Affinage

UBE2D2

Ubiquitin-conjugating enzyme E2 D2 · UniProt P62837

Round 2 corrected
Length
147 aa
Mass
16.7 kDa
Annotated
2026-04-28
84 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBE2D2 (UbcH5B) is a broadly acting E2 ubiquitin-conjugating enzyme that partners with both RING-type and HECT-type E3 ligases to ubiquitinate diverse substrates, functioning in protein quality control, signal transduction, cell-cycle progression, receptor trafficking, and mitophagy. Its conserved UBC domain harbors a catalytic cysteine in a surface cleft that forms a thioester intermediate with ubiquitin; RING E3 binding (demonstrated with c-Cbl, cIAP1, APC11, MUL1, AO7/RNF25, and E4B) induces a closed E2~Ub conformation that primes ubiquitin transfer, while non-covalent ubiquitin binding to the E2 backside stimulates chain-building activity (PMID:30523153, PMID:26475854, PMID:39473070). UBE2D2 serves as the cognate E2 for Mdm2-dependent p53 degradation, E6AP/E6-mediated p53 ubiquitination, SCF(β-TrCP)-catalyzed IκBα ubiquitination, CHIP-mediated phospho-tau ubiquitination, c-Cbl-driven EGFR ubiquitination, and Parkin-dependent ubiquitination of mitochondrial outer membrane proteins during mitophagy (PMID:15280377, PMID:7724550, PMID:10918611, PMID:14612456, PMID:18508924, PMID:24906799). In RING E3 pathways UBE2D2 acts predominantly as a monoubiquitin-initiating E2, whereas it supports polyubiquitin chain elongation in HECT E3 pathways, and its essential cellular function in yeast maps to cooperation with HECT-type ligases (PMID:21357418).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1990 High

    Identification of UBC4/UBC5 in yeast established that a dedicated family of E2 enzymes mediates selective degradation of short-lived and abnormal proteins under stress, providing the first functional framework for UBE2D2 orthologues.

    Evidence Genetic deletion of yeast ubc4/ubc5 with in vivo ubiquitin conjugation and protein turnover assays

    PMID:2154373

    Open questions at the time
    • Mammalian orthologues not yet characterized
    • E3 partners unknown
    • Substrate specificity determinants undefined
  2. 1993 High

    The crystal structure of Ubc4 at 2.7 Å revealed the canonical α/β E2 fold with the catalytic cysteine positioned in a surface cleft between two loops, explaining how the active site is accessible for thioester formation and E3 interaction.

    Evidence X-ray crystallography of yeast Ubc4 at 2.7 Å resolution

    PMID:8268156

    Open questions at the time
    • No E3-bound structure yet
    • Mechanism of ubiquitin transfer from thioester not resolved
  3. 1995 High

    Biochemical reconstitution demonstrated that human UBE2D2 is the specific E2 for E6AP/E6-mediated p53 ubiquitination and degradation, establishing UBE2D2 as a physiologically relevant E2 in a disease-linked HECT E3 pathway.

    Evidence Reconstitution from purified components with in vivo inhibition of E2 activity

    PMID:7724550

    Open questions at the time
    • RING vs HECT pathway distinction for UBE2D2 not yet made
    • Self-ubiquitination mechanism unclear
  4. 1999 High

    Discovery that c-Cbl RING domain recruits and allosterically activates UBE2D2-family E2s to ubiquitinate receptor tyrosine kinases revealed the paradigm of RING E3-mediated E2 activation, expanded UBE2D2 function to receptor signaling.

    Evidence In vitro ubiquitination, co-immunoprecipitation, RING domain mutagenesis

    PMID:10514377

    Open questions at the time
    • Structural basis of RING-induced E2 activation not yet determined
    • In vivo confirmation of E2 identity pending
  5. 2000 High

    UBE2D2 orthologues were shown to function with APC/C (via APC11 RING) for cyclin B/securin ubiquitination and with SCF(β-TrCP) for phospho-IκBα ubiquitination, demonstrating that a single E2 services multiple major cell-cycle and NF-κB signaling E3 complexes.

    Evidence Biochemical reconstitution with recombinant APC11 and SCF complexes, quantitative activity comparison

    PMID:10918611 PMID:10922056

    Open questions at the time
    • Whether UBE2D2 initiates or elongates ubiquitin chains in these pathways unresolved
    • Redundancy among UBE2D family members not dissected
  6. 2003 High

    Two studies established additional physiological E3 partnerships: CHIP/Hsc70 uses UBE2D2 to ubiquitinate phospho-tau, and fission yeast genetics revealed that Ubc4 specifically elongates ubiquitin chains on APC/C substrates after initiation by a distinct E2.

