Affinage

ELP5

Elongator complex protein 5 · UniProt Q8TE02

Length
300 aa
Mass
33.2 kDa
Annotated
2026-04-28
22 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ELP5 is an essential subunit of the six-subunit Elongator complex, functioning within the Elp4/5/6 heterohexameric ring that adopts a RecA-like ATPase fold and binds tRNA in an ATP-regulated manner (PMID:22343726, PMID:22556426). ELP5 directly bridges the catalytic ELP3 subunit to ELP4, and its loss dismantles the holo-Elongator complex, abolishing both histone acetyltransferase activity (targeting H3-K14 and H4-K8) and wobble uridine-34 tRNA modification (PMID:11904415, PMID:22854966, PMID:31792210). The tRNA modification function of ELP5-containing Elongator is mechanistically linked to codon-dependent translation of specific mRNAs, including hnRNPQ, whose U34-modification-dependent translation drives p53 IRES-mediated expression and thereby controls gemcitabine-induced apoptosis (PMID:31792210). In gallbladder cancer, ELP5 transcription is epigenetically silenced by DNMT3A-mediated promoter hypermethylation that occludes the transcription factor PAX5 (PMID:34823564).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2001 High

    Identification of ELP5 as part of a modular Elp4/5/6 subcomplex within holo-Elongator established the architecture of the six-subunit complex and showed that holo-Elongator dissociates into core (Elp1-3) and accessory (Elp4-6) modules.

    Evidence Tandem affinity purification and salt fractionation in yeast, replicated by two independent laboratories

    PMID:11435442 PMID:11689709

    Open questions at the time
    • No atomic-resolution structure of the Elp4/5/6 subcomplex
    • Enzymatic contribution of the Elp4/5/6 module versus the Elp1-3 catalytic core not delineated
    • Whether this architecture is conserved in metazoan Elongator was unknown
  2. 2002 High

    Demonstration that all three Elp4/5/6 subunits are required for Elongator's histone acetyltransferase activity, and that Elp6 acts as a structural bridge needed for Elp5 to associate with the core, defined the functional dependency of the complex on its accessory ring.

    Evidence In vitro HAT assays on nucleosomal substrates with yeast deletion mutants; co-immunoprecipitation epistasis among subunits

    PMID:11904415 PMID:12424236

    Open questions at the time
    • Which subunit directly contacts the histone substrate was unknown
    • No structural basis for Elp6 bridging role
    • Role in tRNA modification not yet recognized
  3. 2002 Medium

    Discovery that the regulatory protein Kti12 physically contacts holo-Elongator and requires both the Elp1-3 core and Elp5 for binding linked Elongator to zymocin toxicity and implied a regulatory input at the Elp5 surface.

    Evidence Co-immunoprecipitation and yeast genetics

    PMID:11929532 PMID:12424236

    Open questions at the time
    • Direct binding interface between Kti12 and Elp5 not mapped
    • Mechanism by which Kti12 modulates Elongator activity unknown
  4. 2008 Medium

    Identification of Kti11/Dph3 as a physical interactor of both Elp2 and Elp5 expanded the network of regulatory cofactors converging on ELP5, with a separation-of-function mutation distinguishing Elongator-dependent from Elongator-independent Kti11 roles.

    Evidence Co-immunoprecipitation and separation-of-function mutagenesis in yeast

    PMID:18627462

    Open questions at the time
    • Whether Kti11 binds Elp5 directly or via Elp2 not resolved
    • Functional consequence of Kti11–Elp5 interaction on tRNA modification not tested
  5. 2012 High

    Crystal structures of yeast Elp4/5/6 revealed a heterohexameric ring with RecA-like ATPase folds, showed Elp6 bridges Elp4 and Elp5, and demonstrated that this ring binds tRNA in an ATP-regulated manner and histone H3 via the assembled hexameric surface, unifying the complex's HAT and tRNA modification activities at the structural level.

    Evidence X-ray crystallography; in vitro tRNA and histone binding assays with site-directed mutants; in vivo complementation (two independent structural studies)

    PMID:22343726 PMID:22556426

    Open questions at the time
    • How ATP hydrolysis modulates tRNA binding or release mechanistically unclear
    • No structure of intact holo-Elongator at this time
    • Whether histone binding and tRNA binding are mutually exclusive or concurrent
  6. 2012 High

    Characterization of human ELP5 confirmed it directly connects ELP3 to ELP4 and is required for Elongator integrity, extending the yeast findings to mammalian cells and linking ELP5 loss to reduced melanoma cell migration and tumorigenicity.

