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Literature summary extracted from

  • Stewart, M.D.; Ritterhoff, T.; Klevit, R.E.; Brzovic, P.S.
    E2 enzymes more than just middle men (2016), Cell Res., 26, 423-440 .
    View publication on PubMedView publication on EuropePMC

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
2.3.2.23 crystal structure of an E2-Ub oxyester conjugate (Ube2D2) in a closed state showing the interface formed between the E2 crossover helix and the I44 surface of Ub upon binding a RING E3 (BIRC7, PDB ID 4AUQ) Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.3.2.23 CC0651 a small-molecule inhibitor that selectively inhibits Ube2R1, the specialized E2 for SCF E3 ligases, which builds K48-linked polyUb chains on its targets for proteasomal degradation. In a co-crystal structure of Ube2R1, Ub, and CC0651, the inhibitor is sandwiched between the E2 and Ub Homo sapiens
2.3.2.23 additional information backside binding by accessory elements of the RING E3 Rad18 inhibits the intrinsic chain-forming activity of Ube2B; enzyme UBE2E1 performs autoubiquitylation, ubiquitylation results in inhibition of E2 activity; the backside-binding element of the E3 AO7 decreases the processivity of chain building by the E2 Ube2D2 Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.3.2.23 S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [E2 ubiquitin-conjugating enzyme]-L-cysteine Homo sapiens
-
[E1 ubiquitin-activating enzyme]-L-cysteine + S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine
-
?
2.3.2.24 [E1 ubiquitin-activating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine Homo sapiens
-
[E1 ubiquitin-activating enzyme]-L-cysteine + [acceptor protein]-N6-monoubiquitinyl-L-lysine
-
?
2.3.2.25 S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [acceptor protein]-N-terminal-amino acid Homo sapiens
-
[E1 ubiquitin-activating enzyme]-L-cysteine + N-terminal-ubiquitinyl-[acceptor protein]
-
?

Organism

EC Number Organism UniProt Comment Textmining
2.3.2.23 Homo sapiens A1L167
-
-
2.3.2.23 Homo sapiens O00762
-
-
2.3.2.23 Homo sapiens O14933
-
-
2.3.2.23 Homo sapiens P49427
-
-
2.3.2.23 Homo sapiens P49459
-
-
2.3.2.23 Homo sapiens P51668
-
-
2.3.2.23 Homo sapiens P51965
-
-
2.3.2.23 Homo sapiens P60604
-
-
2.3.2.23 Homo sapiens P61077
-
-
2.3.2.23 Homo sapiens P61086
-
-
2.3.2.23 Homo sapiens P61088
-
-
2.3.2.23 Homo sapiens P62253
-
-
2.3.2.23 Homo sapiens P62256
-
-
2.3.2.23 Homo sapiens P62837
-
-
2.3.2.23 Homo sapiens P63146
-
-
2.3.2.23 Homo sapiens P68036
-
-
2.3.2.23 Homo sapiens Q13404
-
-
2.3.2.23 Homo sapiens Q15819
-
-
2.3.2.23 Homo sapiens Q16763
-
-
2.3.2.23 Homo sapiens Q5JXB2
-
-
2.3.2.23 Homo sapiens Q5VVX9
-
-
2.3.2.23 Homo sapiens Q712K3
-
-
2.3.2.23 Homo sapiens Q7Z7E8
-
-
2.3.2.23 Homo sapiens Q8N2K1
-
-
2.3.2.23 Homo sapiens Q8WVN8
-
-
2.3.2.23 Homo sapiens Q969T4
-
-
2.3.2.23 Homo sapiens Q96LR5
-
-
2.3.2.23 Homo sapiens Q9H832
-
-
2.3.2.23 Homo sapiens Q9NPD8
-
-
2.3.2.23 Homo sapiens Q9Y385
-
-
2.3.2.24 Homo sapiens Q9C0C9
-
-
2.3.2.25 Homo sapiens Q96B02
-
-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
2.3.2.23 sumoylation SUMO modification of an E2 occurs on the polyUb chain-building E2, Ube2K. Like Ube2I, the site of modification is on helix alpha1, but on a residue in the E1 and E3 binding interface, consistent with the decreased activity observed in vitro Homo sapiens

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.3.2.23 additional information enzyme UBE2V1 and homologues are catalytically inactive E2-like proteins interacting with Ube2N for K63 chain formation. The enzyme interacts with ubiquitin, and with E3 ligases of types RING, and HECT (in combination with Ube2N). Whereas K63-specific Ube2N uses a tightly bound E2-like subunit (either Ube2V1 or Ube2V2) to position the K63 side chain of the incoming (acceptor) Ub Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligase of type RING Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types HECT, and RBR, but not with E3 RING, and