Affinage

UBE3A

Ubiquitin-protein ligase E3A · UniProt Q05086

Length
875 aa
Mass
100.7 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBE3A encodes E6-AP, a HECT-domain E3 ubiquitin ligase that serves as a master regulator of neuronal development, synaptic plasticity, and protein homeostasis, with loss-of-function mutations causing Angelman syndrome and gain-of-function variants linked to autism spectrum disorder (PMID:8988171, PMID:26255772, PMID:34815418). In neurons, UBE3A is subject to brain-specific genomic imprinting with maternal-only expression enforced by transcriptional collision between the sense transcript and the long noncoding antisense transcript UBE3A-ATS, which is restricted to neurons by a bipartite boundary element (PMID:24385930, PMID:30674673). The catalytically active enzyme functions as a Phe727-dependent trimer whose activity is negatively regulated by PKA phosphorylation at T485; it is predominantly nuclear in mature neurons through PSMD4/RPN10-mediated import, and nuclear UBE3A is both necessary and sufficient for normal neuronal function (PMID:24273172, PMID:26255772, PMID:31235931). UBE3A ubiquitinates diverse neuronal substrates—including Arc, SK2, Ephexin5, p18/LAMTOR1, PTPA, XIAP, and PEG10—to control AMPA receptor trafficking, NMDA receptor-dependent plasticity, mTORC1 signaling, PP2A activity, caspase-mediated dendritic remodeling, and Golgi acidification, while also functioning as a transcriptional coactivator and epigenomic regulator (PMID:20211139, PMID:26166566, PMID:30020076, PMID:31160454, PMID:29175955, PMID:23447592, PMID:21733131, PMID:28925810).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 High

    Establishing that UBE3A is a ubiquitin ligase whose loss causes Angelman syndrome linked the ubiquitin-proteasome system to a specific neurodevelopmental disorder for the first time.

    Evidence Mutation screening (sequencing, SSCP) of AS patients identifying frameshift and splice-site mutations in UBE3A, contextualized by its known HECT-domain ligase activity

    PMID:8988171

    Open questions at the time
    • No neuronal substrates identified
    • Imprinting mechanism not yet elucidated
    • No structure-function analysis of disease mutations
  2. 2004 High

    Discovery that the E6/E6-AP complex ubiquitinates the telomerase repressor NFX1-91 expanded UBE3A's substrate repertoire beyond p53 and demonstrated its role in HPV-mediated telomerase activation.

    Evidence Yeast two-hybrid screen, in vitro ubiquitination of NFX1-91, shRNA knockdown of E6-AP with hTERT promoter readout

    PMID:15371341

    Open questions at the time
    • Relevance to neuronal UBE3A function unclear
    • No in vivo validation of NFX1-91 as substrate
  3. 2006 High

    Defining the LXXLL motif as the universal E6-E6AP interaction interface and showing E6-AP requirement for Scribble/Dlg degradation clarified how HPV E6 proteins co-opt UBE3A to degrade tumor suppressors.

    Evidence RNAi and E6-AP-knockout MEFs; mutagenesis of LXXLL motif; in vivo Scribble degradation assays

    PMID:17023019 PMID:17085449

    Open questions at the time
    • LXXLL motif function in E6-independent neuronal context not addressed
    • No structural detail of the E6-E6AP interface
  4. 2009 High

    Identification of p27 and alpha-synuclein as UBE3A substrates extended its roles to cell cycle control and neurodegenerative protein clearance.

    Evidence In vitro ubiquitination and co-IP for both substrates; p27 elevation in Ube3a-maternal-deficient mouse brain; alpha-synuclein colocalization in Lewy bodies

    PMID:19591933 PMID:19645749

    Open questions at the time
    • Alpha-synuclein as substrate is from a single lab (medium confidence)
    • Physiological relevance of p27 regulation in postmitotic neurons unclear
  5. 2010 High

    Demonstrating that UBE3A ubiquitinates Arc to control AMPA receptor surface expression provided the first mechanistic link between UBE3A loss and excitatory synaptic dysfunction in Angelman syndrome.