    Evidence In vitro reconstitution with purified CHIP/tau; genetic epistasis and in vivo ubiquitination state analysis in S. pombe

    PMID:12724408 PMID:14612456

    Open questions at the time
    • Whether chain elongation role applies in mammalian APC/C pathway unknown
    • Tau ubiquitination in vivo dependence on UBE2D2 not shown
  7. 2004 High

    UBE2D2 was confirmed as the physiological E2 for Mdm2-dependent p53 ubiquitination by combining in vitro reconstitution with siRNA knockdown that stabilized both p53 and Mdm2 in cells; NMR solution structure provided the first human UBE2D2 atomic model.

    Evidence E2 panel screen, siRNA in human cells, NMR structure determination, NMR-based E3-interaction mapping with CNOT4

    PMID:15062086 PMID:15280377 PMID:15522302

    Open questions at the time
    • How Mdm2 selects UBE2D2 over other E2s in vivo unclear
    • Catalytic role of Asn77 not experimentally resolved
  8. 2008 High

    UBE2D2 was linked to receptor trafficking via c-Cbl-mediated EGFR ubiquitination at the plasma membrane and on endosomes, and to placental biology via SCF(FBXW2)-dependent degradation of GCM1, broadening the physiological context of this E2.

    Evidence siRNA knockdown with EGFR trafficking analysis; in vitro ubiquitination, co-IP, RNAi with GCM1 half-life measurement

    PMID:18508924 PMID:18703417

    Open questions at the time
    • Redundancy between UBE2D family members in EGFR pathway not resolved
    • Structural basis of SCF(FBXW2)–UBE2D2 interaction not determined
  9. 2010 High

    The 2.2 Å crystal structure of UBE2D2~ubiquitin conjugate revealed a self-assembling spiral mediated by non-covalent backside ubiquitin binding, providing a structural mechanism for how E2~Ub oligomerization bridges substrate lysine to the catalytic cysteine.

    Evidence X-ray crystallography at 2.2 Å with in vitro ubiquitination assays

    PMID:20152160

    Open questions at the time
    • Physiological relevance of spiral assembly in vivo uncertain
    • Whether all RING E3s use this mechanism unknown
  10. 2011 High

    Yeast genetic dissection revealed that the essential function of UBE2D2 orthologues is with HECT-type E3s (likely Rsp5), not RING E3s, and that UBE2D2 acts as a monoubiquitinating E2 in RING pathways while performing chain elongation in HECT pathways — the N78S mutation selectively ablated RING- but not HECT-dependent activity.

    Evidence Yeast genetic rescue with separation-of-function mutations, in vitro reconstitution distinguishing HECT vs RING pathways

    PMID:21357418

    Open questions at the time
    • Whether this HECT-preference applies in mammalian cells untested
    • In vivo relevance of backside ubiquitin binding contradicted by S23R having no phenotype
  11. 2014 High

    UBE2D2 was identified as one of three E2s required for Parkin-dependent mitophagy, contributing to ubiquitination of mitofusins, TOM20, TOM70, VDAC1, and Parkin itself, placing UBE2D2 in the PINK1/Parkin mitochondrial quality control pathway.

    Evidence siRNA knockdown with mitophagy assays, mitochondrial substrate ubiquitination analysis, epistasis with Parkin active-site mutant

    PMID:24906799

    Open questions at the time
    • Relative contributions of UBE2D2 vs UBE2N vs UBE2L3 to specific substrates unclear
    • Whether UBE2D2 is recruited directly by Parkin RING or indirectly not resolved
  12. 2015 High

    Co-crystal structure of AO7/RNF25 with UBE2D2 revealed a unique clamp mechanism where a U5BR region engages the E2 backside, paradoxically inhibiting activity by blocking stimulatory non-covalent ubiquitin binding — demonstrating that E3s can tune E2 activity by competing for the backside surface.

    Evidence Co-crystallization, RING-E2 interface mutagenesis, quantitative ubiquitination rate assays

    PMID:26475854

    Open questions at the time
    • Whether other E3s use analogous clamp mechanisms unknown
    • Physiological substrates of AO7/UBE2D2 not identified
  13. 2018 High

    High-resolution (1.7 Å) crystal structure of cIAP1 RING dimer with UBE2D2~Ub conjugate plus backside ubiquitin provided the most complete structural snapshot of RING-induced closed E2~Ub conformation primed for transfer, revealing how backside ubiquitin contacts the α1β1-loop to further stabilize the active state.

