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Information on EC 2.3.2.25 - N-terminal E2 ubiquitin-conjugating enzyme and Organism(s) Homo sapiens and UniProt Accession P51965
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2.3.2.25 N-terminal E2 ubiquitin-conjugating enzymeIUBMB Comments
The enzyme ubiquitinylates the N-terminus of the acceptor protein. It is not reactive towards free lysine.
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
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S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine
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[acceptor protein]-N-terminal-amino acid
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[E1 ubiquitin-activating enzyme]-L-cysteine
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N-terminal-ubiquitinyl-[acceptor protein]
Synonyms
ubiquitin conjugating enzyme, ubiquitin conjugating enzyme e2, e2 ube2w, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
UBE2W
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [acceptor protein]-N-terminal-amino acid = [E1 ubiquitin-activating enzyme]-L-cysteine + N-terminal-ubiquitinyl-[acceptor protein]
in contrast to other ubiquitin-conjugating enzymes which form an isopeptide bond, this enzyme catalyzes the formation of a peptide bond at the N-terminus of the acceptor protein
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SYSTEMATIC NAME
IUBMB Comments
S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine:acceptor protein ubiquitin ligase (peptide bond-forming)
The enzyme ubiquitinylates the N-terminus of the acceptor protein. It is not reactive towards free lysine.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
S-ubiquitinyl-[N-terminal E2 ubiquitin-conjugating E2 enzyme]-L-cysteine + [CARP2 protein]-N-terminal-amino acid
[N-terminal E2 ubiquitin-conjugating enzyme]-L-cysteine + N-ubiquitinyl-[ CARP2 protein]-N-terminal amino acid
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S-ubiquitinyl-[N-terminal E2 ubiquitin-conjugating E2 enzyme]-L-cysteine + [cIAP2 protein]-N-terminal-amino acid
[N-terminal E2 ubiquitin-conjugating enzyme]-L-cysteine + N-ubiquitinyl-[ cIAP2 protein]-N-terminal amino acid
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S-ubiquitinyl-[N-terminal E2 ubiquitin-conjugating E2 enzyme]-L-cysteine + [MDM2 protein]-N-terminal-amino acid
[N-terminal E2 ubiquitin-conjugating enzyme]-L-cysteine + N-ubiquitinyl-[ MDM2 protein]-N-terminal amino acid
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S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [acceptor protein]-N-terminal-amino acid
[E1 ubiquitin-activating enzyme]-L-cysteine + N-terminal-ubiquitinyl-[acceptor protein]
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S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [alpha-synuclein]-N-terminal-amino acid
[E1 ubiquitin-activating enzyme]-L-cysteine + N-terminal-ubiquitinyl-[alpha-synuclein]
full-length alpha-synuclein
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S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [SUMO-2]-N-terminal-amino acid
[E1 ubiquitin-activating enzyme]-L-cysteine + N-terminal-ubiquitinyl-[SUMO-2]
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N-terminal mono-ubiquitylation of SUMO-2 primes it for poly-ubiquitylation by the Ubc13-UEV1 (ubiquitin-conjugating enzyme E2 variant 1) heterodimer
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S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [tau tetra-repeat domain]-N-terminal-Lys18
[E1 ubiquitin-activating enzyme]-L-cysteine + N-terminal-ubiquitinyl-[tau tetra-repeat domain]
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S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [Ube2W]-N-terminal-amino acid
[E1 ubiquitin-activating enzyme]-L-cysteine + N-terminal-ubiquitinyl-[Ube2W]
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isoform Ube2W ubiquitylates its own N-terminus
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[ubiquitin-carrier protein E2]-S-ubiquitinyl-L-cysteine + [ataxin-3]-NH2
[ubiquitin-carrier protein E2]-L-cysteine + N-terminal-ubiquitinyl-[ataxin-3]
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[ubiquitin-carrier protein E2]-S-ubiquitinyl-L-cysteine + [protein-tau]-NH2
[ubiquitin-carrier protein E2]-L-cysteine + N-terminal-ubiquitinyl-[protein-tau]
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[ubiquitin-carrier protein Ubc16]-S-ubiquitinyl-L-cysteine + [CHIP]-NH2
[ubiquitin-carrier protein Ubc16]-L-cysteine + N-terminal-ubiquitinyl-[CHIP]
CHIP is a U-box E3 ubiquitin ligase known to interact productively with many E2 enzymes
isoform Ubc16 N-terminally mono-ubiquitinates the ubiquitin E3 ligase CHIP
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[ubiquitin-carrier protein Ubc16]-S-ubiquitinyl-L-cysteine + [SUMO-2]-NH2