    Evidence In vitro ubiquitination assay, co-IP, shRNA knockdown in neurons with synaptic AMPA receptor quantification

    PMID:20211139

    Open questions at the time
    • Whether Arc is the primary driver of AS synaptic phenotype versus other substrates
    • No assessment of Arc ubiquitination chain type
  6. 2011 High

    Three parallel advances established the imprinting mechanism and dosage sensitivity: topoisomerase inhibitors unsilence paternal Ube3a by suppressing Ube3a-ATS; Ube3a triplication suppresses glutamatergic transmission causing autism-like phenotypes; and UBE3A acts as a transcriptional coactivator at the MC1R promoter.

    Evidence High-content drug screen with in vivo replication (topotecan); BAC transgenic dosage mice with electrophysiology; ChIP and luciferase reporter assays at Mc1r promoter

    PMID:21733131 PMID:21974935 PMID:22190039

    Open questions at the time
    • Transcriptional coactivator function mechanism (ubiquitin-dependent or independent?) unresolved
    • Glutamatergic synapse substrates in overexpression model not identified
  7. 2012 High

    Proteomic mapping revealed UBE3A exists in multiple distinct complexes—a proteasome-associated complex and a HERC2/NEURL4/MAPK6 complex—establishing that UBE3A operates in separable biochemical contexts.

    Evidence Mass spectrometry-based proteomics with reciprocal co-IP validation and siRNA functional assays

    PMID:22645313

    Open questions at the time
    • Function of the HERC2/NEURL4/MAPK6 complex in neurons not defined
    • Whether HERC2 modulation of E6AP activity occurs in vivo in brain
  8. 2013 High

    A cluster of discoveries in 2013 resolved the imprinting mechanism (transcriptional collision via Ube3a-ATS with R-loop involvement), the oligomeric state of active UBE3A (Phe727-dependent trimer), and two new cellular functions (Golgi acidification/sialylation and polarized dendrite morphogenesis).

    Evidence Poly(A) knock-in mice showing transcriptional collision; R-loop DRIP at Snord116; in vitro activity assays with F727 mutagenesis; Golgi pH measurement and EM in AS neurons; shRNA with isoform-specific rescue of dendritic polarity

    PMID:23283345 PMID:23447592 PMID:23918391 PMID:24273172 PMID:24385930

    Open questions at the time
    • How UBE3A regulates Golgi pH (direct substrate unknown)
    • Trimer structure not solved at atomic resolution
    • Rpn10 as Drosophila substrate not yet confirmed in mammalian neurons
  9. 2015 High

    Discovery that PKA phosphorylation at T485 inhibits UBE3A activity, and that an autism-linked mutation abolishing this site causes hyperactivity and excess spine growth, established a direct regulatory switch connecting kinase signaling to UBE3A dosage-sensitive pathology; concurrently, SK2 was identified as a substrate controlling NMDA receptor-dependent plasticity.

    Evidence In vitro kinase assay, phospho-site mutagenesis, patient-derived cell assays, in vivo spine counting; SK2 ubiquitination in vitro with pharmacological rescue in AS mice

    PMID:26166566 PMID:26255772

    Open questions at the time
    • Upstream signals controlling PKA-UBE3A axis in neurons not mapped
    • Whether SK2 ubiquitination is T485-dependent
  10. 2015 High

    An alternative Ube3a transcript (Ube3a1) was shown to function as a coding-independent competing endogenous RNA that sequesters miR-134 to control dendrite growth and spine maturation, revealing a non-enzymatic gene function.

    Evidence Coding sequence replacement experiments in rat hippocampal neurons; miR-134 knockout epistasis

    PMID:25867122

    Open questions at the time
    • Relative contribution of Ube3a1 ceRNA function versus E3 ligase activity to AS phenotypes
    • Whether this mechanism is conserved in human neurons
  11. 2016 High

    Nuclear UBE3A overexpression was shown to downregulate Cbln1 in VTA glutamatergic neurons causing sociability deficits, directly connecting UBE3A gain-of-function to autism-relevant circuit dysfunction; separately, Drosophila Ube3a was shown to ubiquitinate BMP receptor Tkv at K227 to control synapse development.