    Evidence X-ray crystallography at 1.7 Å with in vitro ubiquitin transfer assays

    PMID:30523153

    Open questions at the time
    • How closed conformation promotes aminolysis vs hydrolysis not fully explained
    • Dynamics of transition between open and closed states not captured
  14. 2022 High

    Structure of MUL1 RING with UBE2D2 showed that RING binding induces the closed E2~Ub conformation and accelerates ubiquitin transfer onto p53-TAD, with the N77A mutation pre-forming the closed state — establishing that conformational priming is a general RING-mediated activation mechanism across diverse E3 ligases.

    Evidence Crystal structure of RING(MUL1):UBE2D2, oxyester hydrolysis kinetics, binding affinity measurements

    PMID:35048531

    Open questions at the time
    • In vivo relevance of MUL1-mediated p53 ubiquitination via UBE2D2 not shown
    • Whether N77A phenocopies RING activation in cellular context untested
  15. 2023 Medium

    UBE2D2 was identified as a regulator of VEGFR2 proteolysis in endothelial cells: its depletion increased surface VEGFR2, enhanced VEGF-A signaling, and promoted tubulogenesis, extending UBE2D2 function to angiogenic receptor turnover.

    Evidence siRNA screen, surface biotinylation, recycling assays, tubulogenesis assay in endothelial cells

    PMID:37226882

    Open questions at the time
    • E3 ligase partnering with UBE2D2 for VEGFR2 ubiquitination not identified
    • Redundancy with UBE2D1 not fully resolved
    • In vivo angiogenesis phenotype not tested
  16. 2024 High

    Engineered ubiquitin variants that specifically bind UBE2D2 at the E1-binding site and backside ubiquitin-binding surface inhibit chain building, providing tool reagents and confirming that both interfaces are functionally essential for E2 activity.

    Evidence Structural and biophysical characterization, in vitro ubiquitin chain-building inhibition, mutagenesis

    PMID:39473070

    Open questions at the time
    • UbV inhibitors not tested in cellular systems
    • Selectivity against all UBE2D paralogs not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the structural and kinetic basis for UBE2D2 selectivity among its many E3 partners in vivo; how cells regulate UBE2D2 allocation across competing RING and HECT pathways; and whether paralog-specific functions exist within the UBE2D family that cannot be captured by single-gene knockdown.
  • No paralog-selective knockout or degron studies in mammalian systems
  • No global substrate profiling for UBE2D2 specifically
  • No disease-causing mutations in UBE2D2 identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 7 GO:0031386 protein tag activity 3
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 2 GO:0005739 mitochondrion 1 GO:0005768 endosome 1
Pathway
R-HSA-392499 Metabolism of proteins 11 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2 R-HSA-168256 Immune System 1
Partners
CBLCHIPCIAP1MDM2MUL1PRKNUBE3AUBE4B

