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Showing UBE3A — E6-AP is a alias.

UBE3A

Ubiquitin-protein ligase E3A · UniProt Q05086

Length
875 aa
Mass
100.7 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBE3A (E6-AP) is the founding member of the HECT-domain family of E3 ubiquitin ligases, accepting ubiquitin from an E2 as a thioester intermediate at a conserved active-site cysteine before transferring it directly to substrates (PMID:7708685). It was originally identified as the cellular factor that, in complex with HPV-16 E6, ubiquitinates p53 for degradation, and it confers intrinsic ligase activity even without E6 (PMID:8221889). The catalytically active enzyme assembles as a trimer stabilized by Phe727, and HPV E6 stimulates activity by promoting trimer formation and repositioning E6 and p53 near the catalytic center (PMID:24273172, PMID:30361475); activity is further tuned by PKA phosphorylation at T485, which is inhibitory, and by gain-of-function variants such as Q588E that hyperactivate the enzyme (PMID:26255772, PMID:34815418). Loss-of-function mutations in UBE3A cause Angelman syndrome (PMID:8988171, PMID:8988172), a neurodevelopmental disorder whose pathophysiology reflects the gene's neuron-specific maternal imprinting, in which the paternal allele is silenced in cis by the antisense transcript UBE3A-ATS through transcriptional collision that blocks paternal elongation (PMID:9288101, PMID:24385930). In neurons UBE3A is predominantly nuclear, with the nuclear isoform—imported through binding to PSMD4—being the critical determinant of AS phenotypes (PMID:31235931). Through its ligase activity UBE3A controls excitatory synapse development and plasticity by ubiquitinating substrates including Arc, the potassium channel SK2, Ephexin5, the PP2A activator PTPA, and the Ragulator subunit p18/LAMTOR1, thereby coupling protein turnover to AMPA-receptor trafficking, LTP, mTORC1 signaling, and dendritic spine maturation (PMID:20211139, PMID:26166566, PMID:34593829, PMID:31160454, PMID:30020076). A broad substrate repertoire extends this role beyond the synapse to chromatin (Ring1B), transcription factors (SOX9), apoptotic and cytoskeletal control (XIAP), and metabolic and retrotransposon-derived proteins (TKT, PEG10) (PMID:20351251, PMID:24155239, PMID:29175955, PMID:35264729, PMID:34467244). In non-neuronal cells UBE3A additionally functions as a transcriptional coactivator of nuclear hormone receptors, a function biochemically separable from its ligase activity (PMID:9891052).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Established that UBE3A is a functional ubiquitin ligase by showing the E6/E6-AP complex ubiquitinates p53, defining the enzyme's first substrate and biochemical role.

    Evidence In vitro ubiquitination reconstitution with purified E1/E2/E3 components and biochemical fractionation

    PMID:8221889

    Open questions at the time
    • Did not define the catalytic mechanism or active-site residue
    • Restricted to the HPV-E6 context
  2. 1995 High

    Resolved how UBE3A transfers ubiquitin, defining the HECT mechanism in which ubiquitin forms a thioester on a conserved active-site cysteine before transfer to substrate.

    Evidence In vitro thioester assay with site-directed mutagenesis of the conserved cysteine

    PMID:7708685

    Open questions at the time
    • Did not address substrate selection or higher-order enzyme assembly
  3. 1997 High

    Linked UBE3A to human disease and to imprinted neuronal regulation, showing loss-of-function mutations cause Angelman syndrome and that the gene is preferentially expressed from the maternal allele in specific neurons.

    Evidence Mutation sequencing in AS patients; in situ hybridization in mouse UPD models

    PMID:8988171 PMID:8988172 PMID:9288101

    Open questions at the time
    • Mechanism enforcing paternal silencing unknown
    • Disease-relevant substrates unidentified
  4. 1999 Medium

    Distinguished a second molecular function, showing UBE3A coactivates nuclear hormone receptor transcription independently of its ligase activity, and that most AS mutations spare coactivation while disrupting ligase function.

