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Information on EC 2.3.2.26 - HECT-type E3 ubiquitin transferase
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EC Tree
2.3.2.26 HECT-type E3 ubiquitin transferaseIUBMB Comments
In the first step the enzyme transfers ubiquitin from the E2 ubiquitin-conjugating enzyme (EC 2.3.2.23) to a cysteine residue in its HECT domain (which is located in the C-terminal region), forming a thioester bond. In a subsequent step the enzyme transfers the ubiquitin to an acceptor protein, resulting in the formation of an isopeptide bond between the C-terminal glycine residue of ubiquitin and the epsilon-amino group of an L-lysine residue of the acceptor protein. cf. EC 2.3.2.27, RING-type E3 ubiquitin transferase and EC 2.3.2.31, RBR-type E3 ubiquitin transferase.
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Word Map
- 2.3.2.26
- ligases
- proteasome
- smads
-
polyubiquitination
-
ubiquitin-proteasome
- adaptor
- tumorigenesis
- lysosomal
- osteoblast
- pten
-
ubiquitin-dependent
- endosomal
-
itch
-
ubiquitin-mediated
-
morphogenetic
-
endocytosis
- factor-beta
- rhoa
-
osteogenic
- rsp5
-
deubiquitinating
- oncoproteins
-
angelman
-
cell-expressed
- tgf-beta
- papillomavirus
-
e6-associated
- runx2
-
tensin
-
deubiquitinase
-
e3-ubiquitin
-
escrt
- ebola
- ehrlichiae
-
liddle
-
4-like
-
ubiquitin-binding
- chaffeensis
-
monoubiquitination
-
virus-like
-
proteasome-mediated
-
amiloride-sensitive
-
k63-linked
-
ubiquitin-conjugating
-
autoubiquitination
- analysis
-
ubiquitin-activating
- synthesis
-
ubiquitin-ligase
-
ubiquitination-mediated
-
smad1/5
- medicine
-
receptor-regulated
The enzyme appears in viruses and cellular organisms
Reaction Schemes
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=
+
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine
+
[acceptor protein]-L-lysine
=
[E2 ubiquitin-conjugating enzyme]-L-cysteine
+
[acceptor protein]-N6-ubiquitinyl-L-lysine
Synonyms
nedd4, smurf1, smurf2, huwe1, nedd4l, nedd4-1, e6-ap, ube3c, trp120, trip12, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
HECT domain E3 ubiquitin ligase
HECT-type E3 ligase
HECT-type ubiquitin E3 ligase
Herc4
Itch
Nedd4
Nedd4L
RSP5
Smurf2
TRIP12
Ube3C
UBR1
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-N6-ubiquitinyl-L-lysine
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [HECT-type E3 ubiquitin transferase]-L-cysteine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [HECT-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine
(1a)
-
-
-
[HECT-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [HECT-type E3 ubiquitin transferase]-L-cysteine + [acceptor protein]-N6-ubiquitinyl-L-lysine
(1b)
-
-
-
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-N6-ubiquitinyl-L-lysine
overall reaction
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-
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[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-N6-ubiquitinyl-L-lysine
HECT ligases directly catalyse protein ubiquitination and non-covalently interact with ubiquitin. The ubiquitin bindung surface on the HECT might act to bind a ubiquitin moiety that is already conjugated to a protein substrate, thus promoting polyubiquitination. Mutation in the ubiquitin bindung surface strongly impairs free-chain fdormation and ubiquitination of all substrates tested
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine:[acceptor protein] ubiquitin transferase (isopeptide bond-forming)
In the first step the enzyme transfers ubiquitin from the E2 ubiquitin-conjugating enzyme (EC 2.3.2.23) to a cysteine residue in its HECT domain (which is located in the C-terminal region), forming a thioester bond. In a subsequent step the enzyme transfers the ubiquitin to an acceptor protein, resulting in the formation of an isopeptide bond between the C-terminal glycine residue of ubiquitin and the epsilon-amino group of an L-lysine residue of the acceptor protein. cf. EC 2.3.2.27, RING-type E3 ubiquitin transferase and EC 2.3.2.31, RBR-type E3 ubiquitin transferase.
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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-(ubiquitin)n-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [adenomatous polyposis coli]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-(ubiquitin)n-[adenomatous polyposis coli]-L-lysine
-
adenomatous polyposis coli protein functions as a negative regulator of the Wnt signaling pathway
isoform HECTD1 modifies adenomatous polyposis coli with Lys63 polyubiquitin
-
?