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 Yeast UBC4 and UBC5 (orthologues of human UBE2D2) are ubiquitin-conjugating enzymes that mediate selective degradation of short-lived and abnormal proteins; they are heat-inducible, generate high-molecular-weight ubiquitin-protein conjugates in vivo, and their loss impairs cell growth and stress tolerance. Genetic deletion (ubc4ubc5 mutants), in vivo ubiquitin conjugation assays, protein turnover measurements The EMBO journal High 2154373
1993 The three-dimensional structure of yeast Ubc4 (UBE2D2 orthologue) was solved at 2.7 Å; it is an α/β protein with four α-helices and a four-stranded antiparallel β-sheet, with the ubiquitin-accepting catalytic cysteine located in a cleft between two loops. Tertiary structure is highly conserved among class I E2 enzymes, and a conserved surface adjacent to the catalytic cysteine mediates protein-protein interactions during ubiquitin thioester formation. X-ray crystallography (molecular replacement, 2.7 Å resolution) Biochemistry High 8268156
1995 Human UBC4 (UBE2D2) specifically ubiquitinates E6-associated protein (E6AP) and is required for HPV E6/E6AP-mediated ubiquitination and degradation of p53 in vitro; inhibition of UBC4 activity in vivo blocks E6-stimulated p53 degradation, defining UBC4 as the E2 in this pathway. Reconstitution of ubiquitination from purified components, in vivo inhibition assays Proceedings of the National Academy of Sciences of the United States of America High 7724550
1995 Yeast UBC4 monoubiquitinates itself in vivo at Lys144 via an intermolecular (E2–E2) reaction requiring a second lysine (K64) and direct homointeraction between UBC4 monomers, demonstrating E2–E2 interactions as a general phenomenon. Epitope-tagged ubiquitin co-expression, site-directed mutagenesis, chemical mapping, cross-linking analysis Biochemistry Medium 7756256
1999 c-Cbl functions as a RING-type E3 ubiquitin ligase that recruits and allosterically activates an E2 ubiquitin-conjugating enzyme (Ubc4/5 family, including UBE2D2 orthologue) through its RING domain to ubiquitinate tyrosine-phosphorylated receptor protein-tyrosine kinase substrates. In vitro ubiquitination assays, co-immunoprecipitation, RING domain mutagenesis Science High 10514377
2000 APC11 (RING-H2 finger subunit of the APC/C) together with UBC4 (UBE2D2 orthologue) is sufficient to ubiquitinate APC/C substrates cyclin B and securin in vitro, and to synthesize multiubiquitin chains; the integrity of the RING-H2 finger is required for this activity. Reconstitution of ubiquitination with recombinant proteins, mass spectrometry identification, RING domain mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 10922056
2000 UBC4 (UBE2D2 orthologue) cooperates with SCF(β-TRCP) E3 complex to catalyze phosphorylation-dependent ubiquitination of IκBα in a reconstituted system; Ubc4 is 19-fold more efficient than Ubc3/CDC34 in this reaction and is in excess over Ubc3 in THP.1 cells, suggesting it is the preferentially used E2 in vivo. Both E2s associate physically with the SCF(β-TRCP) complex. Reconstitution of IκBα ubiquitination from recombinant components, co-immunoprecipitation with SCF complex from human cells, activity comparison assays Oncogene High 10918611
2003 In fission yeast, UbcP1/Ubc4 (UBE2D2 orthologue) and UbcP4/Ubc11 play non-redundant, essential roles in mitotic cyclin Cdc13 degradation via APC/C; Ubc4 specifically elongates short ubiquitin chains initiated by UbcP4/Ubc11, demonstrating distinct roles for the two E2s in polyubiquitin chain assembly on APC/C substrates. Genetic analysis (mutant phenotypes, non-complementation), in vivo ubiquitination state analysis of Cdc13 Molecular and cellular biology High 12724408
2004 UbcH5B (UBE2D2) supports Mdm2-mediated ubiquitination of p53 and Mdm2 auto-ubiquitination in vitro; siRNA knockdown of UbcH5B/C in cells causes accumulation of both Mdm2 and p53, inhibits p53 ubiquitination and degradation, identifying UbcH5B/C as physiological E2s for Mdm2 in maintaining low p53/Mdm2 levels in unstressed cells. In vitro E2 panel screen, siRNA knockdown, p53/Mdm2 protein level and ubiquitination analysis in intact cells The Journal of biological chemistry High 15280377
2004 The solution structure of UbcH5B (UBE2D2) was determined by NMR; the structure shows the conserved E2 fold but with a distinct orientation of the N-terminal helix (involved in E3 binding) compared to crystal structures, and conformational freedom of the catalytic Asn77 side chain, which may have implications for catalytic mechanism. NMR spectroscopy (homology modeling, relaxation data, automated NOE assignments) Journal of molecular biology High 15522302
