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Information on EC 2.3.2.34 - E2 NEDD8-conjugating enzyme and Organism(s) Homo sapiens and UniProt Accession Q969M7
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2.3.2.34 E2 NEDD8-conjugating enzymeIUBMB Comments
Some RING-type E3 ubiquitin transferases (EC 2.3.2.27) are not able to bind a substrate protein directly. Instead, they form complexes with a cullin scaffold protein and a substrate recognition module, which are known as CRL (Cullin-RING-Ligase) complexes. The cullin protein needs to be activated by the ubiquitin-like protein NEDD8 in a process known as neddylation. Like ubiquitin, the NEDD8 protein ends with two glycine residues. EC 6.2.1.64, E1 NEDD8-activating enzyme, activates NEDD8 in an ATP-dependent reaction by forming a high-energy thioester intermediate between NEDD8 and one of its cysteine residues. The activated NEDD8 is subsequently transferred to a cysteine residue of an E2 NEDD8-conjugating enzyme, and is eventually conjugated to a lysine residue of specific substrates in the presence of the appropriate E3 transferase (EC 2.3.2.32, cullin-RING-type E3 NEDD8 transferase).
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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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[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine
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[E2 NEDD8-conjugating enzyme]-L-cysteine
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[E1 NEDD8-activating enzyme]-L-cysteine
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[E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
Synonyms
ubc12, ube2m, ube2f, nedd8-conjugating enzyme, nedd8 e2, e2 nedd8-conjugating enzyme, nedd8-conjugating enzyme e2, neddylation e2-conjugating enzyme, e2 neddylation conjugating enzyme, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
NEDD8-carrier-protein E2
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NEDD8-conjugating enzyme E2
Ubc12
UBE2F
UBE2M
NEDD8-conjugating enzyme E2
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UBE2F
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UBE2M
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine:[E2 NEDD8-conjugating enzyme] [NEDD8-protein]-yl transferase
Some RING-type E3 ubiquitin transferases (EC 2.3.2.27) are not able to bind a substrate protein directly. Instead, they form complexes with a cullin scaffold protein and a substrate recognition module, which are known as CRL (Cullin-RING-Ligase) complexes. The cullin protein needs to be activated by the ubiquitin-like protein NEDD8 in a process known as neddylation. Like ubiquitin, the NEDD8 protein ends with two glycine residues. EC 6.2.1.64, E1 NEDD8-activating enzyme, activates NEDD8 in an ATP-dependent reaction by forming a high-energy thioester intermediate between NEDD8 and one of its cysteine residues. The activated NEDD8 is subsequently transferred to a cysteine residue of an E2 NEDD8-conjugating enzyme, and is eventually conjugated to a lysine residue of specific substrates in the presence of the appropriate E3 transferase (EC 2.3.2.32, cullin-RING-type E3 NEDD8 transferase).
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
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
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?
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
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?
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
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?
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
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?
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
conjugation of NEDD8 to UBC12 requires the involvement of APP-BP1 and UBA3
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additional information
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RBX2 is specific for UBE2F, which mediates neddylation of the RBX2 partner, cullin 5
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additional information
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RBX2 is specific for UBE2F, which mediates neddylation of the RBX2 partner, cullin 5
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additional information
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RBX2 is specific for UBE2F, which mediates neddylation of the RBX2 partner, cullin 5
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additional information
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the enzyme participates in neddylation of DNA-dependent protein kinase catalytic subunit
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additional information
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UBC12 is specific for RBX1 and mediates neddylation of RBX1-associated cullins 1, 2, 3 and 4
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additional information
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UBC12 is specific for RBX1 and mediates neddylation of RBX1-associated cullins 1, 2, 3 and 4
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additional information
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UBC12 is specific for RBX1 and mediates neddylation of RBX1-associated cullins 1, 2, 3 and 4
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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
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
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?
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
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?
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
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?
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
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?
[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine
[E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
conjugation of NEDD8 to UBC12 requires the involvement of APP-BP1 and UBA3
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?