    Evidence Co-IP, transactivation reporter assays, and analysis of AS patient mutants

    PMID:9891052

    Open questions at the time
    • Relative contribution of coactivation versus ligase activity to AS unresolved
    • Single-lab finding
  5. 2012 Medium

    Defined how paternal UBE3A is silenced, showing the antisense UBE3A-ATS transcript represses the paternal allele in cis and that its premature termination reactivates paternal expression.

    Evidence Mouse genetic termination-cassette models with strand-specific expression readout

    PMID:22493002

    Open questions at the time
    • Precise molecular mechanism of cis repression not yet defined here
  6. 2013 High

    Explained how HPV E6 stimulates UBE3A, demonstrating the active enzyme is a Phe727-stabilized trimer and that E6 drives trimer formation.

    Evidence Biochemical chain-formation assays, size-exclusion chromatography, Phe727 mutagenesis, and structural modeling

    PMID:24273172

    Open questions at the time
    • Trimer relevance in neuronal contexts not addressed
  7. 2013 Medium

    Demonstrated transcriptional-collision as the imprinting mechanism, showing truncation of Ube3a-ATS reactivates paternal Ube3a and rescues motor, cognitive, and LTP deficits in AS mice.

    Evidence Poly(A) cassette knock-in mouse with allele-specific expression and phenotypic rescue

    PMID:24385930

    Open questions at the time
    • Timing window for therapeutic reactivation not defined
    • Translation to human alleles untested here
  8. 2010 High

    Connected UBE3A ligase activity to synaptic function, showing it ubiquitinates Arc to regulate AMPA receptor surface levels and excitatory synapse development.

    Evidence In vitro ubiquitination and loss-of-function in neurons with synaptic readouts

    PMID:20211139

    Open questions at the time
    • Other synaptic substrates not yet enumerated at this stage
  9. 2015 High

    Identified post-translational and disease-relevant regulation of activity, showing PKA phosphorylation at T485 inhibits UBE3A and that an autism-linked mutation disrupting this site hyperactivates the enzyme and increases dendritic spines.

    Evidence In vitro kinase assay, mutagenesis, patient-derived cells, and in vivo spine imaging

    PMID:26255772

    Open questions at the time
    • Upstream signals controlling PKA regulation in vivo not mapped
  10. 2015 Medium

    Expanded the synaptic substrate set toward plasticity mechanisms, identifying SK2 channels as substrates whose UBE3A-dependent endocytosis governs NMDA-receptor activation and LTP.

    Evidence In vitro ubiquitination, Co-IP, and electrophysiology with pharmacological SK2 blockade in UBE3A-deficient mice

    PMID:26166566

    Open questions at the time
    • Single-lab; SK2 ubiquitination-site mapping not provided
  11. 2018 Medium

    Linked UBE3A loss to elevated mTORC1 signaling, identifying p18/LAMTOR1 as a substrate whose accumulation drives spine and plasticity deficits rescuable by p18 knockdown.

    Evidence In vitro ubiquitination, Co-IP, and in vivo rescue in AS mice

    PMID:30020076

    Open questions at the time
    • Single-lab finding
  12. 2019 High

    Established the nuclear isoform as the disease-critical species, showing both isoforms import via PSMD4 binding but only nuclear-isoform loss recapitulates AS phenotypes.

    Evidence Fractionation, PSMD4 binding assays, isoform-specific conditional knockout mice with behavioral/EEG phenotyping, and patient-mutation analysis

    PMID:31235931

    Open questions at the time
    • Nuclear substrates driving the phenotype not fully defined
    • Cytosolic-pool functions remain unclear
  13. 2019 Medium

    Added a phosphatase-regulatory substrate, identifying PTPA as a UBE3A target whose accumulation elevates PP2A activity, with PP2A inhibition rescuing AS phenotypes.

    Evidence SILAC ubiquitination assay, Co-IP, PP2A activity measurement, and in vivo rescue in AS mice

    PMID:31160454

    Open questions at the time
    • Single-lab finding
  14. 2021 Medium

    Pinpointed a hippocampal driver substrate, showing genetic deletion of the UBE3A substrate Ephexin5 rescues hippocampal behavior, physiology, and spine deficits in AS mice.

