2.3.2.25: N-terminal E2 ubiquitin-conjugating enzyme
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For detailed information about N-terminal E2 ubiquitin-conjugating enzyme, go to the full flat file.
Word Map on EC 2.3.2.25
Reaction
Synonyms
E2 Ube2w, E2 ubiquitin-conjugating enzyme, Ubc16, UbcH6, UBE2E1, UBE2O, UBE2W, ubiquitin conjugating enzyme, ubiquitin conjugating enzyme E2, ubiquitin-conjugating enzyme (E2), ubiquitin-conjugating enzyme E2, ubiquitin-protein ligase W
ECTree
2.3.2.25 N-terminal E2 ubiquitin-conjugating enzymeAdvanced search results
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General Information on EC 2.3.2.25 - N-terminal E2 ubiquitin-conjugating enzyme
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GENERAL INFORMATION 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
evolution
humans have about 40 E2s that are involved in the transfer of Ub or Ub-like (Ubl) proteins (e.g. SUMO and NEDD8). Common functional and structural features that define unifying themes among E2s, overview. Highly specific chain builders such as Ube2N, Ube2S, and Ube2R1 can only transfer their conjugated Ub to another Ub molecule. This leads to a division of labor among E2s in which one E2 initiates or primes chain synthesis and a second E2 builds and extends the polyUb chain. Ube2W is fundamentally different in its reactivity (and therefore, its substrates) from all other characterized E2s. Along with its unique reactivity profile, Ube2W has an unusual UBC domain
malfunction
metabolism
physiological function
additional information
malfunction
knockdown of two E2s, Ube2o or Ube2t (EC 2.3.2.23), appears to be capable of suppressing LT-stimulated caspase-1 activation. siRNA knockdown of Ube2o expression in the engineered RAW-RA cells efficiently blocks RFP-ASC specks formation as well as release of cellular EGFP in response to LT stimulation
malfunction
the absence of Ube2W in HdhQ200 KI mice significantly increases levels of soluble monomeric mHTT while reducing insoluble oligomeric species. Ube2W null mice show an incompletely penetrant multi-organ defect and post-natal lethality. Mutational analysis reveals that neither wild-type Ube2W nor enzyme mutants alter cell viability. Ube2W deficiency results in decreased mHTT inclusion formation and reduced neurotoxicity, overview. Ube2W deficiency does not alter transcript levels of Htt or striatal markers in HdhQ200 mice
malfunction
the expression levels of UBE2W in mouse testes are significantly deceased in the testes with hypospermatogenesis. When UBE2W expression is successfully downregulated in spermatogenic cells, the rate of apoptosis is significantly increased and the P53/Bcl-2/caspase 6/caspase 9 signal pathways are activated. UBE2W downregulation promotes cell apoptosis and correlates with hypospermatogenesis
malfunction
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the absence of Ube2W in HdhQ200 KI mice significantly increases levels of soluble monomeric mHTT while reducing insoluble oligomeric species. Ube2W null mice show an incompletely penetrant multi-organ defect and post-natal lethality. Mutational analysis reveals that neither wild-type Ube2W nor enzyme mutants alter cell viability. Ube2W deficiency results in decreased mHTT inclusion formation and reduced neurotoxicity, overview. Ube2W deficiency does not alter transcript levels of Htt or striatal markers in HdhQ200 mice
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malfunction
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the expression levels of UBE2W in mouse testes are significantly deceased in the testes with hypospermatogenesis. When UBE2W expression is successfully downregulated in spermatogenic cells, the rate of apoptosis is significantly increased and the P53/Bcl-2/caspase 6/caspase 9 signal pathways are activated. UBE2W downregulation promotes cell apoptosis and correlates with hypospermatogenesis
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metabolism
the N-end rule E3 ligase UBR2 is required for LT-induced NLRP1B inflammasome activation. LT is known to cleave NLRP1B after Lys44. The cleaved NLRP1B, bearing an N-terminal leucine, is targeted by UBR2-mediated ubiquitination and degradation. UBR2 partners with the E2 ubiquitin-conjugating enzyme UBE2O in this process. NLRP1B undergoes constitutive autocleavage before the C-terminal CARD domain. UBR2-mediated degradation of LT-cleaved NLRP1B thus triggers release of the noncovalent-bound CARD domain for subsequent caspase-1 activation. Metabolic pathway, overview