not with ubiquitin. UBE2L3 is a cysteine-only reactive E2 Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types HECT, RBR, and RING, but not with ubiquitin. UBE2N builds K63 Ub-chains, inetracts with UBE2V1 and UBE2V2 for K63 chain formation. K63-specific Ube2N uses a tightly bound E2-like subunit (either Ube2V1 or Ube2V2) to position the K63 side chain of the incoming (acceptor) Ub. A substrate that is modified by Ube2W (EC 2.3.2.25) can serve as the template for chain building by Ube2N and Ube2K. K63-linked polyUb is built directly onto the active site cysteine of Ube2N Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING and HECT Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING and HECT. UBE2G1 is a K48 chain-building enzyme even in the absence of an E3 Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING, and RBR. Ube2L6 is a bispecific E2 active with ISG15 and ubiquitin (Ub) Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING, HECT, and RBR Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING, HECT, and RBR, but not with ubiquitin Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING, HECT, and RBR, but not with ubiquitin. Ube2E1 provides an example of E2 regulation by autoubiquitylation. Modification occurs on a lysine near the active site and on lysines in the unstructured N-terminal extension of Ube2E1 Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING, HECT, and RBR. It is K48 chain-building enzyme even in the absence of an E3. Ube2K has a unique region near its active site that interacts with a tyrosine near K48 in the acceptor Ub to provide K48-linkage specificity Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING, HECT, and RBR. Its shows hydroxyl specificity (serine/threonine) Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING, HECT, and RBR. Ube2R1 is a K48 Ub chain-building enzyme. Ube2R1 is the cognate E2 of SCF E3 ligases. K48-specific Ube2R2 has a short about 12 amino acid insertion proximal to the E2 active site that determines specificity. The highly specific chain builders such as Ube2N, Ube2S, and Ube2R1 can only transfer their conjugated Ub to another Ub molecule Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING, HECT, and RBR. Ube2R2 is a K48 Ub chain-building enzyme. Ube2R1 is the cognate E2 of SCF E3 ligases. K48-specific Ube2R1 has a short about 12 amino acid insertion proximal to the E2 active site that determines specificity Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING, HECT, and RBR. Ube2S is a K11 Ub chain-building enzyme. highly specific chain builders such as Ube2N, Ube2S, and Ube2R1 can only transfer their conjugated Ub to another Ub molecule Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with E3 ligases of types RING, HECT, and RBR. Ube2T monoubiquitylates its substrate FANCD2 on a specific lysine with its RING E3 FANCL in the Fanconi Anemia DNA repair pathway Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with the C-terminal extension. Ube2Z is a bispecific E2 active with FAT10 (ubiquitin D) and ubiquitin (Ub) Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with ubiquitin and E3 ligases, of types RING, HECT, RBR. The preference of Ube2E3 to generate monoubiquitylated products arises from specific interactions involving K48 on Ub and backside residues of the E2 Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with ubiquitin, and E3 ligases of types RING, HECT, and RBR Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with ubiquitin, and E3 ligases of types RING, HECT, and RBR. Backside binding by Ub increases the intrinsic lysine reactivity of Ube2D2-Ub, indicating an allosteric effect Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with ubiquitin, and E3 ligases of types RING, HECT, and RBR. Neither HECTs nor RBRs enhance the intrinsic lysine reactivity of Ube2D3. In the open conformation, Ube2D3-Ub is highly reactive towards free cysteine, but shows greatly reduced reactivity towards free lysine when compared with free Ube2D3-Ub Homo sapiens ?