2004 The structural model of the UbcH5B (UBE2D2)/CNOT4 RING complex was determined by NMR chemical shift perturbation mapping of UbcH5B residues important for CNOT4 binding, combined with HADDOCK docking; the model reveals E2/E3 interface residues and differences from the c-Cbl/UbcH7 complex that underlie E2–E3 specificity. NMR chemical shift perturbation experiments, computational docking (HADDOCK), mutagenesis Structure High 15062086
2008 UBE2D2 is responsible for SCF(FBXW2)-mediated ubiquitination and proteasomal degradation of the placental transcription factor GCM1; UBE2D2 enzyme activity is required for GCMa ubiquitination, UBE2D2 associates with the SCF(FBXW2) complex, and RNAi knockdown of UBE2D2 prolongs GCM1 half-life in vivo. In vitro ubiquitination assay screen, co-immunoprecipitation, RNAi knockdown with protein half-life measurement Biology of reproduction High 18703417
2008 Ubc4/5 (UBE2D2 orthologue) cooperates with c-Cbl E3 ligase to ubiquitinate the EGF receptor (EGFR) both at the plasma membrane and after internalization on Hrs-positive endosomes; sustained EGFR tyrosine phosphorylation facilitates polyubiquitination in endosomes, which is required for efficient Hrs interaction and lysosomal sorting. Localization studies (fluorescence microscopy), siRNA knockdown, in vitro ubiquitination assays, time-course analysis of EGFR ubiquitination and trafficking Molecular biology of the cell High 18508924
2010 Crystal structure of UbcH5b (UBE2D2)~ubiquitin intermediate at 2.2 Å reveals the E2~Ub conjugate self-assembles into an infinite spiral through a backside interaction; this assembly provides multiple active E2 sites, and biochemical assays support a model in which self-assembled UbcH5b~Ub bridges the gap between substrate lysine and the E2 catalytic cysteine to enable efficient ubiquitination. X-ray crystallography (2.2 Å), in vitro ubiquitination assays Structure High 20152160
2010 The E4B U box domain (E3/E4 ubiquitin ligase) binds UbcH5c and Ubc4 (UBE2D2 family) as a monomer; crystal and NMR structures of E4B U box free and bound to UbcH5c/Ubc4 reveal an allosteric regulation of the E2 enzymes by E4B U box, providing a molecular basis for assembly of the ubiquitylation machinery involving E4B. X-ray crystallography, NMR spectroscopy, calorimetry-based binding assays Structure High 20696396
2011 In yeast, the essential function of Ubc4/Ubc5 (UBE2D2 orthologues) is with a HECT-type E3 (likely the essential HECT E3 Rsp5), not RING E3s; the N78S mutation selectively eliminating RING-catalyzed isopeptide bond formation (but not HECT transthiolation) rescues the lethal ubc4/ubc5 deletion. In RING E3-catalyzed pathways Ubc4 acts as a monoubiquitinating E2, and backside ubiquitin binding (S23R mutation) has no observable in vivo effect. Yeast genetic rescue assays with point mutations, in vitro reconstitution distinguishing HECT vs RING pathways The Journal of biological chemistry High 21357418
2014 UBE2D2 (along with UBE2N and UBE2L3) is required for Parkin-dependent mitophagy; knockdown of UBE2D2/UBE2D3 reduces autophagic clearance of depolarized mitochondria without affecting PINK1 stabilization or Parkin translocation. Combined knockdown of all three E2s significantly reduces mitochondrial polyubiquitylation and p62 recruitment. UBE2D2 contributes to ubiquitination of mitofusins, TOM20, TOM70, VDAC1, and Parkin itself. siRNA knockdown, mitophagy assays, ubiquitination analysis of mitochondrial substrates, epistasis analysis with Parkin C431S mutant Journal of cell science High 24906799
2015 The RING E3 AO7 (RNF25) binds UbcH5B (UBE2D2) with unusually high affinity via a unique UbcH5B-binding region (U5BR) connected to the RING domain, forming a clamp surrounding the E2 and engaging both the RING-interacting surface and the backside of UbcH5B. High-affinity clamp binding paradoxically decreases ubiquitination rate by blocking stimulatory non-covalent ubiquitin binding to the UbcH5B backside; when backside binding cannot occur, the clamp enhances ubiquitination. Co-crystallization of AO7/UbcH5B complex, mutagenesis of RING-E2 interface, in vitro ubiquitination rate assays The Journal of biological chemistry High 26475854