    Evidence Conditional Ube3a overexpression with Cbln1 viral rescue and DREADD activation; in vivo Drosophila genetics with site-directed mutagenesis of Tkv K227

    PMID:27232889 PMID:28297715

    Open questions at the time
    • Whether Cbln1 is a direct UBE3A substrate or indirectly regulated
    • Conservation of Tkv/BMP receptor ubiquitination in mammalian neurons
  12. 2017 High

    UBE3A was shown to ubiquitinate XIAP, triggering a caspase-3-microtubule cleavage cascade that remodels dendritic arbors, providing a mechanism by which UBE3A overexpression causes dendritic retraction in autism models.

    Evidence XIAP ubiquitination assay, caspase-3 activation measurement, tubulin cleavage assay in primary neurons and 2X Ube3a mouse model

    PMID:29175955

    Open questions at the time
    • Whether XIAP degradation is relevant to UBE3A loss-of-function (AS) phenotypes
    • Specificity of caspase-3 activation to dendrite pruning versus apoptosis
  13. 2018 High

    Two advances deepened mechanistic understanding: cross-linking MS revealed how HPV E6 binding repositions substrates near UBE3A's catalytic center, and p18/LAMTOR1 was identified as a UBE3A substrate linking its loss to hyperactive mTORC1 signaling and impaired synaptic plasticity in AS.

    Evidence XL-MS of full-length E6AP-E6-p53 complex; in vitro ubiquitination of p18, lysosomal fractionation, mTORC1 assay, and in vivo p18 knockdown rescue of LTP

    PMID:30020076 PMID:30361475

    Open questions at the time
    • Whether E6-induced conformational changes apply to E6-independent substrates
    • Other mTORC1-independent mechanisms downstream of p18 accumulation
  14. 2019 High

    Nuclear UBE3A was demonstrated to be both necessary and sufficient for neuronal function: PSMD4-mediated nuclear import distinguishes isoforms, and mice lacking only nuclear UBE3A fully recapitulate AS; a bipartite boundary element restricting UBE3A-ATS to neurons was also defined; and PTPA ubiquitination linked UBE3A to PP2A regulation with in vivo rescue.

    Evidence Isoform-specific conditional KO mice with PSMD4 co-IP; CRISPR deletion of boundary element in iPSC-derived neurons; SILAM proteomics identifying PTPA, with PP2A inhibition rescuing AS deficits in vivo

    PMID:30674673 PMID:31160454 PMID:31235931

    Open questions at the time
    • Nuclear substrates responsible for AS phenotypes not fully catalogued
    • Whether PSMD4 interaction requires UBE3A ligase activity
    • PP2A regulation in different neuronal subtypes not examined
  15. 2020 High

    PEG10, a retrotransposon-derived protein, was identified as a UBE3A-regulated target whose reduction phenocopies UBE3A reinstatement transcriptomically, suggesting PEG10 mediates a significant portion of UBE3A's downstream gene expression effects; human isoform-specific nuclear localization mechanisms were also clarified.

    Evidence Unbiased proteomics in AS patient-derived neurons with ASO-mediated UBE3A modulation; CRISPR isoform-knockout hESCs differentiated to neurons with subcellular fractionation

    PMID:32879944 PMID:34467244

    Open questions at the time
    • Whether PEG10 is a direct UBE3A ubiquitination substrate or indirectly regulated
    • Functional consequences of PEG10 accumulation in AS neurons beyond transcriptome
  16. 2021 High

    Ephexin5 was validated as a direct UBE3A substrate whose genetic deletion rescues hippocampal deficits in AS mice, establishing pathway-specific therapeutic relevance; large-scale variant screening identified Q588E as a hyperactivating mutation at a conserved HECT regulatory site.

    Evidence In vitro Ephexin5 ubiquitylation with genetic epistasis rescue in AS mice; large-scale activity screen with Q588E knock-in mouse behavioral phenotyping

    PMID:34593829 PMID:34815418

    Open questions at the time
    • How Ephexin5 specifically drives hippocampal versus other regional phenotypes
    • Structural basis of Q588-mediated regulation
  17. 2023 High

    A T485A gain-of-function knock-in mouse revealed that UBE3A hyperactivity acts in neural progenitors and glia regardless of imprinting status, with parent-of-origin-dependent effects in neurons, and transiently expands specific interneuron populations.