    Evidence In vitro ubiquitination and genetic epistasis rescue with multiple phenotypic readouts

    PMID:34593829

    Open questions at the time
    • Single-lab; relative contribution among multiple substrates unresolved
  15. 2021 High

    Defined a regulatory residue for activity and a distinct gain-of-function disease axis, showing Q588E hyperactivates UBE3A and causes phenotypes distinct from AS.

    Evidence Large-scale in vitro variant activity screen, mutagenesis, and Q588E knock-in mouse phenotyping

    PMID:34815418

    Open questions at the time
    • Substrate-level consequences of hyperactivation not fully mapped
  16. 2021 Medium

    Connected UBE3A loss to a retrotransposon-derived protein, identifying PEG10 as a substrate accumulating in AS neurons with effects on RNA binding, stress granules, and neuronal migration.

    Evidence Unbiased proteomics in AS patient neurons with ASO modulation, proteasome inhibition, and in vivo overexpression

    PMID:34467244

    Open questions at the time
    • Single-lab; causal role of PEG10 in AS behavior untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved which combination of nuclear substrates and pathways accounts for Angelman syndrome pathology, and how the many identified substrates are prioritized for therapeutic targeting.
  • No hierarchy established among Arc, SK2, Ephexin5, PTPA, p18, TKT, and PEG10 substrates
  • Nuclear-isoform substrate specificity incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 8 GO:0140096 catalytic activity, acting on a protein 7 GO:0016874 ligase activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1643685 Disease 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
BMAL1HERC2HPV E6MAPK6NEURL4P53PSMD4PTPA
Complex memberships
E6/E6-AP-p53 complexHERC2-NEURL4-MAPK6 complexproteasome