2016 UBE2D2 does not interact with the muscle-specific E3 ligase MuRF1 (no binding detected by yeast two-hybrid or Surface Plasmon Resonance) and is unable to promote degradation of the MuRF1 substrate α-actin in cells; UBE2D2 mRNA is progressively repressed during muscle atrophy, making it a poor candidate for MuRF1-dependent muscle wasting. Yeast two-hybrid, Surface Plasmon Resonance, HEK293T cell degradation assays, mRNA expression analysis during hindlimb suspension The international journal of biochemistry & cell biology Medium 27378730
2018 Crystal structure of cIAP1 RING dimer bound to UbcH5B (UBE2D2) covalently linked to ubiquitin and a noncovalent ubiquitin at 1.7 Å reveals that cIAP1 RING promotes a closed UbcH5B~Ub conformation priming the thioester for transfer; noncovalent ubiquitin binds the backside of UbcH5B and contacts the α1β1-loop, further stabilizing the closed active conformation. X-ray crystallography (1.7 Å), in vitro ubiquitin transfer assays, biochemical analysis of UbcH5B conformation The Journal of biological chemistry High 30523153
2021 UbcH5b (UBE2D2) strongly supports HECTD3 auto-ubiquitination in vitro; the triterpenoid PC3-15 directly binds UbcH5b and inhibits UbcH5b-mediated ubiquitination. The UbcH5b–p62 axis confers TNBC resistance to lapatinib by promoting autophagy; PC3-15 inhibits lapatinib-induced autophagy and restores lapatinib sensitivity in vitro and in mouse xenografts. FRET-based ubiquitination assay, direct binding assay (PC3-15 to UbcH5b), p62 ubiquitination assay, cell viability/autophagy assays, xenograft experiments Cancer letters Medium 33607208
2021 miR-30b-5p upregulated by ox-LDL reduces UBE2D2 ubiquitination activity, leading to stabilization of KAT2B, which promotes HMGB1 acetylation, nuclear exit, and secretion from endothelial cells, driving pro-inflammatory M1 macrophage polarization; UBE2D2 thus acts upstream of KAT2B in this inflammatory signaling pathway. Luciferase reporter assay (miR-30b-5p binding to UBE2D2), co-IP, ubiquitination assays, flow cytometry, Transwell migration Atherosclerosis Medium 33812169
2022 The RING domain of MUL1 (mitochondrial E3 ligase) recruits UBE2D2 and the substrate p53-TAD as a ternary complex; RING(MUL1) binding induces closed conformation of UBE2D2~Ub and strongly accelerates hydrolysis (ubiquitin transfer); the N77A mutation of UBE2D2 pre-forms the closed conformation even without RING(MUL1). TADp53 binding affinity is enhanced when presented to the RING(MUL1):UBE2D2~Ub complex (multivalent recognition of disordered substrate). Crystal structure determination (RING(MUL1):UBE2D2 complex), oxyester hydrolysis assays, binding affinity measurements, UBE2D2 mutagenesis The FEBS journal High 35048531
2023 UBE2D2 (and UBE2D1) regulate VEGFR2 ubiquitination and proteolysis in endothelial cells; depletion of UBE2D2 increases steady-state and plasma membrane VEGFR2 levels, enhances VEGF-A-stimulated MAPK/PLCγ1/Akt signaling, increases VEGFR2 recycling to the plasma membrane, and stimulates endothelial tubulogenesis. Reverse genetics siRNA screen, surface biotinylation, recycling assays, western blotting, tubulogenesis assay Journal of cell science Medium 37226882
2024 Ubiquitin variants (UbVs) that bind Ube2d2 (UbcH5b) with low micromolar affinity and high specificity were identified; structural and biophysical characterization shows two UbVs inhibit ubiquitin chain building — one blocks the E1-binding site and a second additional site blocks non-covalent ubiquitin backside binding on Ube2d2, demonstrating the functional importance of both interfaces for E2 activity. Structural characterization, biophysical binding assays, in vitro ubiquitin chain-building inhibition assays, mutagenesis The FEBS journal High 39473070
2003 CHIP E3 ubiquitin ligase together with Hsc70 and the E2 enzyme UbcH5B (UBE2D2) ubiquitinates phosphorylated tau (an Alzheimer's disease-associated modification); phosphorylation of tau is a recognition requirement for CHIP/UbcH5B-mediated ubiquitination, and CHIP rescues phosphorylated tau-induced cell death. In vitro ubiquitination assay (co-incubation of purified components), cell death rescue assay, comparison with other E3 ligases The Journal of biological chemistry High 14612456
2025 UBE2D2 promotes gastric cancer progression by supporting autophagy-dependent stabilization of CST1 (Cystatin SN); UBE2D2 knockdown destabilizes GPx4 via the CST1 axis, enhancing ROS accumulation and ferroptosis. UBE2D2 knockdown suppresses GC cell proliferation, invasion, migration, and EMT in vitro and in vivo. Proteomic screening, UBE2D2 knockdown in vitro and in vivo (xenograft), ferroptosis assays (ROS, GPx4), mechanistic pathway validation International journal of biological macromolecules Medium 40912429