    Evidence Mouse knock-in of T503A (murine T485A equivalent); parent-of-origin behavioral testing; interneuron lineage tracing

    PMID:37389991

    Open questions at the time
    • Substrates mediating interneuron expansion not identified
    • Whether gain-of-function effects in glia contribute to ASD phenotypes

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the identity of nuclear UBE3A substrates that drive AS core phenotypes; the structural basis of the UBE3A trimer at atomic resolution; how UBE3A regulates Golgi pH; and whether substrate-specific therapeutic strategies can separately address loss-of-function (AS) and gain-of-function (ASD) pathologies.
  • No atomic-resolution structure of UBE3A trimer
  • Golgi pH regulation substrate unknown
  • Therapeutic substrate hierarchy not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 10 R-HSA-112316 Neuronal System 7 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-4839726 Chromatin organization 1
Partners
ARCCSN6HERC2HIF1ANMAPK6NEURL4PSMD4PTPA
Complex memberships
E6-E6AP complexHERC2-NEURL4-MAPK6 complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 UBE3A/E6-AP encodes a ubiquitin-protein ligase whose loss-of-function mutations (frameshift, splice-site) cause Angelman syndrome, establishing that UBE3A functions in ubiquitin-mediated protein degradation during brain development. Mutation analysis (sequencing, SSCP) of AS patients; functional prediction based on known HECT-domain ligase activity Nature genetics High 8988171
2010 UBE3A ubiquitinates Arc, a synaptic protein that promotes AMPA receptor internalization, thereby controlling the degradation of Arc and regulating excitatory synapse development; loss of UBE3A increases Arc expression and decreases synaptic AMPA receptor number. Co-immunoprecipitation, in vitro ubiquitination assay, shRNA knockdown in neurons, immunostaining of synaptic AMPA receptors, neuronal activity induction experiments Cell High 20211139
2011 Topoisomerase I and II inhibitors (e.g., topotecan) unsilence the paternal Ube3a allele in neurons by reducing transcription of the Ube3a antisense transcript (Ube3a-ATS) in cis, restoring catalytically active UBE3A protein. Unbiased high-content drug screen in primary cortical neurons; allele-specific expression assays; in vivo topotecan administration in mice Nature High 22190039
2011 Tripling the dosage of Ube3a in mice suppresses glutamatergic (but not GABAergic) synaptic transmission by reducing presynaptic release probability, synaptic glutamate concentration, and postsynaptic action potential coupling, reconstituting autism-like behavioral traits. Bacterial artificial chromosome transgenic mice with defined Ube3a copy number; electrophysiological recordings; behavioral assays Science translational medicine High 21974935
2013 Premature termination of the Ube3a antisense transcript (Ube3a-ATS) by poly(A) cassette insertion reactivates expression of Ube3a from the paternal chromosome, with the imprinting mechanism involving biallelic transcription initiation but suppressed elongation of paternal Ube3a through transcriptional collision between sense and antisense polymerases. Poly(A) cassette insertion knock-in mice; allele-specific RT-PCR; behavioral and LTP rescue experiments PLoS genetics High 24385930
2013 R-loop formation at the paternally expressed Snord116 locus mediates topotecan-induced inhibition of Ube3a-ATS expression, demonstrating that topotecan unsilences paternal Ube3a primarily via stabilizing RNA:DNA hybrids at G-skewed repeat elements within Snord116, leading to chromatin decondensation. Bisulfite sequencing, R-loop immunoprecipitation (DRIP), chromatin decondensation assays, neural precursor cells from paternal Snord116 deletion mice Proceedings of the National Academy of Sciences of the United States of America High 23918391
2013 Drosophila Ube3a (ortholog of human UBE3A) directly ubiquitinates three proteasome-related proteins (Rpn10, Uch-L5, CG8209) and the ribosomal protein Rps10b; only Rpn10 is targeted for degradation upon ubiquitination, indicating non-degradative roles. Genetic interaction between Ube3a and Rpn10 was confirmed in vivo. In vitro ubiquitination assays in neuronal cells; mass spectrometry substrate screen; Drosophila genetic interaction (overexpression epistasis); ubiquitinated protein accumulation assays Cellular and molecular life sciences : CMLS Medium 24292889