-
-
2.3.2.23 additional information the enzyme interacts with ubiquitin, E3 ligases of types RING, HECT, and RBR, with Cue1, and with itself. UBE2G2 is a K48 chain-building enzyme dependent on E3. Chain building directly on E2 active sites has been reported in limited cases (e.g. Ube2G2, and Ube2D in collaboration with the bacterial effector SspH2) Homo sapiens ?
-
-
2.3.2.23 S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [E2 ubiquitin-conjugating enzyme]-L-cysteine
-
Homo sapiens [E1 ubiquitin-activating enzyme]-L-cysteine + S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine
-
?
2.3.2.23 S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [E2 ubiquitin-conjugating enzyme]-L-cysteine backside interaction was of Ub non-covalently bound to Ube2D3 via the hydrophobic patch centered on I44, a Ub surface used in many different protein-protein interactions. Although weak in affinity, the interaction promotes an increase in processivity of polyUb chain building by Ube2D3 Homo sapiens [E1 ubiquitin-activating enzyme]-L-cysteine + S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine
-
?
2.3.2.24 additional information the enzyme interacts with E3 ligases of types RING and RBR, and with its own N-terminus Homo sapiens ?
-
-
2.3.2.24 [E1 ubiquitin-activating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine
-
Homo sapiens [E1 ubiquitin-activating enzyme]-L-cysteine + [acceptor protein]-N6-monoubiquitinyl-L-lysine
-
?
2.3.2.25 additional information 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 Homo sapiens ?
-
-
2.3.2.25 S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [acceptor protein]-N-terminal-amino acid
-
Homo sapiens [E1 ubiquitin-activating enzyme]-L-cysteine + N-terminal-ubiquitinyl-[acceptor protein]
-
?

Subunits

EC Number Subunits Comment Organism
2.3.2.23 More UBE2A shows the UBC domain organization Homo sapiens
2.3.2.23 More UBE2B shows the Ext-UBC domain organization Homo sapiens
2.3.2.23 More UBE2B shows the UBC domain organization Homo sapiens
2.3.2.23 More UBE2D1 shows the UBC domain organization Homo sapiens
2.3.2.23 More UBE2D2 shows the UBC domain organization Homo sapiens
2.3.2.23 More UBE2D3 shows the UBC domain organization Homo sapiens
2.3.2.23 More UBE2D4 shows the UBC domain organization Homo sapiens
2.3.2.23 More UBE2E1 shows the Ext-UBC domain organization Homo sapiens
2.3.2.23 More UBE2E3 shows the Ext-UBC domain organization Homo sapiens
2.3.2.23 More UBE2G1 shows the UBC + insert domain organization Homo sapiens
2.3.2.23 More UBE2G2 shows the UBC + insert domain organization Homo sapiens
2.3.2.23 More UBE2H shows the Ext-UBC domain organization Homo sapiens
2.3.2.23 More UBE2J1 shows the UBC + insert-Ext domain organization Homo sapiens
2.3.2.23 More UBE2J2 shows the UBC + insert-Ext domain organization Homo sapiens
2.3.2.23 More UBE2K shows the UBC domain organization Homo sapiens
2.3.2.23 More UBE2K shows the UBC-UBA domain organization, an additional structured domain is linked to their UBC domain. Ube2K has a unique region near its active site that interacts with a tyrosine near K48 in the acceptor Ub to provide K48-linkage specificity Homo sapiens
2.3.2.23 More UBE2L6 shows the UBC domain organization Homo sapiens
2.3.2.23 More UBE2N shows the UBC domain organization Homo sapiens
2.3.2.23 More UBE2NL shows the UBC domain organization Homo sapiens
2.3.2.23 More UBE2Q1 shows the Ext-UBC + insert domain organization Homo sapiens
2.3.2.23 More UBE2QL shows the UBC + insert domain organization Homo sapiens
2.3.2.23 More UBE2R1 shows the UBC + insert-Ext domain organization Homo sapiens
2.3.2.23 More UBE2R2 shows the UBC + insert-Ext domain organization Homo sapiens
2.3.2.23 More UBE2S shows the UBC-Ext domain organization Homo sapiens