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 The HPV-16 E6/E6-AP complex functions as an E3 ubiquitin-protein ligase that ubiquitinates p53, requiring E1 and a novel E2 enzyme; E6-AP itself confers the E3 ligase activity and can ubiquitinate p53 even in the absence of E6. In vitro ubiquitination reconstitution with purified components; biochemical fractionation and identification of required factors Cell High 8221889
1995 E6-AP defines the HECT domain family of E3 ubiquitin ligases: it accepts ubiquitin from E2 as a thioester intermediate at a conserved cysteine in the HECT domain, then directly transfers ubiquitin to substrates. Mutation of this conserved cysteine abolishes ubiquitin thioester formation. In vitro ubiquitin thioester assay; site-directed mutagenesis of conserved cysteine residue in E6-AP and related proteins Proceedings of the National Academy of Sciences of the United States of America High 7708685
1997 Loss-of-function mutations in UBE3A (frameshift, splicing mutations) cause Angelman syndrome, establishing UBE3A as the AS gene and implicating defective ubiquitin-mediated protein degradation in AS pathogenesis. Mutation analysis (sequencing) of UBE3A in AS patients without deletion/UPD/imprinting defects; identification of de novo and inherited loss-of-function mutations Nature genetics High 8988171 8988172
1997 Ube3a exhibits neuron-specific imprinting with preferential maternal expression in hippocampal neurons, cerebellar Purkinje cells, and mitral cells of the olfactory bulb in mice; expression of the paternal allele is markedly reduced in these neurons compared to non-neuronal brain cells. In situ hybridization in mice with segmental paternal uniparental disomy; comparison of Ube3a expression between UPD and non-UPD littermates Nature genetics High 9288101
1998 E6-AP can ubiquitinate itself (autoubiquitination) via intermolecular transfer, leading to its own proteasomal degradation in vivo. Highly ubiquitinated E6-AP cannot bind p53 in the presence of E6, and substrate (p53) binding to E6-AP interferes with its autoubiquitination, suggesting autoubiquitination controls E6-AP levels. In vitro ubiquitination assay; overexpression in vivo; co-immunoprecipitation of ubiquitinated E6-AP with p53/E6 European journal of biochemistry Medium 9688277
1999 E6-AP/UBE3A directly interacts with and coactivates transcriptional activity of nuclear hormone receptors (progesterone receptor and other steroid receptors) in a hormone-dependent manner. The ubiquitin ligase function and the coactivator function are separable and independent. Most AS patient mutations disrupt the ubiquitin ligase activity while leaving coactivator function intact. Co-immunoprecipitation; transactivation reporter assays; analysis of AS patient-derived E6-AP mutants for E3 versus coactivation activity Molecular and cellular biology Medium 9891052
2004 The E6/E6-AP E3 ubiquitin ligase complex targets the telomerase repressor NFX1-91 for ubiquitination and degradation, resulting in derepression of the hTERT promoter and elevated telomerase activity. E6-AP is required for E6-mediated telomerase induction. Yeast two-hybrid screen; shRNA knockdown of E6-AP; assessment of NFX1-91 ubiquitination and hTERT promoter activity Genes & development Medium 15371341
2008 E6-AP/UBE3A interacts with misfolded polyglutamine proteins (soluble and aggregated forms), ubiquitinates them, promotes their proteasomal degradation, and suppresses their aggregation and toxicity in cellular and transgenic mouse models. Knockdown of E6-AP enhances aggregate formation and cell death. Co-immunoprecipitation; in vitro ubiquitination assay; knockdown and overexpression in cell culture and transgenic mouse models The Journal of biological chemistry Medium 18201976
2009 E6-AP/UBE3A interacts with and directly ubiquitinates the cyclin-dependent kinase inhibitor p27 in vitro, promoting its proteasomal degradation. Knockdown of E6-AP increases p27 levels and causes cell cycle arrest. Co-immunoprecipitation; in vitro ubiquitination assay; siRNA knockdown with cell cycle analysis; measurement of p27 levels in E6-AP-deficient mouse brain Neurobiology of disease Medium 19591933
2009 E6-AP/UBE3A promotes proteasome-dependent degradation of wild-type and mutant forms of alpha-synuclein, including toxic oligomeric forms. E6-AP colocalizes with alpha-synuclein in juxtanuclear aggregates and is a component of Lewy bodies in post-mortem Parkinson's disease brain. Co-immunoprecipitation; overexpression with proteasome inhibitor; immunofluorescence colocalization; analysis of post-mortem human brain Journal of neurochemistry Medium 19645749
2010 E6-AP/UBE3A ubiquitinates the polycomb protein Ring1B for canonical (degradative) ubiquitination, targeting the same lysines as Ring1B's own non-degradative self-ubiquitination. Loss of E6-AP increases Ring1B levels and ubiquitinated histone H2A, and represses HoxB9 expression in vivo. In vitro ubiquitination assay; co-immunoprecipitation; analysis of E6-AP knockout mice for Ring1B, H2A ubiquitination, and HoxB9 expression Proceedings of the National Academy of Sciences of the United States of America Medium 20351251