[ubiquitin-carrier protein Ubc16]-L-cysteine + N-terminal-ubiquitinyl-[SUMO-2]
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isoform Ubc16 shows specific protein N-terminal monoubiquitylation activity. Ubc16 conjugates ubiquitin not only 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. N-terminal mono-ubiquitylation of SUMO-2 primes it for poly-ubiquitylation by the Ubc13-UEV1 ubiquitin-conjugating enzyme E2 variant 1 heterodimer
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additional information
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Ube2w is not reactive toward free lysine and contains novel residues in its active site that are important for activity
to confirm N-terminal ubiquitination lysine-less and N-terminally blocked substrates are generated. The lysine-less substrate is ubiquinated, but not the N-terminally blocked one
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additional information
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in vitro, UBE2W can modify the N-terminus of both alpha-synuclein and a tau tetra-repeat domain with a single ubiquitin. The reaction does not continue beyond monoubiquitination as UBE2W specifically recognizes disordered sequences at the N-terminus of the substrate
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additional information
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the enzyme UBE2W is specific for N-terminal amine group, it interacts with E3 ligase of type RING, HECT, and RBR. 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 different 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. 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. The E2 Ube2W shows unique ability to monoubiquitylate proteins on their N-termini. Ube2W appears to monoubiquitylate the RING E3 ligases TRIM5alpha and TRIM21, a prerequisite for their K63 polyubiquitylation by Ube2N/Ube2V2
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [acceptor protein]-N-terminal-amino acid
[E1 ubiquitin-activating enzyme]-L-cysteine + N-terminal-ubiquitinyl-[acceptor protein]
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.5
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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
metabolism
physiological function
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
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
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
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
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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
to obtain homogenous and pure ubiquitin (Ub)-modified alphasynuclein (alphaS) and tauK18, engineered constructs that expressed fusion proteins with a single Ub moiety immediately before the first residue of alphaS or tauK18 (Ub-alphaS and Ub-tauK18) are genetically engineered. These engineered N-terminal Ub-fusion proteins are protected from deubiquitination by a Gly76Ser substitution of the C-terminal residue of Ub. No filamentous aggregates from Ub-alphaS are detected under TEM, thus, the morphology of filamentous aggregates is affected by N-terminal Ub modification. Meanwhile, oligomers from both tauK18 and Ub-tauK18 are reproducibly detected early in the aggregation process. An apparent reduction of the fraction of soluble oligomers with time is detected in both unmodified and Ub-modified tauK18 beyond 50 and 70 h, respectively. Comparisons of modified and unmodified proteins' aggregation behaviour, overview. Proteasomes are able to target Ub-modified aggregates
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant biotin-tagged enzyme from HEK-293T cells by NeutrAvidin affinity chromatography, release from the coloumn by TEV protease cleavage
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Tatham, M.H.; Geoffroy, M.C.; Shen, L.; Plechanovova, A.; Hattersley, N.; Jaffray, E.G.; Palvimo, J.J.; Hay, R.T.
RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation
Nat. Cell Biol.
10
538-546
2008
Homo sapiens (Q96B02)
Scaglione, K.M.; Basrur, V.; Ashraf, N.S.; Konen, J.R.; Elenitoba-Johnson, K.S.; Todi, S.V.; Paulson, H.L.
The ubiquitin-conjugating enzyme (E2) Ube2w ubiquitinates the N terminus of substrates
J. Biol. Chem.
288
18784-18788
2013
Homo sapiens
Tatham, M.H.; Plechanovova, A.; Jaffray, E.G.; Salmen, H.; Hay, R.T.
Ube2W conjugates ubiquitin to alpha-amino groups of protein N-termini
Biochem. J.
453
137-145
2013
Homo sapiens (Q96B02)
Schumacher, F.R.; Wilson, G.; Day, C.L.
The N-terminal extension of UBE2E ubiquitin-conjugating enzymes limits chain assembly
J. Mol. Biol.
425
4099-4111
2013
Homo sapiens (P51965)
Stewart, M.D.; Ritterhoff, T.; Klevit, R.E.; Brzovic, P.S.
E2 enzymes more than just middle men
Cell Res.
26
423-440
2016
Homo sapiens (Q96B02)
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