2.3.2.23 More UBE2V1 shows the Ext-UBC domain organization Homo sapiens
2.3.2.23 More UBE2V2 shows the Ext-UBC domain organization Homo sapiens
2.3.2.23 More UBE2Z shows the Ext-UBC-Ext domain organization Homo sapiens
2.3.2.23 More UBEE2 shows the Ext-UBC domain organization Homo sapiens
2.3.2.24 More UBE2O shows the Ext-UBC-Ext domain organization Homo sapiens
2.3.2.25 More UBE2W shows the UBC domain organization Homo sapiens

Synonyms

EC Number Synonyms Comment Organism
2.3.2.23 CDC34
-
Homo sapiens
2.3.2.23 Cdc34B
-
Homo sapiens
2.3.2.23 E2-20K
-
Homo sapiens
2.3.2.23 E2-25K
-
Homo sapiens
2.3.2.23 HOYS7
-
Homo sapiens
2.3.2.23 Mms2
-
Homo sapiens
2.3.2.23 Rad6a
-
Homo sapiens
2.3.2.23 RAD6B
-
Homo sapiens
2.3.2.23 Ubc1
-
Homo sapiens
2.3.2.23 Ubc13
-
Homo sapiens
2.3.2.23 Ubc3B
-
Homo sapiens
2.3.2.23 Ubc4/5
-
Homo sapiens
2.3.2.23 Ubc6
-
Homo sapiens
2.3.2.23 UBC7
-
Homo sapiens
2.3.2.23 Ubc8
-
Homo sapiens
2.3.2.23 UBCE4
-
Homo sapiens
2.3.2.23 UbcH10
-
Homo sapiens
2.3.2.23 UBCH2
-
Homo sapiens
2.3.2.23 UbcH3
-
Homo sapiens
2.3.2.23 UbcH5A
-
Homo sapiens
2.3.2.23 UbcH5B
-
Homo sapiens
2.3.2.23 UbcH5C
-
Homo sapiens
2.3.2.23 UbcH5D
-
Homo sapiens
2.3.2.23 UbcH6
-
Homo sapiens
2.3.2.23 UbcH7
-
Homo sapiens
2.3.2.23 UbcH8 may refer to both UBE2E2 and UBE2L2 Homo sapiens
2.3.2.23 UbcH8 UbcH8 may refer to both Ube2E2 and Ube2L6 Homo sapiens
2.3.2.23 UbcH9
-
Homo sapiens
2.3.2.23 UbcM2
-
Homo sapiens
2.3.2.23 UbcM4
-
Homo sapiens
2.3.2.23 UBE2A
-
Homo sapiens
2.3.2.23 UBE2B
-
Homo sapiens
2.3.2.23 UBE2C
-
Homo sapiens
2.3.2.23 UBE2D1
-
Homo sapiens
2.3.2.23 UBE2D2
-
Homo sapiens
2.3.2.23 UBE2D3
-
Homo sapiens
2.3.2.23 UBE2D4
-
Homo sapiens
2.3.2.23 UBE2E1
-
Homo sapiens
2.3.2.23 UBE2E2
-
Homo sapiens
2.3.2.23 UBE2E3
-
Homo sapiens
2.3.2.23 Ube2G
-
Homo sapiens
2.3.2.23 UBE2G1
-
Homo sapiens
2.3.2.23 UBE2G2
-
Homo sapiens
2.3.2.23 UBE2H
-
Homo sapiens
2.3.2.23 Ube2J1
-
Homo sapiens
2.3.2.23 UBE2J2
-
Homo sapiens
2.3.2.23 UBE2K
-
Homo sapiens
2.3.2.23 UBE2L3
-
Homo sapiens
2.3.2.23 UBE2L6
-
Homo sapiens
2.3.2.23 UBE2N
-
Homo sapiens
2.3.2.23 Ube2NL
-
Homo sapiens
2.3.2.23 UBE2Q1
-
Homo sapiens
2.3.2.23 UBE2Q2
-
Homo sapiens
2.3.2.23 UBE2QL
-
Homo sapiens
2.3.2.23 UBE2R1
-
Homo sapiens
2.3.2.23 UBE2R2
-
Homo sapiens
2.3.2.23 UBE2S
-
Homo sapiens
2.3.2.23 UBE2T
-
Homo sapiens
2.3.2.23 UBE2U
-
Homo sapiens
2.3.2.23 Ube2V
-
Homo sapiens
2.3.2.23 UBE2V1
-
Homo sapiens
2.3.2.23 UBE2V2
-
Homo sapiens
2.3.2.23 UBE2Z
-
Homo sapiens
2.3.2.23 ubiquitin-conjugating enzyme E2
-
Homo sapiens
2.3.2.23 Uev1
-
Homo sapiens
2.3.2.23 Uev1A
-
Homo sapiens
2.3.2.23 Uev2
-
Homo sapiens
2.3.2.24 E2-230K
-
Homo sapiens
2.3.2.24 UBE2O
-
Homo sapiens
2.3.2.24 ubiquitin-conjugating enzyme E2
-
Homo sapiens
2.3.2.25 Ubc16
-
Homo sapiens
2.3.2.25 UBE2W
-
Homo sapiens
2.3.2.25 ubiquitin-conjugating enzyme E2
-
Homo sapiens

Expression

EC Number Organism Comment Expression
2.3.2.23 Homo sapiens Ube2L3 undergoes transcriptional regulation in response to aryl hydrocarbon receptor (AHR) signaling. The resulting increase in Ube2L3 levels leads to degradation of cell cycle control proteins, identifying a connection between AHR signaling and the previously established role that Ube2L3 plays in cell cycle regulation up

General Information

EC Number General Information Comment Organism
2.3.2.23 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 Homo sapiens
2.3.2.23 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 Homo sapiens
2.3.2.23 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. Either Ube2C or a Ube2D family member transfers the first Ub onto human APC/C substrates and Ube2S then builds the K11-linked polyUb chains that are a hallmark of APC/C-mediated proteasomal degradation Homo sapiens