2010 Ube3A regulates excitatory synapse development by ubiquitinating and promoting degradation of Arc, a synaptic protein that promotes AMPA receptor internalization. Loss of Ube3A in neurons increases Arc and decreases AMPA receptors at excitatory synapses. Activity-driven neuronal activity induces Ube3A transcription. In vitro ubiquitination assay; biochemical measurement of Arc and AMPA receptor levels; loss-of-function in neurons with phenotypic readout of synapse development Cell High 20211139
2012 UBE3A/E6AP exists in multiple distinct protein complexes including the proteasome and a high-molecular-weight complex containing HERC2, NEURL4, and MAPK6. HERC2 modulates the ubiquitin ligase activity of E6AP. E6 (HPV) associates with the HERC2-containing complex through its binding to E6AP. Proteomic/mass spectrometry-based affinity purification; co-immunoprecipitation validation of interactions including HERC2, NEURL4, MAPK6 Molecular and cellular biology Medium 22645313
2013 Catalytically active E6AP/UBE3A is a trimer; Phe727 is critical for trimer stabilization, and its mutation decreases kcat 62-fold without affecting E2 binding or thioester formation. HPV E6 promotes trimer formation (Kactivation ~1.5 nM), explaining how E6 stimulates E6AP ligase activity. Biochemical analysis of ubiquitin chain formation; size-exclusion chromatography; mutagenesis of Phe727; crystallography-informed structural model; peptide and small-molecule antagonist studies The Journal of biological chemistry High 24273172
2013 E6-AP/UBE3A acts as a ubiquitin ligase toward SOX9, binding via SOX9's HMG domain, ubiquitinating SOX9 in vitro and in vivo, and promoting its proteasomal degradation. E6-AP-deficient mice show SOX9 accumulation in chondrocytes and brain. Proteomics-based identification; co-immunoprecipitation; in vitro ubiquitination assay; siRNA knockdown; analysis of E6-AP knockout mice The Journal of biological chemistry Medium 24155239
2013 Loss of Ube3a causes structural disruption and under-acidification of the Golgi apparatus, leading to osmotic swelling and a marked reduction in protein sialylation both in vitro (Ube3a knockdown cells) and in vivo (AS mouse cortex). Golgi ultrastructural analysis by electron microscopy; pH measurements in Ube3a knockdown cell lines and AS mouse neurons; sialylation assay in vitro and in vivo The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 23447592
2014 Postnatal neurons progressively silence paternal Ube3a protein expression during the first postnatal week as they mature. Maternal Ube3a protein localizes increasingly to the nucleus during postnatal development. Astrocytes and oligodendrocytes express Ube3a biallelically. Allele-specific immunofluorescence imaging in AS model mice (distinguishing maternal vs. paternal Ube3a protein) throughout postnatal development; cell-type specific analysis The Journal of comparative neurology Medium 24254964
2015 PKA phosphorylates UBE3A at residue T485 (outside the catalytic domain) and inhibits UBE3A ubiquitin ligase activity toward itself and other substrates. A de novo autism-linked missense mutation disrupts this phosphorylation site, causing enhanced UBE3A activity in vitro, enhanced substrate turnover in patient-derived cells, and excessive dendritic spine development in vivo. In vitro kinase assay with PKA; site-directed mutagenesis; analysis of patient-derived cells; in vivo dendritic spine imaging Cell High 26255772
2015 UBE3A directly ubiquitinates SK2 (small-conductance potassium channel) in its C-terminal domain, facilitating SK2 endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels cause decreased NMDA receptor activation and impaired hippocampal LTP. Blocking SK2 ameliorates synaptic plasticity and fear conditioning deficits. In vitro ubiquitination assay; Co-IP; biochemical measurement of SK2 levels; electrophysiology (LTP) in UBE3A-deficient mice; pharmacological SK2 blockade Cell reports Medium 26166566
2015 UBE3A increasing expression in the nucleus downregulates Cbln1 in VTA glutamatergic neurons, impairing sociability. This Ube3a-dependent repression of Cbln1 weakens glutamatergic transmission and is reversible by viral restoration of Cbln1 or chemogenetic VTA neuron activation. In vivo mouse genetics (conditional alleles); viral vector rescue; chemogenetic activation; behavioral assays; Cbln1 measurement in VTA Nature Medium 28297715
2016 UBE3A is highly enriched in axon terminals and euchromatin-rich nuclear domains of neurons, as determined by high-resolution light and electron microscopic immunocytochemistry, suggesting roles at individual synapses and in nuclear transcription regulation. High-resolution light microscopy and electron microscopic immunocytochemistry in rodent neurons The Journal of comparative neurology Medium 27339004