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science (New York, N.Y.) 1480 24292625
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2000 Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. The Journal of biological chemistry 890 10722742
1999 The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science (New York, N.Y.) 862 10514377
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2014 HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science (New York, N.Y.) 732 24968937
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. PloS one 644 18213395
2006 A ubiquitin ligase complex assembles linear polyubiquitin chains. The EMBO journal 643 17006537
2004 The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 587 15103385
2003 Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Molecular cell 573 14690596
1999 SUMO-1 modification activates the transcriptional response of p53. The EMBO journal 554 10562557
2006 Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. Nature cell biology 528 16547522
1990 Ubiquitin-conjugating enzymes UBC4 and UBC5 mediate selective degradation of short-lived and abnormal proteins. The EMBO journal 447 2154373
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2002 CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Molecular cell 405 12150907
2007 Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proceedings of the National Academy of Sciences of the United States of America 401 17460044
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2003 CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. The Journal of biological chemistry 390 14612456
2002 TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature 389 11907583
2010 MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Molecular cell 388 20864041
2001 A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matalpha2 repressor degradation. Genes & development 387 11641273
2001 The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proceedings of the National Academy of Sciences of the United States of America 366 11724934
2003 Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum. The Journal of biological chemistry 326 14593114
2000 The RING-H2 finger protein APC11 and the E2 enzyme UBC4 are sufficient to ubiquitinate substrates of the anaphase-promoting complex. Proceedings of the National Academy of Sciences of the United States of America 156 10922056
2004 Regulation of p53 by the ubiquitin-conjugating enzymes UbcH5B/C in vivo. The Journal of biological chemistry 130 15280377
2004 Structural model of the UbcH5B/CNOT4 complex revealed by combining NMR, mutagenesis, and docking approaches. Structure (London, England : 1993) 111 15062086
1995 Reconstitution of p53-ubiquitinylation reactions from purified components: the role of human ubiquitin-conjugating enzyme UBC4 and E6-associated protein (E6AP). Proceedings of the National Academy of Sciences of the United States of America 100 7724550
2014 The ubiquitin-conjugating enzymes UBE2N, UBE2L3 and UBE2D2/3 are essential for Parkin-dependent mitophagy. Journal of cell science 95 24906799
2010 Crystal structure of UbcH5b~ubiquitin intermediate: insight into the formation of the self-assembled E2~Ub conjugates. Structure (London, England : 1993) 90 20152160
2008 Ubc4/5 and c-Cbl continue to ubiquitinate EGF receptor after internalization to facilitate polyubiquitination and degradation. Molecular biology of the cell 84 18508924
1993 Tertiary structures of class I ubiquitin-conjugating enzymes are highly conserved: crystal structure of yeast Ubc4. Biochemistry 83 8268156
2000 The Ustilago maydis ubc4 and ubc5 genes encode members of a MAP kinase cascade required for filamentous growth. Molecular plant-microbe interactions : MPMI 78 10875339
2020 Exosomes Mediated Transfer of Circ_UBE2D2 Enhances the Resistance of Breast Cancer to Tamoxifen by Binding to MiR-200a-3p. Medical science monitor : international medical journal of experimental and clinical research 70 32756532
1999 Activation of a UBC4-dependent pathway of ubiquitin conjugation during postnatal development of the rat testis. Developmental biology 54 10419697
1996 A novel rat homolog of the Saccharomyces cerevisiae ubiquitin-conjugating enzymes UBC4 and UBC5 with distinct biochemical features is induced during spermatogenesis. Molecular and cellular biology 50 8754804
1993 A major ubiquitin conjugation system in wheat germ extracts involves a 15-kDa ubiquitin-conjugating enzyme (E2) homologous to the yeast UBC4/UBC5 gene products. The Journal of biological chemistry 42 8419375
2010 Molecular basis for the association of human E4B U box ubiquitin ligase with E2-conjugating enzymes UbcH5c and Ubc4. Structure (London, England : 1993) 41 20696396
2000 SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4. Oncogene 38 10918611
2005 Saccharomyces cerevisiae Ub-conjugating enzyme Ubc4 binds the proteasome in the presence of translationally damaged proteins. Genetics 35 16118187
2004 Solution structure of the ubiquitin-conjugating enzyme UbcH5B. Journal of molecular biology 30 15522302
2015 Insights into Ubiquitination from the Unique Clamp-like Binding of the RING E3 AO7 to the E2 UbcH5B. The Journal of biological chemistry 29 26475854
2003 Two ubiquitin-conjugating enzymes, UbcP1/Ubc4 and UbcP4/Ubc11, have distinct functions for ubiquitination of mitotic cyclin. Molecular and cellular biology 29 12724408