2.3.2.23 malfunction backside binding by accessory elements of the RING E3 Rad18 inhibits the intrinsic chain-forming activity of Ube2B, thus promoting monoubiquitylation of PCNA and histone 2B Homo sapiens
2.3.2.23 malfunction Disruption of specific interactions involving K48 on Ub and backside residues of the E2 by mutation of either Ub or E2 backside residues results in the rapid generation of K63-linked Ub chains by Ube2E3 Homo sapiens
2.3.2.23 malfunction mutations designed to disrupt canonical E2/RING interactions that would involve the APC/C RING domain subunit (Apc11) do not affect activity Homo sapiens
2.3.2.23 metabolism ubiquitin-conjugating enzymes (E2s) are the central players in the trio of enzymes responsible for the attachment of ubiquitin (Ub) to cellular proteins Homo sapiens
2.3.2.23 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 enzyme Ube2W (EC 2.3.2.25) can transfer Ub to the alpha-amino group of small lysine-less peptides but not to free lysine, whereas Ube2D3, for example, can transfer Ub to lysine but not to the alpha-amino group Homo sapiens
2.3.2.23 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 Homo sapiens
2.3.2.23 metabolism ubiquitin-conjugating enzymes (E2s) are the central players in the trio of enzymes responsible for the attachment of ubiquitin (Ub) to cellular proteins. Either Ube2C or a Ube2D family member transfers the first Ub onto human APC/C substrates and Ube2S then builds the K11-linked polyUb chains that are a hallmark of APC/C-mediated proteasomal degradation. The APC/C appears to repurpose its RING subunit to bind and track the growing Ub chain during Ube2S-mediated catalysis, presumably inhibiting incorrect chain building by the promiscuous Ube2D E2s. E2 regulation mechanisms, overview Homo sapiens
2.3.2.23 metabolism ubiquitin-conjugating enzymes (E2s) are the central players in the trio of enzymes responsible for the attachment of ubiquitin (Ub) to cellular proteins. Enzyme UBE2J1 is involved in the ERAD pathway. E2 regulation mechanisms, overview Homo sapiens
2.3.2.23 metabolism ubiquitin-conjugating enzymes (E2s) are the central players in the trio of enzymes responsible for the attachment of ubiquitin (Ub) to cellular proteins. UBE2G2 is an E2 involved in the ERAD pathway. E2 regulation mechanisms, overview Homo sapiens
2.3.2.23 metabolism ubiquitin-conjugating enzymes (E2s) are the central players in the trio of enzymes responsible for the attachment of ubiquitin (Ub) to cellular proteins. Ube2R1 and its yeast counterpart Cdc34 are dedicated E2s for the large multi-subunit SCF (Skp/Cullin/F-Box) E3s that target proteins to the proteasome for degradation. Both of these enzymes also have an acidic C-terminal extension that interacts with a basic canyon on the cullin subunit of an SCF complex, helping to position the E2 near the RING subunit while allowing for rapid association and turnover in chain building. A disulfide bond formed between the Ub E1 Uba1 and the E2 Ube2R1 upon oxidative stress is associated with increased Ube2R1 substrate stability and delayed cell cycle progression. E2 regulation mechanisms, overview Homo sapiens
