immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 11904415
2002 Structural integrity of the Elp4/5/6 (HAP) subcomplex requires ELP6; deletion of elp6 abolishes the interaction between Elp5 and Elp2, and disrupts association of the HAP subcomplex with core Elongator (Elp1/2/3). Co-immunoprecipitation, subunit interaction mapping in deletion strains The Journal of biological chemistry High 12424236
2005 ELP6, along with ELP1–ELP5 and KTI11–KTI13, is required for an early step in the synthesis of the mcm5 and ncm5 modifications on wobble uridines in tRNA; tRNA immunoprecipitation showed direct association of Elongator subunits with tRNA substrates. Analysis of modified nucleosides in individual tRNA species by HPLC; tRNA immunoprecipitation (RIP) RNA (New York, N.Y.) High 15769872
2006 The tRNA modification (mcm5 group formation) function of Elongator, requiring ELP6 among other subunits, accounts for its roles in transcriptional elongation and polarized exocytosis phenotypes, as elevated expression of two tRNA species suppresses all these phenotypes in Elongator-deficient cells. Genetic suppression by tRNA overexpression; phenotypic rescue assays Molecular cell High 17018299
2012 The yeast Elp4/5/6 subcomplex forms a heterohexameric ring-like structure in which each subunit adopts a RecA-like ATPase fold; the hexameric Elp456 ring binds tRNAs in an ATP-regulated manner, directly supporting the role of Elongator in tRNA modification. X-ray crystallography; in vitro tRNA-binding assays; ATP-regulation assays; site-directed mutagenesis Nature structural & molecular biology High 22343726
2012 Crystal structure of the yeast Elp4-6 subcomplex shows that Elp6 acts as a structural bridge assembling Elp4 and Elp5; each subunit has a RecA-ATPase-like fold; the hexameric ring assembly is required for specific histone H3 binding as shown by GST pulldown and mutagenesis. X-ray crystallography; site-directed mutagenesis; GST pulldown; biochemical assembly assays The Journal of biological chemistry High 22556426
2012 Human ELP6 (C3ORF75) is identified as a bona fide subunit of human Elongator; ELP5 (DERP6) is required for complex integrity and directly connects ELP3 to ELP4; depletion of ELP6 impairs migration, invasion, and tumorigenicity of melanoma cells. Biochemical co-purification; RNAi knockdown; cell migration/invasion assays; tumorigenicity assays The Journal of biological chemistry High 22854966
2016 Full yeast Elongator adopts a bilobal, asymmetric architecture (~850 kDa) with the hexameric Elp456 subassembly anchored to one of the two Elp123 lobes; single-particle EM combined with cross-linking mass spectrometry placed ELP6 within this overall architecture. Single-particle electron microscopy; cross-linking coupled to mass spectrometry; molecular modeling EMBO reports High 27872205
2022 Patient-derived missense mutations in human ELP6 impair tRNA modification activity of the Elongator complex in vitro and in human and murine cells; structural determination of human and murine Elp456 locates mutated residues; modeling pathogenic ELP6 variants in mice recapitulates neurological defects (developmental delay, epilepsy, motor dysfunction) distinct from those caused by Elp123 mutations. Cryo-EM/crystal structure of human/murine Elp456; in vitro tRNA modification assay; HPLC-MS tRNA modification analysis in patient cells; mouse modeling EMBO molecular medicine High 35698786
2022 In human Elongator assembly, hELP4/5/6 is recruited to hELP1/2/3 via hELP3; hELP1 stabilizes hELP3; hELP2 enhances integrity and substrate-binding ability of the dimeric hELP1/2/3; ELP6 is part of the peripheral subcomplex. Co-purification of recombinant human subunits; pulldown assays; single-particle electron microscopy ACS omega Medium 35128251
2013 Human ELP6 protein (~30 kDa) is expressed intracellularly in developing and mature granulocytes (neutrophils, eosinophils) and monocytes in human bone marrow, but not in lymphocytes or erythrocytes. Western blot; flow cytometry with monoclonal antibody; RT-PCR Human antibodies Medium 24284306
2024 Arabidopsis ELP4 interacts directly with ELP6 but not directly with ELP5 in vivo, and ELP6 acts as a structural bridge in the AtELP456 heterotrimer, a configuration structurally conserved with yeast Elp456 despite low sequence homology. In vivo protein-protein interaction assays (yeast two-hybrid / co-IP in planta); structural prediction and comparative analysis International journal of molecular sciences Medium 38673955
2025 ELP6 knockdown in melanoma cells causes G1 phase cell cycle arrest, reduced cell viability, decreased p42 MAPK expression, and reduced responsiveness to the MEK1/2 inhibitor U0126, placing ELP6 function upstream of the ERK1/2 signalling pathway. shRNA knockdown; flow cytometry cell cycle analysis; western blot for ERK pathway components; pharmacological inhibitor assays Oncology letters Medium 40177137

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 An early step in wobble uridine tRNA modification requires the Elongator complex. RNA (New York, N.Y.) 379 15769872
2006 Elevated levels of two tRNA species bypass the requirement for elongator complex in transcription and exocytosis. Molecular cell 230 17018299
2002 Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo. Proceedings of the National Academy of Sciences of the United States of America 221 11904415
2005 The Kluyveromyces lactis gamma-toxin targets tRNA anticodons. RNA (New York, N.Y.) 177 16244131