metabolism
the proteasome can target soluble oligomers assembled from ubiquitin-modified proteins independently of its peptidase activity, consistent with our recently reported fibril-fragmenting activity. Proteasomes are able to target oligomers assembled from N-terminally ubiquitinated proteins. The results suggest a possible disassembly mechanism by which N-terminal ubiquitination and the proteasome may together impede aggregate formation
metabolism
UBE2W expression correlates with testis development and hypospermatogenesis. UBE2W expression affects cell apoptosis by P53/Bcl-2/caspase 6/caspase 9 signal pathways, quantitative RT-PCR expression analysis, overview
metabolism
ubiquitin (Ub) conjugation requires the sequential action of enzymes to target ubiquitin to substrates: Ub activating enzyme (E1), Ub conjugating enzyme (E2) and Ub ligase (E3). Given the diversity in Ub-chain lengths, linkages and substrate attachment sites, dramatically different kinds of ubiquitination can occur. Ube2W can function with various ubiquitin ligases including the C-terminus of Hsc-70-interacting protein (CHIP) and the BRCA1/BARD1 complex to mono-ubiquitinate select substrates at their N-termini
metabolism
ubiquitin-conjugating enzymes (E2s) are the central players in the trio of enzymes responsible for the attachment of ubiquitin (Ub) to cellular proteins. E2 regulation mechanisms, overview
metabolism
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ubiquitin (Ub) conjugation requires the sequential action of enzymes to target ubiquitin to substrates: Ub activating enzyme (E1), Ub conjugating enzyme (E2) and Ub ligase (E3). Given the diversity in Ub-chain lengths, linkages and substrate attachment sites, dramatically different kinds of ubiquitination can occur. Ube2W can function with various ubiquitin ligases including the C-terminus of Hsc-70-interacting protein (CHIP) and the BRCA1/BARD1 complex to mono-ubiquitinate select substrates at their N-termini
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metabolism
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UBE2W expression correlates with testis development and hypospermatogenesis. UBE2W expression affects cell apoptosis by P53/Bcl-2/caspase 6/caspase 9 signal pathways, quantitative RT-PCR expression analysis, overview
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physiological function
Ube2W is an E2 ubiquitin-conjugating enzyme with specific protein N-terminal monoubiquitylation activity. Ube2W conjugates ubiquitin to its own N-terminus, but also to that of the small ubiquitin-like modifier SUMO in a manner dependent on the SUMO-targeted ubiquitin ligase RNF4, i.e.RING finger protein 4
physiological function
humans have about 40 E2s that are involved in the transfer of Ub or Ub-like (Ubl) proteins (e.g. SUMO and NEDD8). Although the majority of E2s are only twice the size of Ub, this remarkable family of enzymes performs a variety of functional roles. Ube2W exhibits no intrinsic activity towards free lysine. Instead, Ube2W attaches Ub to the N-terminal alpha-amino group of proteins to form a Ub-fusion protein product. While still an aminolysis reaction and therefore not fundamentally differ not from the reaction with lysine, intrinsic reactivity assays revealed that Ube2W can transfer Ub to the alpha-amino group of small lysine-less peptides but not to free lysine. This feature distinguishes Ube2W as fundamentally different in its reactivity (and therefore, its substrates) from all other characterized E2s. Along with its unique reactivity profile, Ube2W has an unusual UBC domain. Ube2W recognizes and modifies disordered N-termini independently of substrate sequence through interactions between its own disordered C-terminal region and the substrate backbone. The requirement of a disordered N-terminus on its substrate explains the strict monoubiquitylating activity of Ube2W, as the N-terminus of Ub is highly structured and is therefore not a good substrate for Ube2W. The preference for N-terminal modification by Ube2W may not be absolute, as the retroviral restriction RING E3 TRIM5alpha is monoubiquitylated by Ube2W despite being acetylated on its N-terminus. Ube2W may also facilitate isopeptide bond formation, possibly if an N-terminus is blocked. Nevertheless, the preference of Ube2W for disordered N-termini gives it a (so far) unique target selection mechanism for a primary modification event that can subsequently be exploited by other E2 enzymes to form Ub chains. Ube2W may work as a chain-initiating E2 in the innate immune response where K63-linked chains play a critical role