S-(ubiquitin)n-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [Dvl2]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-(ubiquitin)n-[Dvl2]-L-lysine
Dvl2 i.e. dishevelled, a central mediator for both Wnt/beta-catenin and Wnt/planar cell polarity pathways
isoform NEDD4L mediates polyubiquitination of Dvl2 at Lys6, Lys27, and Lys29
-
?
S-(ubiquitin)n-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [Glis3]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-(ubiquitin)n-[Glis3]-L-lysine
-
Glis i.e. transcription factor Gli-similar 3
isoform Itch significantly contributes to Glis3 polyubiquitination and reduces Glis3 stability by enhancing its proteasomal degradation. Itch-mediated degradation of Glis3 requires the PPxY motif-dependent interaction between Glis3 and the WW-domains of Itch as well as the presence of the Glis3 zinc finger domains. Itch dramatically inhibits Glis3-mediated transactivation and endogenous Ins2 expression by increasing Glis3 protein turnover
-
?
S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [caspase-8]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[caspase-8]-L-lysine
-
isoform HECTD3 ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation
-
?
S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [ING2]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[ING2]-L-lysine
ING2 i.e. candidate tumor suppressor Inhibitor of Growth 2
isoform Smurf1 interacts with and targets ING2 for poly-ubiquitination and proteasomal degradation. The ING2 binding domain in Smurf1 was mapped to the catalytic HECT domain. The C-terminal PHD domain of ING2 is required for Smurf1-mediated degradation
-
?
S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [Sav]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[Sav]-L-lysine
S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [Spry2]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[Spry2]-L-lysine
Spry2 is a regulator of receptor tyrosine kinase signaling in development and disease
isoform Nedd4 polyubiquitinates Spry2 via Lys48 on ubiquitin and decreases its stability. The Spry2/Nedd4 association involves theWW domains of Nedd4 and requires phosphorylation of the Mnk2 kinase sites, Ser112 and Ser121, on Spry2. The phospho-Ser112/121 region on Spry2 that binds WW domains of Nedd4 is a non-canonical WW domain binding region that does not contain Pro residues after phospho-Ser
-
?
S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [ubiquitin]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[ubiquitin]-L-lysine
-
isoform NleL functionally and structurally mimics eukaryotic HECT E3 ligases and catalyzes formation of unanchored polyubiquitin chains using Lys6 and Lys48 linkage. The catalytic cysteine residue forms a thioester intermediate with ubiquitin
-
?
S-ubiquitinyl-[HECT-type E3 ubiquitin transferase]-L-cysteine + [Sox6 protein]-L-lysine
[HECT-type E3 ubiquitin transferase]-L-cysteine + N6-ubiquitinyl-[Sox6 protein]-L-lysine
S-ubiquitinyl-[Ubc-18]-L-cysteine + [IFY-1]-L-lysine
[Ubc-18]-L-cysteine + N6-ubiquitinyl-[IFY-1]-L-lysine
-
IFY-1 i.e. anaphase inhibitor securin
-
-
?
S-ubiquitinyl-[UbcH5a]-L-cysteine + [ubiquitin mutant G76V]-L-lysine
[UbcH5a]-L-cysteine + N6-ubiquitinyl-[mutant G76V]-L-lysine
-
-
-
?
S-ubiquitinyl-[UbcH5a]-L-cysteine + [ubiquitin-DELTAGG]-L-lysine
[UbcH5a]-L-cysteine + N6-ubiquitinyl-[ubiquitin-DELTAGG]-L-lysine
ubiquitin-DELTAGG i.e. mutant ubiquitin lacking the two C-terminal glycine residues, cannot be conjugated to other proteins
-
-
?
S-ubiquitinyl-[UbcH7]-L-cysteine + [endophilin A]-L-lysine
[UbcH7]-L-cysteine + N6-ubiquitinyl-[endophilin A]-L-lysine
-
isoform Itch ubiquitinates SH3 domain-containing protein endophilin A1 and the SH3/proline-rich domain interaction facilitates this activity. EGF treatment of cells stimulates endophilin A1 ubiquitination
-
?