2013 Ube3a is required for polarized dendrite morphogenesis in pyramidal neurons; knockdown selectively inhibits apical dendrite outgrowth and disrupts the polarized distribution of the Golgi apparatus, blocking Reelin-induced rapid Golgi deployment into dendrites. shRNA knockdown in vivo and in vitro; rescue with specific Ube3a isoform 2; Golgi localization immunostaining; AS mouse model cortical analysis The Journal of neuroscience : the official journal of the Society for Neuroscience High 23283345
2013 Loss of Ube3a causes severe under-acidification (elevated pH) and structural swelling of the Golgi apparatus in neurons, leading to markedly reduced protein sialylation—a process dependent on intralumenal Golgi pH. Golgi pH measurement in Ube3a knockdown cell lines and AS mice cortical neurons; electron microscopy of Golgi structure; lectin blotting for sialylation The Journal of neuroscience : the official journal of the Society for Neuroscience High 23447592
2013 Active E6AP/UBE3A is an oligomer (proposed trimer); Phe727-dependent trimer formation is critical for catalytic activity (mutation reduces kcat 62-fold without affecting E2-ubiquitin binding or thioester formation), and HPV E6 promotes trimer formation through E6 homodimerization to enhance E6AP activity. 125I-polyubiquitin chain formation assays; biophysical characterization; site-directed mutagenesis of Phe727; small molecule antagonist studies; recombinant E6 protein complementation The Journal of biological chemistry High 24273172
2015 PKA phosphorylates UBE3A at residue T485 (outside the catalytic domain) and inhibits its 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 and in patient-derived cells, and excessive dendritic spine development in the brain. In vitro kinase assay; phosphorylation site mutagenesis; patient-derived cell substrate turnover assays; in vivo dendritic spine counting in mutant mice Cell High 26255772
2015 UBE3A directly ubiquitinates SK2 (small-conductance Ca2+-activated K+ channel) in its C-terminal domain, facilitating SK2 endocytosis; in UBE3A-deficient mice, increased postsynaptic SK2 levels reduce NMDA receptor activation and impair hippocampal long-term synaptic plasticity and fear conditioning memory. Co-immunoprecipitation; in vitro ubiquitination assay; SK2 endocytosis assay; electrophysiology in AS mice; pharmacological SK2 blockade rescue Cell reports High 26166566
2015 An alternative Ube3a transcript (Ube3a1 RNA), encoding a truncated catalytically inactive protein, functions in a coding-independent manner through its unique 3' UTR and the microRNA pathway to prevent exuberant dendrite growth and promote spine maturation; it acts as a competing endogenous RNA to suppress miR-134 activity. shRNA knockdown of Ube3a1 in rat hippocampal neurons; coding sequence replacement experiments; miR-134 activity assays; miR-134 knockout mouse epistasis Nature neuroscience High 25867122
2012 UBE3A/E6AP exists as part of multiple distinct protein complexes: the proteasome and an independent high-molecular-weight complex containing HERC2, NEURL4, and MAPK6; new interacting partners HIF1AN, NEURL4, and MAPK6 were identified. HERC2 modulates E6AP ubiquitin ligase activity. UBE3C (not E6AP) contributes to proteasomal processivity. Mass spectrometry-based proteomics; reciprocal co-immunoprecipitation validation; siRNA knockdown functional assays Molecular and cellular biology High 22645313
2016 Increasing UBE3A in the nucleus downregulates the glutamatergic synapse organizer Cbln1, impairing sociability in mice; this effect maps to VTA glutamatergic neurons where Cbln1 deletion impairs sociability and weakens glutamatergic transmission. Viral-vector chemogenetic activation or restoration of Cbln1 in VTA glutamatergic neurons reverses the sociability deficits. In vivo mouse genetics (conditional Ube3a overexpression); viral vector delivery of Cbln1; DREADD-based chemogenetic activation; electrophysiology of VTA synapses Nature High 28297715