2016 Drosophila ube3a ubiquitinates the BMP receptor Thickveins (Tkv) at lysine 227 in its cytoplasmic tail and promotes its proteasomal degradation, thereby repressing BMP signaling. Loss of ube3a increases Tkv levels and causes synaptic overgrowth and compromised endocytosis at NMJs. This regulation is conserved in mammalian cells. Drosophila genetics; Co-IP; in vitro ubiquitination assay; site-specific mutagenesis (K227); genetic epistasis with BMP pathway; conservation confirmed in mammalian cell assays PLoS genetics High 27232889
2017 UBE3A ubiquitinates XIAP, leading to caspase-3 activation and microtubule cleavage, which drives dendritic retraction. In Ube3A 2X ASD transgenic mice, XIAP is decreased, caspase-3 is elevated, and dendritic branching and spine density are reduced in cortical neurons. Ubiquitination assay; immunoblotting for XIAP and caspase-3; analysis of Ube3A 2X transgenic mouse cortex; primary neuron culture overexpression studies The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 29175955
2018 Binding of HPV E6 induces conformational rearrangements in E6AP, positioning E6 and p53 in the immediate vicinity of the E6AP catalytic center, thereby stimulating E6AP ubiquitin ligase activity and facilitating ubiquitin transfer onto p53. Crosslinking mass spectrometry of full-length E6AP-E6-p53 complex; functional ubiquitination assays Nature communications High 30361475
2018 UBE3A ubiquitinates p18/LAMTOR1 (a subunit of the Ragulator complex), targeting it for proteasomal degradation. UBE3A deficiency increases lysosomal localization of p18 and elevates mTORC1 activity. p18 knockdown in AS mice reduces mTORC1 activity and restores dendritic spine maturation, LTP, and learning. In vitro ubiquitination assay; Co-IP; biochemical measurement of mTORC1 signaling in AS mouse hippocampus; in vivo p18 knockdown rescue eLife Medium 30020076
2019 The two major UBE3A isoforms have distinct subcellular localizations: one is predominantly nuclear, one is predominantly cytoplasmic. Both undergo nuclear import via direct binding to PSMD4 (RPN10/S5A), but the N-terminus of the cytoplasmic isoform prevents nuclear retention. Mice lacking only the nuclear isoform recapitulate AS behavioral and electrophysiological phenotypes; mice lacking only the cytosolic isoform are unaffected. Several AS-associated missense mutations interfere with nuclear targeting or retention. Subcellular fractionation; direct binding assays (Co-IP with PSMD4); isoform-specific conditional knockout mice; behavioral and EEG phenotyping; analysis of AS patient mutations Nature neuroscience High 31235931
2019 UBE3A ubiquitinates PTPA (an activator of PP2A), promoting its degradation. Loss of maternal Ube3a increases PTPA, promotes PP2A holoenzyme assembly, and elevates PP2A activity. Reducing PTPA or pharmacologically inhibiting PP2A restores dendritic spine maturation and rescues motor impairment in AS mice. SILAC-based ubiquitination assay; Co-IP; PP2A activity measurement; in vivo rescue in AS mice by PTPA knockdown and PP2A inhibitor (LB-100) Proceedings of the National Academy of Sciences of the United States of America Medium 31160454
2019 UBE3A interacts with IRF (interferon regulatory factor) and enhances IRF-dependent transcription in neurons, indicating a nuclear transcriptional regulatory function in addition to its ubiquitin ligase role. Genome-wide transcriptome in UBE3A-deficient AS mice showed enrichment of IRF-downstream genes. Transcriptome analysis (RNA-seq) of UBE3A-deficient AS mouse brain; in vitro biochemical interaction assay between UBE3A and IRF; transcriptional reporter assay Human molecular genetics Low 30690483
2019 Transketolase (TKT), nuclear-enriched, is a novel direct UBE3A substrate identified by proteomics and elevated in AS model neuronal nuclei. Cross-species proteomic comparison using SILAC; direct UBE3A substrate ubiquitination assay validation; confirmation in AS rat brain and human iPSC-derived neurons Molecular psychiatry Medium 35264729
2015 The Ube3a ubiquitin ligase interacts with circadian clock components BMAL1 and BMAL2 and modulates BMAL1 turnover; inactivation of Ube3a elevates BMAL1 levels in brain regions controlling circadian behavior in AS model mice. Co-immunoprecipitation of Ube3a with BMAL1/BMAL2; measurement of BMAL1 protein levels in Ube3a-deficient brain; circadian behavioral phenotyping in AS mice Current biology : CB Medium 25660546
2011 E6-AP facilitates ERα-mediated transcription at estrogen-responsive promoters by recruiting histone acetyltransferase p300 and other chromatin-modifying enzymes; E6-AP knockdown reduces p300 recruitment and histone acetylation at the pS2 promoter. Chromatin immunoprecipitation (ChIP) under E6-AP knockdown conditions; measurement of ERα target gene mRNA levels Steroids Low 21530567