2.3.2.23 metabolism ubiquitin-conjugating enzymes (E2s) are the central players in the trio of enzymes responsible for the attachment of ubiquitin (Ub) to cellular proteins. Ube2W (EC 2.3.2.25) appears to monoubiquitylate the RING E3 ligases TRIM5alpha and TRIM21, a prerequisite for their K63 polyubiquitylation by Ube2N/Ube2V2. E2 regulation mechanisms, overview Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. Deletion of the N-terminal extension of Ube2E family members switches their (in vitro) activity from mono- to polyubiquitylation Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. Enzyme UBE2NL has no catalytic cysteine Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. K48-specific Ube2R1 has a short about 12 amino acid insertion proximal to the E2 active site that determines specificity Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. K48-specific Ube2R2 has a short about 12 amino acid insertion proximal to the E2 active site that determines specificity Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. Multi-subunit E3s make use of the E2 backside surface. The APC/C engages Ube2C using both a RING subunit Apc11 and the WHB domain of a cullin subunit Apc2, the latter interaction being via the E2's backside. While use of two subunits to recruit the E2 serves to ensure specificity for Ube2C, the additional interaction also appears to direct substrate ubiquitylation by reducing the degrees of freedom available for the E2/RING assembly Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. Structures of E2-Ub bound to a HECT (NEDD4L) or RBR (HOIP) E3 reveal a Ube2D2-Ub conjugate in an open conformation, poised for transthiolation to the E3 active-site cysteine Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. Ube2D3-Ub and Ube2N-Ub conjugates show an array of orientations that involve little or no contact between the E2 and ubiquitin (open states) and some conformations (closed states) that involve contacts between the Ub hydrophobic patch centered on Ub I44 and residues in the E2 crossover helix. Although Ube2D3-Ub and Ube2N-Ub conjugates are highly dynamic, the ensembles of conformations adopted by them are different in terms of the relative fraction of closed versus open states Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. UBE2E3 can be thought of having an intrinsic ability to build polyUb chains that is inhibited by Ub binding on its backside. The two opposite effects of backside Ub binding suggest that it can act as either a throttle or a brake for chain building Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. Ube2G1 has a short about 12 amino acid insertion proximal to the E2 active site that determines specificity Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. Ube2G2 has a short about 12 amino acid insertion proximal to the E2 active site that determines specificity. In the case of Ube2G2, binding of a non-RING region (G2BR) of its E3, gp78, to the backside of the UBC domain alters the acidic loop conformation, which is helical in the free E2 structure but is unwound in the G2BR-bound structure. The unwinding generates a series of interactions among E2, E3, and Ub that help stabilize a closed E2-Ub conformation to increase aminolysis reactivity. The requirement of an extra, allosteric interaction between Ube2G2 and gp78 ensures that the K48 chain-building E2 cannot work with any RING E3 it happens to contact. The human ERAD E3 ligase, gp78, uses the non-RING G2BR to interact with the backside of its E2, Ube2G2. G2BR binding in trans can increase the affinity of Ube2G2-Ub for the gp78 RING and can enhance both E3-dependent and E3-independent Ub transfer activity, suggesting cooperative allosteric interactions between RING and G2BR binding. The situation is different in the case of uncharged Ube2G2, which binds the E3 with lower affinity due to loss of some G2BR contacts, an effect that promotes dissociation of reacted (or inactive) E2 from the E3, allowing for exchange with active E2-Ub conjugate Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. Ube2N-Ub conjugates show an array of orientations that involve little or no contact between the E2 and ubiquitin (open states) and some conformations (closed states) that involve contacts between the Ub hydrophobic patch centered on Ub I44 and residues in the E2 crossover helix. Although the Ube2N-Ub conjugates is highly dynamic, the ensembles of conformations adopted by it are different in terms of the relative fraction of closed versus open states Homo sapiens