2016 Drosophila Ube3a specifically ubiquitinates lysine 227 within the cytoplasmic tail of the BMP type I receptor Thickveins (Tkv) and promotes its proteasomal degradation, thereby negatively regulating BMP signaling and controlling NMJ synapse development and endocytosis. In vivo Drosophila genetics (ube3a mutants); immunochemistry; Schneider 2 cell ubiquitination assay; site-directed mutagenesis of Tkv K227; mammalian cell conservation experiment PLoS genetics High 27232889
2017 UBE3A/E6AP ubiquitinates XIAP (X-linked inhibitor of apoptosis protein), leading to its degradation, subsequent caspase-3 activation, and microtubule cleavage, which causes retraction-based remodeling of dendritic arborization in neurons. Overexpression experiments in primary cultured neurons; ubiquitination assay of XIAP by E6AP; caspase-3 activation measurement; tubulin cleavage assay; Ube3A 2X ASD mouse model validation The Journal of neuroscience : the official journal of the Society for Neuroscience High 29175955
2009 E6-AP/UBE3A interacts with and directly ubiquitinates the cyclin-dependent kinase inhibitor p27 in vitro, promoting proteasome-mediated degradation of p27; partial knockdown of E6-AP increases p27 levels and causes cell cycle arrest. Co-immunoprecipitation; in vitro ubiquitination assay; E6-AP siRNA knockdown with p27 measurement; E6-AP maternal-deficient mouse brain p27 levels Neurobiology of disease High 19591933
2009 E6-AP/UBE3A promotes proteasome-dependent degradation of both wild-type and mutant forms of alpha-synuclein, including toxic oligomeric forms; E6-AP is a component of Lewy bodies and colocalizes with alpha-synuclein in juxtanuclear aggregates and at the centrosome upon proteasome inhibition. Co-immunoprecipitation; overexpression degradation assay; immunofluorescence colocalization; immunohistochemistry of post-mortem PD brain Journal of neurochemistry Medium 19645749
2018 UBE3A/E6AP ubiquitinates p18/LAMTOR1, a subunit of the Ragulator complex, leading to its proteasomal degradation and thereby regulating mTORC1 activity; UBE3A deficiency in AS mice increases lysosomal p18 levels and Ragulator-Rag complex localization, elevating mTORC1 activity and impairing synaptic plasticity. In vitro ubiquitination assay; co-immunoprecipitation; lysosomal fractionation; mTORC1 activity measurement in AS mice hippocampus; in vivo p18 knockdown rescue of LTP and learning eLife High 30020076
2019 UBE3A directly ubiquitinates PTPA (an activator of PP2A), leading to its degradation; Ube3a maternal deficiency increases PTPA level, promotes PP2A holoenzyme assembly, and elevates PP2A activity, causing dendritic spine maturation defects. PP2A inhibition or PTPA knockdown rescues synaptic and motor deficits in AS mice. Stable-isotope labeling (SILAM) proteomics; in vitro ubiquitination assay; PP2A activity assay; conditional knockdown in AS mice; pharmacological PP2A inhibition rescue Proceedings of the National Academy of Sciences of the United States of America High 31160454
2019 Two major UBE3A isoforms have distinct nuclear versus cytoplasmic subcellular localization; both undergo nuclear import through direct binding to PSMD4/S5A/RPN10, but the amino terminus of the cytoplasmic isoform prevents nuclear retention. Mice lacking only the nuclear UBE3A isoform recapitulate AS behavioral and electrophysiological phenotypes, while mice lacking only the cytosolic isoform are unaffected. AS-associated UBE3A missense mutations interfere with nuclear targeting or nuclear retention. Isoform-specific conditional knockout mice; subcellular fractionation; co-immunoprecipitation of isoforms with PSMD4; behavioral phenotyping; electrophysiology; mutant AS isoform localization assays Nature neuroscience High 31235931
2018 Cross-linking mass spectrometry demonstrates that binding of HPV E6 to E6AP induces conformational rearrangements in E6AP, repositioning E6 and p53 near the catalytic center of E6AP, mechanistically explaining how E6 stimulates E6AP ubiquitin ligase activity while facilitating ubiquitin transfer onto p53. Cross-linking mass spectrometry (XL-MS) with multiple cross-linking approaches; functional ubiquitination assays with full-length E6AP-E6-p53 complex Nature communications High 30361475