[AIP2-ubiquitin-conjugating enzyme E2]-S-ubiquitin-L-cysteine + [EGR2]-L-lysine
[AIP2-ubiquitin-conjugating enzyme E2]-L-cysteine + [EGR2]-N6-ubiquitinyl-L-lysine
EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand expression during activation-induced T-cell death
-
-
?
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [Dvl2]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [Dvl2]-N6-ubiquitinyl-L-lysine
-
-
-
?
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [my-opioid receptor MOR1]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [my-opioid receptor MOR1]-N6-ubiquitinyl-L-lysine
-
-
-
?
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [Spo12]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [Spo12]-N6-ubiquitinyl-L-lysine
-
-
-
-
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [Ubl4A]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [Ubl4A]-N6-ubiquitinyl-L-lysine
Ubl4A, i.e. subunit of the Bag6 chaperone holdase complex. HUWE1 degrades unassembled Ubl4A in the cytoplasm
-
-
?
[HECT-E3-ubiquitin-carrier protein Arel1]-S-ubiquitin-L-cysteine + [SMAC]-L-lysine
[HECT-E3-ubiquitin-carrier protein Arel1]-L-cysteine + [SMAC]-N6-ubiquinyl-L-lysine
SMAC i.e. proapoptotic protein second mitochondria-derived activator of caspase
-
-
?
[HECT-E3-ubiquitin-carrier protein NEDD4L]-S-ubiquitin-L-cysteine + [Ubc5B]-L-lysine
[HECT-E3-ubiquitin-carrier protein NEDD4]-L-cysteine + [Ubc5B]-N6-ubiquinyl-L-lysine
-
-
-
-
?
[HECT-E3-ubiquitin-carrier protein NEDD4]-S-ubiquitin-L-cysteine + [gamma-epithel Na+-channel]-L-lysine
[HECT-E3-ubiquitin-carrier protein NEDD4]-L-cysteine + [gamma-epithel Na+-channel]-N6-ubiquinyl-L-lysine
His-tagged Ube2D3, in addition the reaction mixture contains purified E1 enzyme and ubiquitin
-
-
?
[HECT-E3-ubiquitin-carrier protein NEDD4]-S-ubiquitin-L-cysteine + [SQSTM1]-L-lysine
[HECT-E3-ubiquitin-carrier protein NEDD4]-L-cysteine + [SQSTM1]-N6-ubiquinyl-L-lysine
SQSTM1 i.e. an autophagic cargo receptor involved in selective autophagy
-
-
?
[Nedd4-1-ubiquitin-conjugating enzyme E2]-S-ubiquitin-L-cysteine + [activated Cdc42-associated tyrosine kinase]-L-lysine
[Nedd4-1ubiquitin-conjugating enzyme E2]-L-cysteine + [activated Cdc42-associated tyrosine kinase]-N6-ubiquitinyl-L-lysine
activated Cdc42-associated tyrosine kinase is ubiquitinated by HECT E3 ubiquitin ligase Nedd4-1 and degraded along with epidermal growth factor receptor in response to epidermal growth factor stimulation. Activated Cdc42-associated tyrosine kinase interacts with Nedd4-1 through a conserved PPXY WW-binding motif. The WW3 domain in Nedd4-1 is critical for binding to activated Cdc42-associated tyrosine kinase. Deletion of the sterile alpha motif SAM-domain at the N-terminus dramatically reduces the ubiquitination of activated Cdc42-associated tyrosine kinase by Nedd4-1, while deletion of the Uba domain dramatically enhances the ubiquitination. Activated Cdc42-associated tyrosine kinase degradation is processed by lysosomes, not proteasomes
-
-
?
[Nedd4-1-ubiquitin-conjugating enzyme E2]-S-ubiquitin-L-cysteine + [epidermal growth factor receptor]-L-lysine
[Nedd4-1-ubiquitin-conjugating enzyme E2]-L-cysteine + [epidermal growth factor receptor]-N6-ubiquitinyl-L-lysine
epidermal growth factor receptor and activated Cdc42-associated tyrosine kinase are ubiquitinated by ubiquitin ligase Nedd4-1 in response to epidermal growth factor stimulation
-
-
?