2011 UBE3A acts as a transcriptional regulator of MC1R: UBE3A is physically associated with the Mc1r promoter (by ChIP) and induces MC1R promoter activity, requiring the E-box/SP1 element. Ube3a-null mice show reduced MC1R expression and relative skin hypopigmentation. Luciferase reporter assay; chromatin immunoprecipitation (ChIP); analysis of Ube3a-null mice for MC1R expression and pigmentation Pigment cell & melanoma research Low 21733131
2015 CSN6 (COP9 signalosome subunit 6) associates with E6AP and stabilizes E6AP expression by reducing E6AP poly-ubiquitination, thereby regulating E6AP-mediated p53 degradation in cervical cancer. CSN6-E6AP axis is regulated by EGF/Akt signaling. Co-immunoprecipitation; ubiquitination assay; measurement of E6AP protein levels upon CSN6 manipulation; xenograft tumor growth assay Oncotarget Low 26318036
2019 DDI1 is a direct UBE3A substrate: UBE3A-dependent ubiquitination sites and ubiquitin chain types on DDI1 were mapped, and a specific deubiquitinating enzyme that reverses UBE3A-mediated DDI1 ubiquitination was identified. Mass spectrometry-based ubiquitination site mapping; identification of chain types; deubiquitinase identification Frontiers in physiology Medium 31130875
2020 Human UBE3A predominantly localizes to the nucleus in neurons. Isoform 1 accounts for most UBE3A protein; neurons lacking isoform 1 display a less severe AS electrophysiological phenotype. Cytoplasmic localization of hUBE3A-Iso2 results from inclusion of an in-frame exon unique to primates, while hUBE3A-Iso3 localizes to the nucleus due to a single amino-acid deletion homologous to the cytosolic mouse isoform. CRISPR/Cas9-generated isogenic isoform-null hESC lines; subcellular fractionation and immunofluorescence; electrophysiology; RNA-seq of human brain Human molecular genetics Medium 32833011 32879944
2021 PEG10, a retrotransposon-derived protein, is a UBE3A substrate: PEG10 protein (but not RNA) increase in Angelman syndrome neurons is dependent on UBE3A and proteasome function. PEG10 binds RNA and ataxia-associated proteins, localizes to stress granules, is secreted in extracellular vesicles, and its overexpression during mouse brain development alters neuronal migration. Unbiased proteomics in AS patient-derived neurons with reciprocal UBE3A modulation by ASO; proteasome inhibitor assay; co-IP with ATXN2/ATXN10; extracellular vesicle analysis; in vivo overexpression in mouse brain Cell reports. Medicine Medium 34467244
2021 Direct ubiquitination of Ephexin5 by UBE3A was demonstrated; deletion of Ephexin5 in AS mice rescues hippocampus-dependent behaviors, CA1 electrophysiology, and dendritic spine deficits, identifying Ephexin5 as a key UBE3A substrate driving hippocampal dysfunction in AS. In vitro ubiquitination assay; genetic epistasis (Ephexin5 knockout crossed to AS mouse model); behavioral, electrophysiological, and morphological rescue experiments Scientific reports Medium 34593829
2021 Identification of numerous gain-of-function UBE3A variants; Q588E hyperactivating mutation strikingly increases UBE3A activity. Q588 forms a regulatory site conserved among HECT domain ubiquitin ligases. Mice carrying Q588E show motor and communication deficits distinct from AS model mice. Large-scale functional variant screen (in vitro ubiquitination activity assay for many variants); mutagenesis; behavioral phenotyping of Q588E knockin mice; structure-function analysis Nature communications High 34815418
2012 The antisense Ube3a-ATS transcript (RNAPII-transcribed, non-polyadenylated, nuclear, short half-life ~4 h) represses Ube3a on the paternal chromosome in cis. Premature termination of Ube3a-ATS or insertion of a transcriptional termination cassette activates paternal Ube3a expression in neurons. Mouse genetic models with targeted deletion of Snrpn promoter and insertion of termination cassette; strand-specific microarray; cell culture ES differentiation model Human molecular genetics Medium 22493002
2019 A bipartite boundary element restricts UBE3A imprinting to mature neurons: CRISPR/Cas9 deletion of this element leads to up-regulation of UBE3A-ATS and, when combined with increased UBE3A-ATS levels, full repression of paternal UBE3A, demonstrating that both loss of boundary element function and elevated UBE3A-ATS are required for paternal silencing. CRISPR/Cas9 genome editing in human iPSC-derived neurons; allele-specific expression analysis Proceedings of the National Academy of Sciences of the United States of America Medium 30674673
2013 Genetic epistasis using truncation of Ube3a-ATS (via poly(A) cassette insertion) activates paternal Ube3a in the mouse brain and rescues motor coordination, cognitive deficits, and impaired LTP in AS mice, demonstrating that transcriptional collision between sense and antisense polymerases suppresses paternal Ube3a elongation. Knock-in mouse model with poly(A) cassette insertion; allele-specific Ube3a expression measurement; behavioral and electrophysiological phenotyping PLoS genetics Medium 24385930