2004 The E6/E6-AP complex is required for E6-mediated telomerase induction; it targets NFX1-91 (a telomerase repressor) for ubiquitination and degradation, thereby derepressing the hTERT promoter. NFX1-123 isoform coactivates hTERT with c-Myc. shRNA knockdown of E6-AP; yeast two-hybrid screen for E6/E6-AP targets; ubiquitination assay of NFX1-91; shRNA knockdown of NFX1-91 with hTERT promoter activity assay Genes & development High 15371341
2006 E6-mediated degradation of the PDZ-domain protein Scribble (and Dlg) requires functional E6-AP in cells; an LXXLL peptide motif on E6-AP is required for both high-risk and low-risk HPV E6 protein association, establishing a common E6-E6AP interaction mechanism for E6 proteins. RNA interference in cell lines; mouse embryo fibroblasts from E6-AP-deficient mice; in vivo degradation assays; mutation of LXXLL motif The Journal of biological chemistry / Virology High 17023019 17085449
2020 UBE3A-dependent regulation of PEG10, a retrotransposon-derived GAG protein, is controlled at the protein (not RNA) level through the ubiquitin-proteasome system; PEG10 binds ATXN2/ATXN10 and RNA, localizes to stress granules, and is secreted in extracellular vesicles. PEG10 reduction in AS patient neurons mimics transcriptome changes caused by UBE3A reinstatement. Unbiased proteomics in AS patient-derived neurons with ASO modulation of UBE3A; proteasome inhibitor studies; co-immunoprecipitation; stress granule localization; extracellular vesicle analysis; mouse brain PEG10 overexpression neuronal migration assay Cell reports. Medicine High 34467244
2021 Ephexin5 is directly ubiquitylated by UBE3A; deletion of Ephexin5 from AS mice specifically rescues hippocampus-dependent behaviors, CA1 physiology, and dendritic spine deficits, identifying Ephexin5 as a key driver of hippocampal dysfunction downstream of UBE3A loss. Direct in vitro ubiquitylation assay; genetic deletion of Ephexin5 in AS mice; hippocampal electrophysiology; spine density quantification; fear conditioning behavior Scientific reports High 34593829
2011 UBE3A acts as a transcriptional coactivator of MC1R; UBE3A is physically associated with the Mc1r promoter (ChIP assay) and induces MC1R promoter activity through an E-box/SP1 element, contributing to hypopigmentation in Angelman syndrome when UBE3A is absent. Luciferase reporter assay; chromatin immunoprecipitation (ChIP); promoter deletion mapping; Ube3a-/- mouse skin phenotype analysis Pigment cell & melanoma research Medium 21733131
2017 UBE3A regulates imprinted gene networks and epigenome-wide marks in neurons; altering UBE3A levels affects DNA methylation of up to half of known imprinted genes and changes H2A.Z positioning through UBE3A's regulation of RING1B (which monoubiquitinates H2A.Z). siRNA knockdown of UBE3A in human neuroblastoma cell lines; genome-wide DNA methylation, H2A.Z ChIP-seq, H3K4me3 ChIP-seq, and RNA-seq Epigenetics Medium 28925810
2016 UBE3A protein is broadly distributed in neurons, with concentrations in axon terminals and euchromatin-rich nuclear domains, as determined by high-resolution light and electron microscopic immunocytochemistry, suggesting dual roles in local synaptic regulation and global gene transcription control. High-resolution immunocytochemistry (light and electron microscopy) in mouse brain neurons The Journal of comparative neurology Medium 27339004
2020 Human UBE3A predominantly localizes to the nucleus in neurons; conserved nuclear enrichment between humans and mice is achieved by distinct isoform-specific mechanisms: a single amino-acid deletion in the N-terminus of human hUBE3A-Iso3 (homologous to cytoplasmic mouse mUBE3A-Iso2) causes nuclear localization, and hUBE3A-Iso2 provides a small cytosolic pool. CRISPR/Cas9 isoform-knockout hESCs differentiated to neurons; subcellular fractionation; RNA-seq of human brain samples; evolutionary sequence analysis Human molecular genetics High 32879944
2015 CSN6 (COP9 signalosome subunit 6) associates with E6AP/UBE3A and stabilizes E6AP expression by reducing E6AP poly-ubiquitination, with the CSN6-E6AP axis regulated by EGF/Akt signaling. Co-immunoprecipitation; ubiquitination assay; EGF/Akt pathway perturbation; mouse xenograft tumor growth Oncotarget Medium 26318036