2.3.2.23 additional information E2 structure-function analysis, overview. Ube2S uses acidic residues in the final UBC domain helix to interact with the acceptor Ub and orient K11 towards the C-terminus of the donor Ub bound to its active site Homo sapiens
2.3.2.23 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 Homo sapiens
2.3.2.23 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. Enzyme Ube2D1 is a promiscuous lysine- and cysteine-reactive E2 Homo sapiens
2.3.2.23 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. Enzyme Ube2D3 is a promiscuous lysine- and cysteine-reactive E2 Homo sapiens
2.3.2.23 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. Enzyme Ube2D4 is a promiscuous lysine- and cysteine-reactive E2 Homo sapiens
2.3.2.23 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. Enzyme UBE2E1 is a monoubiquitylating E2 of its N-terminal extension Homo sapiens
2.3.2.23 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. Enzyme UBE2E1 is a monoubiquitylating E2 of its N-terminal extension. The E2 Ube2E3 regulates the activity of Nrf2, a transcription factor that induces expression of anti-oxidant genes to neutralize reactive oxygen species and restore redox homeostasis. Alkylation of non-catalytic C136 of Ube2E3 (to mimic its oxidation) results in constitutive binding of the E2 to Nrf2, increasing its half-life and thus its transcriptional activity. The regulation also depends on the catalytic activity of Ube2E3. Intriguingly, Ube2E3's C136 replaces the proline in a conserved HPN triad, which has been reported to be required for E2 activity Homo sapiens
2.3.2.23 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. Enzyme UBE2E2 is a monoubiquitylating E2 by of its N-terminal extension Homo sapiens
2.3.2.23 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. Enzyme UBE2N is collaborating with proteins of the Ube2V family to build K63 Ub-chain. Ube2W (EC 2.3.2.25) appears to monoubiquitylate the RING E3 ligases TRIM5alpha and TRIM21, a prerequisite for their K63 polyubiquitylation by Ube2N/Ube2V2, Ube2N/Ube2V2 form a E2/E3 pair Homo sapiens
2.3.2.23 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. Enzymes UBE2V1, UBE2V2, and homologues are catalytically inactive E2-like proteins interacting with Ube2N for K63 chain formation Homo sapiens
2.3.2.23 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. Enzymes UBE2V1, UBE2V2, and homologues are catalytically inactive E2-like proteins interacting with Ube2N for K63 chain formation. PCNA is monoubiquitylated by the E2/E3 pair Ube2N/Ube2V2 and the RING E3 Rad5, together builds a K63-linked chain at the same site, to create a signal that promotes template-switching and engagement of the homologous recombination machinery Homo sapiens
2.3.2.23 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. UBE2A functions in DNA damage repair. PCNA is monoubiquitylated by the Ube2A/B (Rad6) E2s and the RING E3 Rad18 during postreplicative DNA damage repair Homo sapiens
2.3.2.23 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. UBE2C functions in chain-initiation of APC/C Homo sapiens
2.3.2.23 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. UBE2G2 acts in K48 chain-building in dependence of an E3. It is an E2 involved in the ERAD pathway Homo sapiens
2.3.2.23 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. Ube2J2 attaches Ub to the major histocompatibility complex via hydroxyl groups (serine/threonine) in collaboration with a viral RING E3 ligase. Ube2J2 ubiquitylation products are sensitive to treatment with strong base, which hydrolyzes oxyesters but not amide bonds Homo sapiens