[Rsp-ubiquitin-conjugating enzyme UbcH5B]-S-ubiquitin-L-cysteine + [Sna3 cytoplasmic domain]-L-lysine
[Rsp5-ubiquitin-conjugating enzyme UbcH5B]-L-cysteine + [Sna3 cytoplasmic domain]-N6-ubiquitinyl-L-lysine
[TRIP1-ubiquitin-conjugating enzyme E2]-S-ubiquitin-L-cysteine + [APP-BP1]-L-lysine
[TRIP12-ubiquitin-conjugating enzyme E2]-L-cysteine + [APP-BP1]-N6-ubiquitinyl-L-lysine
ubiquitin ligase TRIP12 functions as an E3 enzyme of APP-BP1 and additionally requires an E4 activity for polyubiquitination of APP-BP1. APP-BP1 is part of the ubiquitin-like protein NEDD8 activating enzyme. TRIP12 specifically interacts with the APP-BP1 monomer but not with the APP-BP1/Uba3 heterodimer. Overexpression of TRIP12 enhances the degradation of APP-BP1, whereas knockdown of TRIP12 stabilizes it
-
-
?
[ubiquitin ligase HECTD3]-S-ubiquitin-L-cysteine + [Tara]-L-lysine
[ubiquitin ligase HECTD3]-L-cysteine + [Tara]-N6-ubiquitinyl-L-lysine
Tara, Trio-associated repeat on actin, is an interacting partner of guanine nucleotide exchange factors Trio and TRF1. Ubiquitin-protein ligase HECTD3 directly binds Tara in vitro and forms a complex with Tara in vivo. Overexpression of HECTD3 enhances the ubiquitination of Tara in vivo and promotes the turnover of Tara, whereas depletion of HECTD3 by small interfering RNA decreases Tara degradation
-
-
?
[ubiquitin-conjugating enzyme E2D3]-S-ubiquitin-L-cysteine + [latent membrane protein 2A LMP2A]-L-lysine
[ubiquitin-conjugating enzyme E2D3]-L-cysteine + [latent membrane protein 2A LMP2A]-N6-ubiquitinyl-L-lysine
His-tagged Ube2D3, in addition the reaction mixture contains purified E1 enzyme and ubiquitin
-
-
?
[ubiquitin-conjugating enzyme E2]-S-ubiquitin-L-cysteine + [transcription factor WRKY53]-L-lysine
[ubiquitin-conjugating enzyme E2D3]-L-cysteine + [transcription factor WRKY53]-N6-ubiquitinyl-L-lysine
UPL5 is able to use the WRKY53 protein as a substrate for polyubiquitination in an in vitro system, and induction of UPL5 expression by an ethanol-inducible system in upl5 plants leads to degradation of the WRKY53 protein
-
-
?
S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [Sav]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[Sav]-L-lysine
-
Sav i.e. scaffold protein Salvador, believed to promote Hpo/Wts association
-
-
?
S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [Sav]-L-lysine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[Sav]-L-lysine
-
Sav i.e. scaffold protein Salvador, believed to promote Hpo/Wts association
-
-
?
S-ubiquitinyl-[HECT-type E3 ubiquitin transferase]-L-cysteine + [Sox6 protein]-L-lysine
[HECT-type E3 ubiquitin transferase]-L-cysteine + N6-ubiquitinyl-[Sox6 protein]-L-lysine
-
-
-
?
S-ubiquitinyl-[HECT-type E3 ubiquitin transferase]-L-cysteine + [Sox6 protein]-L-lysine
[HECT-type E3 ubiquitin transferase]-L-cysteine + N6-ubiquitinyl-[Sox6 protein]-L-lysine
-
-
-
-
?
[Rsp-ubiquitin-conjugating enzyme UbcH5B]-S-ubiquitin-L-cysteine + [Sna3 cytoplasmic domain]-L-lysine
[Rsp5-ubiquitin-conjugating enzyme UbcH5B]-L-cysteine + [Sna3 cytoplasmic domain]-N6-ubiquitinyl-L-lysine
a specific HECT domain architecture may be important for ubiquitin ligation to Sna3 cytoplasmic domain, which involves both the catalytic C-lobe and the distal N-lobe packing differently from the arrangement promoting ubiquitin transfer from E2 enzyme to E3-ubiquitin intermediate
-
-
?