    Evidence Reciprocal co-immunoprecipitation; siRNA knockdown in human melanoma cell lines with functional assays

    PMID:22854966

    Open questions at the time
    • Molecular basis of how ELP5 loss reduces invasion not established beyond Elongator disruption
    • Whether ELP5 affects tRNA modification in human cells not yet tested
  7. 2019 High

    A genome-wide CRISPR screen established that ELP5 loss abrogates wobble U34 tRNA modification and thereby specifically impairs translation of hnRNPQ mRNA, connecting Elongator's tRNA modification function to p53 IRES-dependent apoptosis and gemcitabine sensitivity.

    Evidence CRISPR screen; tRNA modification mass spectrometry; polysome profiling; rescue with U34-modification-independent hnRNPQ construct; in vivo xenograft

    PMID:31792210

    Open questions at the time
    • Full set of mRNAs translationally regulated by ELP5-dependent U34 modification not catalogued
    • Whether ELP5 has functions beyond Elongator's tRNA modification role not addressed
    • Contribution of ELP5's HAT activity versus tRNA modification to cancer phenotypes not separated
  8. 2021 Medium

    ELP5 expression in gallbladder cancer is regulated by DNMT3A-mediated promoter hypermethylation that prevents PAX5 binding, providing an epigenetic mechanism for ELP5 silencing in tumors.

    Evidence Methylation-specific qPCR, ChIP-qPCR, EMSA, and luciferase reporter in gallbladder cancer cell lines

    PMID:34823564

    Open questions at the time
    • Whether this epigenetic silencing occurs in other tumor types not tested
    • Whether restored ELP5 expression rescues U34 tRNA modification in gallbladder cancer not shown
    • Single-lab findings await independent validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the Elp4/5/6 ring coordinates ATP-dependent tRNA binding with the catalytic cycle of Elp3 within the full holo-Elongator structure, and whether ELP5 has Elongator-independent functions, remain open questions.
  • No cryo-EM or crystal structure of metazoan holo-Elongator with tRNA substrate in a catalytic intermediate
  • Separation of ELP5's HAT-supporting role from its tRNA modification role not achieved in human cells
  • Complete translational target repertoire downstream of ELP5-dependent U34 modification undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 2 GO:0140657 ATP-dependent activity 2 GO:0003723 RNA binding 1
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-5357801 Programmed Cell Death 1
Partners
DPH3ELP1ELP2ELP3ELP4ELP6KTI12
Complex memberships
Elongator complexElp4/5/6 subcomplex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Elp4, Elp5, and Elp6 are required for the HAT activity of the intact Elongator complex, which acetylates histone H3 (primarily K14) and histone H4 (primarily K8), including nucleosomal substrates; the complex binds both naked and nucleosomal DNA. In vitro HAT assay with purified Elongator complex; yeast deletion mutants; chromatin immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 11904415
2001 Elp4, Elp5, and Elp6 form a discrete subcomplex (HAP subcomplex) within the six-subunit holo-Elongator complex associated with elongating RNA Pol II; disruption of ELP5 is essential for yeast growth, while loss of ELP4 or ELP6 phenocopies loss of the core Elp1-3 subunits. Tandem affinity purification (TAP); gene disruption; microarray expression analysis Molecular and cellular biology High 11435442 11689709
2001 Holo-Elongator dissociates into two subcomplexes at higher salt concentrations: Elp1/2/3 (core) and Elp4/5/6 (HAP), demonstrating modular organization of the complex. Affinity chromatography purification; salt fractionation The Journal of biological chemistry High 11435442 11689709
2002 The structural integrity of the Elp4/5/6 (HAP/TOT5-7) subcomplex requires ELP4/TOT7 and ELP6/TOT6; loss of these genes abolishes the interaction between Elp5 and the core Elongator subunit Elp2/Tot2p. Co-immunoprecipitation; yeast deletion genetics The Journal of biological chemistry Medium 12424236
2002 Kti12/Tot4p physically interacts with the holo-Elongator complex and requires both the Elp1-3 core and Elp5 for this interaction, suggesting it contacts preassembled holo-Elongator to modulate its activity. Co-immunoprecipitation; yeast genetics The Journal of biological chemistry Medium 11929532 12424236
2008 Kti11/Dph3 physically interacts with Elp2 and Elp5, two Elongator subunits; deletion of KTI11 phenocopies Elongator-minus cells, and a C-terminal truncation mutation (kti11-1) that almost entirely abolishes Elongator interaction separates zymocin resistance from other Kti11 functions. Co-immunoprecipitation; yeast genetics; separation-of-function mutation Molecular microbiology Medium 18627462
2012 The Elp4/5/6 subcomplex adopts a heterohexameric ring structure where each subunit has an almost identical RecA-like fold; the complex binds tRNA in an ATP-regulated manner, supporting a role in tRNA modification. X-ray crystallography; in vitro tRNA binding assay; ATP-modulation experiments; in vivo complementation Nature structural & molecular biology High 22343726
2012 Crystal structure of yeast Elp4-6 reveals that Elp6 acts as a structural bridge assembling Elp4 and Elp5; each subunit has a RecA-ATPase-like fold. The hexameric ring assembly of Elp4-6 is required for specific histone H3 binding, as shown by mutagenesis and GST pulldown. X-ray crystallography; site-directed mutagenesis; GST pulldown; biochemical assembly assays The Journal of biological chemistry High 22556426
2012 Human DERP6/ELP5 is an integral subunit of the human Elongator complex that directly connects ELP3 to ELP4 and is required for the structural integrity of the complex; depletion of ELP5 impairs Elongator integrity and reduces migration, invasion, and tumorigenicity of melanoma cells. Biochemical co-purification; siRNA knockdown; cell migration/invasion assays; co-immunoprecipitation The Journal of biological chemistry High 22854966
2019 Loss of ELP5 impairs the integrity and stability of the Elongator complex, abrogates wobble U34 tRNA modification, and thereby impedes U34 modification-dependent translation of hnRNPQ mRNA; reduced hnRNPQ cannot drive P53 IRES-dependent translation, reducing gemcitabine-induced apoptosis in a P53-dependent manner. CRISPR screen; tRNA modification assay; polysome profiling/translation assay; rescue experiments with U34-modification-independent hnRNPQ mutant; in vitro and in vivo functional assays Nature communications High 31792210
2021 ELP5 transcription in gallbladder cancer is epigenetically repressed by DNMT3A-catalysed promoter hypermethylation, which blocks the transcription factor PAX5 from binding the ELP5 promoter; demethylation with DAC restores PAX5 binding and ELP5 expression. RT-qPCR; MS-qPCR; ChIP-qPCR; EMSA; luciferase reporter assay; chromatin accessibility assay Journal of experimental & clinical cancer research Medium 34823564
2006 Human DERP6/ELP5 protein localizes to the cytoplasm when overexpressed, and overexpression activates p53 transcriptional activity. Fluorescence microscopy (subcellular localization); luciferase reporter assay Molecular biology reports Low 16850183