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
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enzyme depletion results in decreased DNA-dependent protein kinase catalytic subunit neddylation
metabolism
physiological function
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UBE2M is a dual E2 for targeted ubiquitylation and degradation of UBE2F, acting as a neddylation E2 to activate cullin 3-Keap1 E3 under physiological condition, but as an ubiquitylation E2 for Parkin-DJ-1 E3 under stressed conditions. UBE2M-induced UBE2F degradation leads to CRL5 inactivation and subsequent NOXA accumulation to suppress the growth of lung cancer cells
metabolism
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the enzyme incorporates with E3 neddylation ligase to induce cullin-RING ligase-5 neddylation, leading to activation of cullin-RING ligase-5 E3 to promote NOXA polyubiquitylation via K11 linkage for proteasomal degradation
metabolism
the N-terminal extension of Ubc12 is a selective peptide motif that optimally recruits NEDD8 E1 for the NEDD8 transfer cascade and plays an important role in mitogenesis
metabolism
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UBC12 pairs with RBX1/ROC1 to regulate the neddylation of cullin 1, 2, 3, 4a, 4b and 7, while UBE2F pairs with RBX2/ROC2 to regulate the neddylation of cullin 5
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). SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging drop vapor diffusion method, using 2.28 M sodium malonate, pH 7.0
hanging drop vapor diffusion method, using 20% (w/v) PEG2000 MME, 0.1 M NaBr, 3% (w/v) sorbitol
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
F5A
the mutant shows a strongly decreased Km value for E1 NEDD8-activating enzyme compared to the wild type
F5A/L7A
the mutant shows a strongly decreased Km value for E1 NEDD8-activating enzyme compared to the wild type
K11A
the mutant shows a wild type Km value for E1 NEDD8-activating enzyme
K12A
the mutant shows a decreased Km value for E1 NEDD8-activating enzyme compared to the wild type
L4A
the mutant shows a decreased Km value for E1 NEDD8-activating enzyme compared to the wild type
L4A/F5A/L7A
the mutant shows a strongly decreased Km value for E1 NEDD8-activating enzyme compared to the wild type
L7A
the mutant shows a strongly decreased Km value for E1 NEDD8-activating enzyme compared to the wild type
M1A
the mutant shows an increased Km value for E1 NEDD8-activating enzyme compared to the wild type
Q10A
the mutant shows a wild type Km value for E1 NEDD8-activating enzyme
Q9A
the mutant shows a decreased Km value for E1 NEDD8-activating enzyme compared to the wild type
S6A
the mutant shows a decreased Km value for E1 NEDD8-activating enzyme compared to the wild type
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
UBE2M is a stress-inducible gene subjected to cis-trans-activation by hypoxia-inducible factor-1alpha and transcription factor AP-1. MLN4924, a small molecule inhibitor of E1 NEDD8-activating enzyme, up-regulates UBE2M via blocking degradation of hypoxia-inducible factor-1alpha and transcription factor AP-1
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Monda, J.; Scott, D.; Miller, D.; Lydeard, J.; King, D.; Harper, J.; Bennett, E.; Schulman, B.
Structural conservation of distinctive N-terminal acetylation-dependent interactions across a family of mammalian NEDD8 ligation enzymes
Structure
21
42-53
2013
Homo sapiens (P61081), Homo sapiens (Q969M7), Homo sapiens
Zhang, S.; Sun, Y.
Cullin RING Ligase 5 (CRL-5) neddylation activation and biological functions
Adv. Exp. Med. Biol.
1217
261-283
2020
Homo sapiens
Guo, Z.; Wang, S.; Xie, Y.; Han, Y.; Hu, S.; Guan, H.; Xie, D.; Bai, C.; Liu, X.; Gu, Y.; Zhou, P.K.; Ma, T.
HUWE1-dependent DNA-PKcs neddylation modulates its autophosphorylation in DNA damage response
Cell Death Dis.
11
400
2020
Homo sapiens
Yin, L.; Xue, Y.; Shang, Q.; Zhu, H.; Liu, M.; Liu, Y.; Hu, Q.
Pharmaceutical inhibition of neddylation as promising treatments for various cancers
Curr. Top. Med. Chem.
19
1059-1069
2019
Homo sapiens (P61081)
Li, L.; Kang, J.; Zhang, W.; Cai, L.; Wang, S.; Liang, Y.; Jiang, Y.; Liu, X.; Zhang, Y.; Ruan, H.; Chen, G.; Wang, M.; Jia, L.
Validation of NEDD8-conjugating enzyme UBC12 as a new therapeutic target in lung cancer
EBioMedicine
45
81-91
2019
Homo sapiens
Osaka, F.; Kawasaki, H.; Aida, N.; Saeki, M.; Chiba, T.; Kawashima, S.; Tanaka, K.; Kato, S.
A new NEDD8-ligating system for cullin-4A
Genes Dev.
12
2263-2268
1998
Homo sapiens (P61081)
Gong, L.; Yeh, E.
Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway
J. Biol. Chem.
274
12036-12042
1999
Homo sapiens (P61081), Homo sapiens
Zhou, W.; Xu, J.; Tan, M.; Li, H.; Li, H.; Wei, W.; Sun, Y.
UBE2M is a stress-inducible dual E2 for neddylation and ubiquitylation that promotes targeted degradation of UBE2F
Mol. Cell
70
1008-1024
2018
Homo sapiens
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