2022 Transketolase (TKT) is identified as a novel direct UBE3A substrate, with TKT elevated in neuronal nuclei of AS rat brain and human iPSC-derived neurons upon UBE3A loss; pathway analysis across AS mouse and rat models identifies proteasomal and tRNA synthetase pathways as consistently dysregulated from postnatal development. Quantitative mass spectrometry proteomics across developmental stages in AS mice and rats; UBE3A reinstatement experiments; direct substrate validation in human iPSC-derived neurons Molecular psychiatry Medium 35264729
2021 UBE3A ubiquitinates and degrades ZNF185, and loss of ZNF185 activates NOTCH signaling to promote esophageal cancer progression. Co-immunoprecipitation; ubiquitination assay; Western blot; xenograft mouse model International journal of biological sciences Low 34421347
2012 E6-AP/UBE3A coimmunoprecipitates with SOD1, promotes ubiquitination and degradation of mutant SOD1 proteins, and overexpression of E6-AP suppresses mutant SOD1 aggregation and cell death, with enhanced effect when co-expressed with Hsp70. Co-immunoprecipitation; ubiquitination assay; aggregation assay; cell death assay in SOD1 cell models Neurobiology of aging Medium 23040663
2021 Large-scale functional variant analysis identifies numerous gain-of-function UBE3A missense variants, including Q588E which markedly hyperactivates UBE3A; Q588 forms a regulatory site conserved among HECT domain ligases; mice carrying Q588E show motor and communication deficits distinct from Angelman syndrome. Large-scale in vitro ubiquitination activity screen; mouse knock-in of Q588E; behavioral phenotyping; structure-function analysis of Q588 regulatory site Nature communications High 34815418
2019 A bipartite boundary element restricts UBE3A-ATS expression and UBE3A imprinting to neurons; removal of this element by CRISPR/Cas9 upregulates UBE3A-ATS and, when combined with the resulting elevation in UBE3A-ATS, fully represses paternal UBE3A, demonstrating that UBE3A imprinting requires both loss of the boundary element function and upregulation of UBE3A-ATS. CRISPR/Cas9-mediated genome editing in human iPSC-derived neurons; allele-specific expression assays Proceedings of the National Academy of Sciences of the United States of America High 30674673
2019 DDI1 (a proteasome receptor) is a direct UBE3A substrate; specific ubiquitination sites and ubiquitin chain types on DDI1 were identified, and one deubiquitinating enzyme capable of reversing UBE3A action on DDI1 was found. In vitro ubiquitination assay; mass spectrometry identification of ubiquitination sites; deubiquitinase screen Frontiers in physiology Medium 31130875
2023 UBE3A T485A (T503A in mouse) gain-of-function mutation elevates UBE3A activity in neural progenitors and glial cells regardless of parent of origin; maternal expression additionally elevates activity in neurons. This promotes transient embryonic expansion of Zcchc12 lineage interneurons and behavioral phenotypes that differ by parent of origin. Mouse knock-in of T503A gain-of-function allele; behavioral testing by parent of origin; immunostaining of interneuron populations; allele-specific UBE3A activity measurement Cell reports High 37389991

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 UBE3A/E6-AP mutations cause Angelman syndrome. Nature genetics 1023 8988171
2010 The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 511 20211139
2012 Suppression of progenitor differentiation requires the long noncoding RNA ANCR. Genes & development 375 22302877
2004 Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Human molecular genetics 299 15615769
2011 Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 290 22190039
2016 The degradation of EZH2 mediated by lncRNA ANCR attenuated the invasion and metastasis of breast cancer. Cell death and differentiation 268 27716745
2011 Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Science translational medicine 224 21974935
2004 Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex. Genes & development 211 15371341
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