physiological function
the ubiquitin conjugating enzyme Ube2W regulates solubility of the Huntington's disease protein, huntingtin (HTT). Potential function of the non-canonical ubiquitin-conjugating enzyme, Ube2W, in the polyQ neurodegenerative disease, Huntington's Disease (HD). Ube2W increases HTT inclusion formation in cultured cells. The effect of Ube2W on HTT most likely occurs post-translationally. But as an E2 that ubiquitinates N-termini, Ube2W can act cotranslationally by interacting with the nascent N-terminal polypeptide as it exits the ribosome and thus alter the rate of HTT protein synthesis itself
physiological function
UBE2O can mediate the ubiquitination of many different substrates. It is involved in cancer. UBE2O may also regulate other biological processes through UBR2-dependent or UBR2-independent N-end rule pathways. The E2 ubiquitin-conjugating enzyme UBE2O partners with UBR2, an E3 ubiquitin ligase of the N-end rule degradation pathway. UBR2 functions together with UBE2O mediating NLRP1B inflammasome activation. UBE2O is the bona fide E2 enzyme controlling LT-induced NLRP1B inflammasome activation. UBR2-UBE2O ubiquitination pathway mediates degradation of LT-cleaved NLRP1B, which releases its C-terminal CARD domain for subsequent caspase-1 activation
physiological function
UBE2W can modify the N-terminus of proteins with ubiquitin. An engineered N-terminal ubiquitin modification changes the aggregation process of both proteins, resulting in the formation of structurally distinct aggregates. The mammalian proteasome holoenzyme can target oligomers assembled from ubiquitinated tau aggregation domain (tauK18) and alpha-synuclein (alphaS), both tauK18 and alphaS may become ubiquitinated on the N-terminus by UBE2W enabling the proteasomes to target and remove oligomers assembled from these modified proteins. The reaction does not continue beyond monoubiquitination as UBE2W specifically recognizes disordered sequences at the N-terminus of the substrate
physiological function
ubiquitin conjugating enzyme (E2) is crucial for mediating N-terminal ubiquitination. Enzyme UBE2W is involved in male infertility, correlation between UBE2W expression and hypospermatogenesis, overview. UBE2W promotes ubiquitin chain formation in response to DNA damage by interacting with Rnf4
physiological function
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the ubiquitin conjugating enzyme Ube2W regulates solubility of the Huntington's disease protein, huntingtin (HTT). Potential function of the non-canonical ubiquitin-conjugating enzyme, Ube2W, in the polyQ neurodegenerative disease, Huntington's Disease (HD). Ube2W increases HTT inclusion formation in cultured cells. The effect of Ube2W on HTT most likely occurs post-translationally. But as an E2 that ubiquitinates N-termini, Ube2W can act cotranslationally by interacting with the nascent N-terminal polypeptide as it exits the ribosome and thus alter the rate of HTT protein synthesis itself
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physiological function
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ubiquitin conjugating enzyme (E2) is crucial for mediating N-terminal ubiquitination. Enzyme UBE2W is involved in male infertility, correlation between UBE2W expression and hypospermatogenesis, overview. UBE2W promotes ubiquitin chain formation in response to DNA damage by interacting with Rnf4
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additional information
amino acid W144 near the C-terminus of Ube2W is critically important for substrate binding
additional information
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amino acid W144 near the C-terminus of Ube2W is critically important for substrate binding
additional information
E2 structure-function analysis, overview. Ube2W recognizes and modifies disordered N-termini independently of substrate sequence through interactions between its own disordered C-terminal region and the substrate backbone. The requirement of a disordered N-terminus on its substrate explains the strict monoubiquitylating activity of Ube2W, as the N-terminus of Ub is highly structured and is therefore not a good substrate for Ube2W
additional information
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amino acid W144 near the C-terminus of Ube2W is critically important for substrate binding
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