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
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
2019 Genome-wide CRISPR screen identifies ELP5 as a determinant of gemcitabine sensitivity in gallbladder cancer. Nature communications 81 31792210
2012 The Elongator subcomplex Elp456 is a hexameric RecA-like ATPase. Nature structural & molecular biology 77 22343726
2002 Molecular analysis of KTI12/TOT4, a Saccharomyces cerevisiae gene required for Kluyveromyces lactis zymocin action. Molecular microbiology 55 11929532
2008 A versatile partner of eukaryotic protein complexes that is involved in multiple biological processes: Kti11/Dph3. Molecular microbiology 48 18627462
2012 DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and migration of melanoma cells as subunits of Elongator. The Journal of biological chemistry 43 22854966
2017 Physical Interactions and Expression Quantitative Traits Loci Identify Regulatory Connections for Obesity and Type 2 Diabetes Associated SNPs. Frontiers in genetics 41 29081791
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
2018 Structural insights into the function of Elongator. Cellular and molecular life sciences : CMLS 28 29332244
2021 Epigenetic activation of the elongator complex sensitizes gallbladder cancer to gemcitabine therapy. Journal of experimental & clinical cancer research : CR 15 34823564
2024 Shared genetic basis and causality between schizophrenia and inflammatory bowel disease: evidence from a comprehensive genetic analysis. Psychological medicine 13 38563283
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
2020 Non-chromatographic purification of thermostable endoglucanase from Thermotoga maritima by fusion with a hydrophobic elastin-like polypeptide. Protein expression and purification 12 32325232
2015 A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes. Physiological genomics 7 25759378
2006 Cloning and characterization of the human gene DERP6, which activates transcriptional activities of p53. Molecular biology reports 7 16850183
2021 Hearing Function: Identification of New Candidate Genes Further Explaining the Complexity of This Sensory Ability. Genes 5 34440402
2024 A comprehensive meta-analysis of transcriptome data to identify signature genes associated with pancreatic ductal adenocarcinoma. PloS one 3 38324544
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
2026 Deletion of Elongator Protein 1 (Elp1) relieves heterochromatin defects in a Pol II mutant of Schizosaccharomyces pombe. Genetics 0 41316862