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 2054 8221889
1997 UBE3A/E6-AP mutations cause Angelman syndrome. Nature genetics 1026 8988171
1995 A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proceedings of the National Academy of Sciences of the United States of America 713 7708685
1997 De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nature genetics 698 8988172
2010 The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 514 20211139
1997 Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nature genetics 415 9288101
1999 The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. Molecular and cellular biology 364 9891052
2004 Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Human molecular genetics 300 15615769
2011 Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Science translational medicine 225 21974935
2004 Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex. Genes & development 211 15371341
2002 Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. Neurobiology of disease 194 11895368
2015 Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model. The Journal of clinical investigation 191 25866966
2012 Ube3a-ATS is an atypical RNA polymerase II transcript that represses the paternal expression of Ube3a. Human molecular genetics 160 22493002
2015 An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A. Cell 136 26255772
2020 Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA. Nature 135 33087932
2013 Truncation of Ube3a-ATS unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model. PLoS genetics 134 24385930
2017 Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1. Nature 121 28297715
1998 Mutation analysis of UBE3A in Angelman syndrome patients. American journal of human genetics 112 9585605
2014 Allelic specificity of Ube3a expression in the mouse brain during postnatal development. The Journal of comparative neurology 111 24254964
2015 UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis. Cell reports 107 26166566
1998 The ubiquitin-protein ligase E6-associated protein (E6-AP) serves as its own substrate. European journal of biochemistry 107 9688277
2015 Epigenetic regulation of UBE3A and roles in human neurodevelopmental disorders. Epigenomics 99 26585570
1997 The E6-Ap ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region. Genome research 99 9110176
2008 E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors. Nuclear receptor signaling 93 18432313
2012 Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Molecular and cellular biology 88 22645313
2015 A coding-independent function of an alternative Ube3a transcript during neuronal development. Nature neuroscience 86 25867122
2010 Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome. Proceedings of the National Academy of Sciences of the United States of America 81 20351251
1998 Ubiquitin, E6-AP, and their role in p53 inactivation. Pharmacology & therapeutics 80 9690814
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2008 E6-AP promotes misfolded polyglutamine proteins for proteasomal degradation and suppresses polyglutamine protein aggregation and toxicity. The Journal of biological chemistry 77 18201976
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2023 An ASO therapy for Angelman syndrome that targets an evolutionarily conserved region at the start of the UBE3A-AS transcript. Science translational medicine 73 36947593
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2017 The Autism Protein Ube3A/E6AP Remodels Neuronal Dendritic Arborization via Caspase-Dependent Microtubule Destabilization. The Journal of neuroscience : the official journal of the Society for Neuroscience 59 29175955
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2006 Association of E6AP (UBE3A) with human papillomavirus type 11 E6 protein. Virology 58 17023019
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2018 UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity. eLife 50 30020076
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2019 UBE3A regulates the transcription of IRF, an antiviral immunity. Human molecular genetics 15 30690483
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