2001 Characterization of a six-subunit holo-elongator complex required for the regulated expression of a group of genes in Saccharomyces cerevisiae. Molecular and cellular biology 152 11689709
2001 RNA polymerase II elongator holoenzyme is composed of two discrete subcomplexes. The Journal of biological chemistry 147 11435442
2005 The elongata mutants identify a functional Elongator complex in plants with a role in cell proliferation during organ growth. Proceedings of the National Academy of Sciences of the United States of America 133 15894610
2003 Urmylation: a ubiquitin-like pathway that functions during invasive growth and budding in yeast. Molecular biology of the cell 95 14551258
2009 Elongator mediates ABA responses, oxidative stress resistance and anthocyanin biosynthesis in Arabidopsis. The Plant journal : for cell and molecular biology 90 19500300
2012 The Elongator subcomplex Elp456 is a hexameric RecA-like ATPase. Nature structural & molecular biology 77 22343726
2001 Kluyveromyces lactis zymocin mode of action is linked to RNA polymerase II function via Elongator. Molecular microbiology 62 11737649
2015 Loss of anticodon wobble uridine modifications affects tRNA(Lys) function and protein levels in Saccharomyces cerevisiae. PloS one 57 25747122
2002 Molecular analysis of KTI12/TOT4, a Saccharomyces cerevisiae gene required for Kluyveromyces lactis zymocin action. Molecular microbiology 55 11929532
2012 DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and migration of melanoma cells as subunits of Elongator. The Journal of biological chemistry 43 22854966
2016 Molecular architecture of the yeast Elongator complex reveals an unexpected asymmetric subunit arrangement. EMBO reports 39 27872205
2002 Subunit communications crucial for the functional integrity of the yeast RNA polymerase II elongator (gamma-toxin target (TOT)) complex. The Journal of biological chemistry 37 12424236
2012 Crystal structure of elongator subcomplex Elp4-6. The Journal of biological chemistry 34 22556426
2020 Signatures of positive selection underlying beef production traits in Korean cattle breeds. Journal of animal science and technology 30 32568261
2018 Structural insights into the function of Elongator. Cellular and molecular life sciences : CMLS 28 29332244
2015 Meta-regulation of Arabidopsis auxin responses depends on tRNA maturation. Cell reports 25 25892242
2022 Functional divergence of the two Elongator subcomplexes during neurodevelopment. EMBO molecular medicine 18 35698786
2020 A Comparative Analysis of Single-Cell Transcriptome Identifies Reprogramming Driver Factors for Efficiency Improvement. Molecular therapy. Nucleic acids 18 32045876
2017 Use of a Yeast tRNase Killer Toxin to Diagnose Kti12 Motifs Required for tRNA Modification by Elongator. Toxins 17 28872616
2023 6-Benzylaminopurine causes lipid dyshomeostasis via disruption of glycerophospholipid metabolism in zebrafish. The Science of the total environment 16 37001669
2018 Elongator promotes the migration and invasion of hepatocellular carcinoma cell by the phosphorylation of AKT. International journal of biological sciences 15 29805303
2023 A novel ELP1 mutation impairs the function of the Elongator complex and causes a severe neurodevelopmental phenotype. Journal of human genetics 14 36864284
2018 Elongator Is Required for Root Stem Cell Maintenance by Regulating SHORTROOT Transcription. Plant physiology 14 30401723
2016 Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans. AIDS (London, England) 13 27088321
2009 Human Elongator complex is involved in cell cycle and suppresses cell growth in 293T human embryonic kidney cells. Acta biochimica et biophysica Sinica 13 19779648
2018 New insights into donor directionality of mating-type switching in Schizosaccharomyces pombe. PLoS genetics 12 29852001
2009 ELP3 localises to mitochondria and actin-rich domains at edges of HeLa cells. Neuroscience letters 11 19429107
2018 Unfolded Protein Response Suppression in Yeast by Loss of tRNA Modifications. Genes 9 30360492
2017 Involvement of BcElp4 in vegetative development, various environmental stress response and virulence of Botrytis cinerea. Microbial biotechnology 9 28474462
2022 Elongator promotes neuritogenesis via regulation of tau stability through acly activity. Frontiers in cell and developmental biology 5 36393857
2014 Identification and expression of the elongator protein 2 (Ajelp2) gene, a novel regeneration-related gene from the sea cucumber Apostichopus japonicus. Molecular biology reports 4 24748431
2022 Biochemical and Structural Characterization of Human Core Elongator and Its Subassemblies. ACS omega 3 35128251
2025 Comparative transcriptomic analysis of retinal response to diverse cellular stresses reveals relative contributions of different cell death processes and signalling networks. Cell death & disease 2 41326361
2024 Evolutionary Conservation in Protein-Protein Interactions and Structures of the Elongator Sub-Complex ELP456 from Arabidopsis and Yeast. International journal of molecular sciences 1 38673955
2025 Role of ELP6 in tumour progression and impact on ERK1/2 signalling pathway inhibitors in skin cutaneous melanoma. Oncology letters 0 40177137
2025 Leishmania donovani elongator protein Elp3a plays a crucial role in modulating the parasite response to genotoxic stress. Microbiology spectrum 0 41347503
2013 Developing and mature human granulocytes express ELP 6 in the cytoplasm. Human antibodies 0 24284306