[Rsp-ubiquitin-conjugating enzyme UbcH5B]-S-ubiquitin-L-cysteine + [Sna3 cytoplasmic domain]-L-lysine
[Rsp5-ubiquitin-conjugating enzyme UbcH5B]-L-cysteine + [Sna3 cytoplasmic domain]-N6-ubiquitinyl-L-lysine
a specific HECT domain architecture may be important for ubiquitin ligation to Sna3 cytoplasmic domain, which involves both the catalytic C-lobe and the distal N-lobe packing differently from the arrangement promoting ubiquitin transfer from E2 enzyme to E3-ubiquitin intermediate
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-
?
additional information
?
-
isoform UPL5 interacts with transcription factor WRKY53 via its leucine zipper domain
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?
additional information
?
-
HECT ligases directly catalyse protein ubiquitination and non-covalently interact with ubiquitin. The ubiquitin bindung surface on the HECT might act to bind a ubiquitin moiety that is already conjugated to a protein substrate, thus promoting polyubiquitination. Mutation in the ubiquitin bindung surface (F707A and Y605A) mutants strongly impairs free-chain formation and ubiquitination of all substrates tested
-
-
?
additional information
?
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Nedd4 has a strong preference for building Lys63 ubiquitin-chains on substrates. Mutant F707A has defective chain elongation on substrate or shorter free chains
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-
?
additional information
?
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C2 domain of isoform Smurf1 functions in substrate selection
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-
?
additional information
?
-
high-risk human papilloma virus E6 oncoproteins interact with the ubiquitin ligase E6AP and target several cellular proteins, including p53 and proteins of the MAGI family, towards ubiquitin-mediated degradation. E6 oncoproteins from major high-risk human papilloma virus types 16, 18, 33 and 58 bind to a 15-mer peptide containing the LxxphiLsh motif of E6AP, where L indicates conserved leucine residues, phi is a hydrophobic residue, h is an amino acid residue with a side-chain capable of accepting hydrogen bonds, s represents a small amino acid residue and xx is a dipeptide where one of the residues is Asp, Asn, Glu or Gln. The equilibrium dissociation constants are in the low micromolar range. Low-risk human papilloma virus 11 E6 does not interact with E6AP. The two zinc-binding domains of E6 are required for E6AP recognition
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?
additional information
?
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isoform E6-AP is loaded with ubiquitin by E2 enzyme UbcH5. A region of UbcH5 encompassing the catalytic site cysteine residue is critical for its ability to interact with E6-AP
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-
?
additional information
?
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isoform E6-AP is loaded with ubiquitin by E2 enzyme UbcH5. A region of UbcH5 encompassing the catalytic site cysteine residue is critical for its ability to interact with E6-AP
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-
?
additional information
?
-
UBE3B shows HECT E3 ubiquitin ligase activity and exhibits time-dependent auto-ubiquitylation activity
-
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-
additional information
?
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UBE3B shows HECT E3 ubiquitin ligase activity and exhibits time-dependent auto-ubiquitylation activity
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-
-
additional information
?
-
UBE3C HECT domain assembles K48-linked polyubiquitin chains
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-
-
additional information
?
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isoform Rsp5 is loaded with ubiquitin by E2 enzyme UbcH5. A region of UbcH5 encompassing the catalytic site cysteine residue is critical for its ability to interact with RSP5
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-
?
additional information
?
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-
isoform Rsp5 is loaded with ubiquitin by E2 enzyme UbcH5. A region of UbcH5 encompassing the catalytic site cysteine residue is critical for its ability to interact with RSP5
-
-
?
additional information
?
-
the type-1/2 substrate-binding sites of isoform UBR1, are located in the first 700 residues of the 1950-residue enzyme. Type-1 site is specific for basic N-terminal residues Arg, Lys, and His. The type-2 site is specific for bulky hydrophobic N-terminal residues Trp, Phe, Tyr, Leu, and Ile. Isoform UBR1 binds, with a Kd of about 1microM to either type-1 or type-2 N-terminal residues of reporter peptides but does not bind to a stabilizing N-terminal residue such as Gly
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-
?
additional information
?
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ubiquitin ligases HECT E3 use a two-step mechanism to ligate ubiquitin to target proteins. The second step of ligation is mediated by a distinct catalytic architecture established by both the HECT E3 and its covalently linked ubiquitin. There exist three-way interactions between ubiquitin and the bilobal HECT domain orienting the E3-ubiquitin thioester bond for ligation, and restricting the location of the substrate-binding domain to prioritize targets lysines for ubiquitination
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-
?
additional information
?