2021 Targeting ubiquitin conjugating enzyme UbcH5b by a triterpenoid PC3-15 from Schisandra plants sensitizes triple-negative breast cancer cells to lapatinib. Cancer letters 27 33607208
2011 Nuclear protein quality is regulated by the ubiquitin-proteasome system through the activity of Ubc4 and San1 in fission yeast. The Journal of biological chemistry 26 21324894
2007 Yeast Chfr homologs retard cell cycle at G1 and G2/M via Ubc4 and Ubc13/Mms2-dependent ubiquitination. Cell cycle (Georgetown, Tex.) 25 18202552
2011 The essential Ubc4/Ubc5 function in yeast is HECT E3-dependent, and RING E3-dependent pathways require only monoubiquitin transfer by Ubc4. The Journal of biological chemistry 24 21357418
2005 Expression, purification, and properties of the Ubc4/5 family of E2 enzymes. Methods in enzymology 24 16275319
2010 Ubc4 and Not4 regulate steady-state levels of DNA polymerase-α to promote efficient and accurate DNA replication. Molecular biology of the cell 23 20660159
2008 Ubiquitin-conjugating enzyme UBE2D2 is responsible for FBXW2 (F-box and WD repeat domain containing 2)-mediated human GCM1 (glial cell missing homolog 1) ubiquitination and degradation. Biology of reproduction 23 18703417
2005 Mice lacking the UBC4-testis gene have a delay in postnatal testis development but normal spermatogenesis and fertility. Molecular and cellular biology 23 16024774
1995 The yeast UBC4 ubiquitin conjugating enzyme monoubiquitinates itself in vivo: evidence for an E2-E2 homointeraction. Biochemistry 23 7756256
2021 miR-30b-5p releases HMGB1 via UBE2D2/KAT2B/HMGB1 pathway to promote pro-inflammatory polarization and recruitment of macrophages. Atherosclerosis 21 33812169
2018 Structural insights into non-covalent ubiquitin activation of the cIAP1-UbcH5B∼ubiquitin complex. The Journal of biological chemistry 18 30523153
2016 UBE2D2 is not involved in MuRF1-dependent muscle wasting during hindlimb suspension. The international journal of biochemistry & cell biology 15 27378730
1993 Selective ubiquitination of calmodulin by UBC4 and a putative ubiquitin protein ligase (E3) from Saccharomyces cerevisiae. FEBS letters 15 8391479
2001 Yeast 2 microm plasmid copy number is elevated by a mutation in the nuclear gene UBC4. Yeast (Chichester, England) 14 11255249
1995 Schizosaccharomyces pombe and Candida albicans cDNA homologues of the Saccharomyces cerevisiae UBC4 gene. Gene 12 7698660
2022 Circular RNA-UBE2D2 accelerates the proliferation and metastasis of non-small cell lung cancer cells via modulating microRNA-376a-3p/Eukaryotic Translation Initiation Factor 4γ2 axis. Bioengineered 10 35196197
2022 MUL1-RING recruits the substrate, p53-TAD as a complex with UBE2D2-UB conjugate. The FEBS journal 8 35048531
2008 The ubiquitin-conjugating enzymes, Ubc4 and Cdc34, mediate cadmium resistance in budding yeast through different mechanisms. Life sciences 8 18466927
2022 Circ_UBE2D2 Attenuates the Progression of Septic Acute Kidney Injury in Rats by Targeting miR-370-3p/NR4A3 Axis. Journal of microbiology and biotechnology 7 35722711
2009 A functional analysis of the yeast ubiquitin ligase Rsp5: the involvement of the ubiquitin-conjugating enzyme Ubc4 and poly-ubiquitination in ethanol-induced down-regulation of targeted proteins. Bioscience, biotechnology, and biochemistry 7 19809202
2007 Dosage rescue by UBC4 restores cell wall integrity in Saccharomyces cerevisiae lacking the myosin type II gene MYO1. Yeast (Chichester, England) 7 17397110
2023 The E2 ubiquitin-conjugating enzymes UBE2D1 and UBE2D2 regulate VEGFR2 dynamics and endothelial function. Journal of cell science 6 37226882
2022 Arabidopsis Ubiquitin-Conjugating Enzymes UBC4, UBC5, and UBC6 Have Major Functions in Sugar Metabolism and Leaf Senescence. International journal of molecular sciences 6 36232444
2022 Ubiquitin-Conjugating Enzymes Ubc1 and Ubc4 Mediate the Turnover of Hap4, a Master Regulator of Mitochondrial Biogenesis in Saccharomyces cerevisiae. Microorganisms 6 36557625
2022 RPS12 and UBC4 Are Related to Senescence Signal Production in the Ribosomal RNA Gene Cluster. Molecular and cellular biology 5 35384721
2020 The RING domain of mitochondrial E3 ubiquitin ligase 1 and its complex with Ube2D2: crystallization and X-ray diffraction. Acta crystallographica. Section F, Structural biology communications 5 31929179
2015 Rad25 protein is targeted for degradation by the Ubc4-Ufd4 pathway. The Journal of biological chemistry 4 25670855
2022 E2UbcH5B-derived peptide ligands target HECT E3-E2 binding site and block the Ub-dependent SARS-CoV-2 egression: A computational study. Computers in biology and medicine 2 35751189
2025 UBE2D2 promotes gastric cancer progression by inhibiting ferroptosis through autophagy-dependent stabilization of CST1. International journal of biological macromolecules 1 40912429
2022 Quantitative proteome dataset profiling of UBC4 and UBC5 deletion strains in Saccharomyces cerevisiae. Data in brief 1 36426069
2019 Construction and Characterization of UBC4 Mutants with Single Residues Swapped from UBC5. Cell biochemistry and biophysics 1 31820282
2025 Rad5 and Ubc4 directly ubiquitinate PCNA at Lys164 in vitro. The Journal of biological chemistry 0 39826694
2024 Structural and biophysical characterisation of ubiquitin variants that inhibit the ubiquitin conjugating enzyme Ube2d2. The FEBS journal 0 39473070
2024 Proteome Profiling of S. cerevisiae Strains Lacking the Ubiquitin-Conjugating Enzymes Ubc4 and Ubc5 During Exponential Growth and After Heat Shock Treatment. Microorganisms 0 39597624