2.3.2.23 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. Ube2L3 plays in cell cycle regulation. Ube2L3 (UbcH7), the E2 used in many structural studies with RING-type E3s, is not reactive towards lysine and only exhibits reactivity towards cysteine. The implication is that Ube2L3, although it binds to many RING domains, is only functional as an E2 with HECT-type E3s. RBRs, such as Parkin and HHARI, have RING domains, but also contain a conserved cysteine residue that forms an obligatory E3-Ub intermediate. Thus, RBRs are functional hybrids that exploit elements found in both RING and HECT E3s Homo sapiens
2.3.2.23 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. Ube2R1 is the cognate E2 of SCF E3 ligases Homo sapiens
2.3.2.23 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. Ube2S is the dedicated E2 for the multi-subunit APC/C E3 that regulates cell cycle progression. On its own, Ube2S-Ub populates closed states to a considerable extent and can catalyze formation of free polyUb chains in the absence of an E3. Two non-RING subunits, Apc2 and Apc4, contribute to Ube2S activation in a mechanism that may involve the C-terminal helix of the Ube2S UBC domain Homo sapiens
2.3.2.23 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. Ube2T, the E2 involved in the Fanconi Anemia DNA repair pathway and specific for E3 ligase FANCL, transfers Ub to a lysine near its active site and two lysines located in its C-terminal extension. Ubiquitylated Ube2T has been observed in vitro and in cells, and its production is enhanced by the E3, FANCL. Unlike Ubc7 autoubiquitylation, (multi)-monoubiquitylated Ube2T does not signal for its degradation, but has decreased Ub transfer activity in vitro Homo sapiens
2.3.2.23 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 (EC 2.3.2.25) can serve as the template for chain building by Ube2N and Ube2K Homo sapiens
2.3.2.23 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. Enzyme Ube2D2 is a promiscuous lysine- and cysteine-reactive E2. OTUB1 DUB activity is enhanced by interaction with free E2s. Binding of Ube2D2 stabilizes the disordered OTUB1 N-terminus in an alpha-helical conformation, which completes the binding site for K48-linked diUb. The E2-mediated conformational change decreases the Km of OTUB1 for diUb by over 35fold, thereby enhancing the rate of OTUB1-dependent polyUb degradation. The E2 acting as an effector protein to stimulate enzyme (DUB) activity Homo sapiens
2.3.2.23 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. UBE2B functions in DNA damage repair. The chain-building activity of other E2s is enhanced by Ub backside binding as well. The interaction is critical for the E3-independent ability of Ube2B to build K11-linked polyUb chains. PCNA is monoubiquitylated by the Ube2A/B (Rad6) E2s and the RING E3 Rad18 during postreplicative DNA damage repair Homo sapiens
2.3.2.24 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 Homo sapiens
2.3.2.24 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 Homo sapiens
2.3.2.24 additional information E2 structure-function analysis, overview. Enzyme UBE2O is a large multidomain E2/E3 hybrid performing the E2 and the E3 reaction Homo sapiens
2.3.2.24 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 Homo sapiens
2.3.2.25 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 Homo sapiens
2.3.2.25 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 Homo sapiens
2.3.2.25 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 Homo sapiens
2.3.2.25 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 Homo sapiens