-
UBR1 and CUP9, a transcriptional repressor of peptide import, interact nonspecifically and specific binding which involves, in particular, the binding by cognate dipeptides to theUBR1 type-1/2 substrate-binding sites, can be restored either by a chaperone such as EF1A or through macromolecular crowding
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-
?
additional information
?
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the type-1/2 substrate-binding sites of isoform UBR1, are located in the first 700 residues of the 1950-residue enzyme. Type-1 site is specific for basic N-terminal residues Arg, Lys, and His. The type-2 site is specific for bulky hydrophobic N-terminal residues Trp, Phe, Tyr, Leu, and Ile. Isoform UBR1 binds, with a Kd of about 1microM to either type-1 or type-2 N-terminal residues of reporter peptides but does not bind to a stabilizing N-terminal residue such as Gly
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-
?
additional information
?
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UBR1 and CUP9, a transcriptional repressor of peptide import, interact nonspecifically and specific binding which involves, in particular, the binding by cognate dipeptides to theUBR1 type-1/2 substrate-binding sites, can be restored either by a chaperone such as EF1A or through macromolecular crowding
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-
?
additional information
?
-
ubiquitin ligases HECT E3 use a two-step mechanism to ligate ubiquitin to target proteins. The second step of ligation is mediated by a distinct catalytic architecture established by both the HECT E3 and its covalently linked ubiquitin. There exist three-way interactions between ubiquitin and the bilobal HECT domain orienting the E3-ubiquitin thioester bond for ligation, and restricting the location of the substrate-binding domain to prioritize targets lysines for ubiquitination
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-
?
additional information
?
-
isoform Rsp5 is loaded with ubiquitin by E2 enzyme UbcH5. A region of UbcH5 encompassing the catalytic site cysteine residue is critical for its ability to interact with RSP5
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-
?
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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-[HECT-type E3 ubiquitin transferase]-L-cysteine + [Sox6 protein]-L-lysine
[HECT-type E3 ubiquitin transferase]-L-cysteine + N6-ubiquitinyl-[Sox6 protein]-L-lysine
S-ubiquitinyl-[HECT-type E3 ubiquitin transferase]-L-cysteine + [Sox6 protein]-L-lysine
[HECT-type E3 ubiquitin transferase]-L-cysteine + N6-ubiquitinyl-[Sox6 protein]-L-lysine
-
-
-
?
S-ubiquitinyl-[HECT-type E3 ubiquitin transferase]-L-cysteine + [Sox6 protein]-L-lysine
[HECT-type E3 ubiquitin transferase]-L-cysteine + N6-ubiquitinyl-[Sox6 protein]-L-lysine
-
-
-
-
?
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4-[[(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino]methyl]-N-(pyridin-4-yl)benzamide
compound exhibits remarkable anticancer activity with tumor growth inhibition values of 98.3% and 100% at 25 mg/kg and 50 mg/kg orally daily, respectively, against human RPMI-8226 multiple myeloma xenograft. Treatment with the compound also shows a decrease of Itch level in human RPMI-8226 multiple myeloma cells
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Calmodulin
UBE3B interacts with calmodulin via its N-terminal isoleucine-glutamine motif. Deletion of the motif (amino acids 29-58) results in loss of calmodulin binding and a significant increase in the in vitro ubiquitylation activity of UBE3B. Changes in calcium levels in vitro disrupt the calmodulin-UBE3B interaction
clomipramine
antidepressant drug, specifically blocks isoform ITCH auto-ubiquitylation, as well as p73 ubiquitylation. Treating a panel of breast, prostate and bladder cancer cell lines with clomipramine, or its homologs, leads to reduced cancer cell growth, and synergize with gemcitabine or mitomycin in killing cancer cells by blocking autophagy. Minimum inhibitory concentration is 0.3 mM
N-acetylphenylalanylamide
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i.e. Phe-823 mimic, acts as a noncompetitive inhibitor of polyubiquitin chain elongation by destabilizing the active trimer
additional information
autoinhibition mechanism of domains C2-HECT is not observed in isoform Smurf1
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ARRDC1
alpha-arrestin, anchoring an ARRDC1-GFP construct to the membrane results in efficient activation and autoubiquitination of NEDD4 ligase
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Ca2+
when the concentration of calcium is increased, calmodulin is released from UBE3B, resulting in an increase in ubiquitylation activity
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE