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Information on EC 2.3.2.33 - RCR-type E3 ubiquitin transferase
for references in articles please use BRENDA:EC2.3.2.33
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EC Tree 2 Transferases
2.3 Acyltransferases
2.3.2 Aminoacyltransferases
2.3.2.33 RCR-type E3 ubiquitin transferase
IUBMB Comments
RCR-type E3 ubiquitin transferases is a class of RING-type E3 ubiquitin transferase (see EC 2.3.2.27) that mediates ubiquitylation of acceptor proteins via an internal cysteine residue. The RING1 domain binds an EC 2.3.2.23, E2 ubiquitin-conjugating enzyme, and transfers the ubiquitin that is bound to it to an internal cysteine residue on a mediator loop of the RCR-type ligase. The ubiquitin may be transferred to a second internal cysteine before the transfer of the ubiquitin from the RCR-type ligase to the substrate.
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-threonine
=
[E2 ubiquitin-conjugating enzyme]-L-cysteine
+
[acceptor protein]-3-O-ubiquitinyl-L-threonine
Synonyms
rpm-1, mycbp2, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
E3 ubiquitin-protein ligase
MYCBP2
PHR1
MYCBP2
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-
PHR1
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-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
overall reaction
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-
-
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [RCR-type E3 ubiquitin transferase]-L-cysteine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine
(1a)
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-
-
[RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine = [RCR-type E3 ubiquitin transferase]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
(1b)
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SYSTEMATIC NAME
IUBMB Comments
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine:acceptor protein ubiquitin transferase (isopeptide bond-forming; RCR-type)
RCR-type E3 ubiquitin transferases is a class of RING-type E3 ubiquitin transferase (see EC 2.3.2.27) that mediates ubiquitylation of acceptor proteins via an internal cysteine residue. The RING1 domain binds an EC 2.3.2.23, E2 ubiquitin-conjugating enzyme, and transfers the ubiquitin that is bound to it to an internal cysteine residue on a mediator loop of the RCR-type ligase. The ubiquitin may be transferred to a second internal cysteine before the transfer of the ubiquitin from the RCR-type ligase to the substrate.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [F-box protein FBXW7]-L-threonine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [F-box protein FBXW7]-3-O-ubiquitinyl-L-threonine
Substrates: -
Products: -
Products: -
?
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [RCR-type E3 ubiquitin transferase]-L-cysteine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine
[RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[RCR-type E3 ubiquitin transferase]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
[RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [F-box protein FBXW7]-L-threonine
[RCR-type E3 ubiquitin transferase]-L-cysteine + [F-box protein FBXW7]-3-O-ubiquitinyl-L-threonine
[RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [ULK1 kinase]-L-threonine
[RCR-type E3 ubiquitin transferase]-L-cysteine + [ULK1 kinase]-3-O-ubiquitinyl-L-threonine
Substrates: -
Products: -
Products: -
?
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
Substrates: -
Products: -
Products: -
?
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
Substrates: overall reaction
Products: -
Products: -
?
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [RCR-type E3 ubiquitin transferase]-L-cysteine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine
Substrates: -
Products: -
Products: -
?
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [RCR-type E3 ubiquitin transferase]-L-cysteine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine
Substrates: -
Products: -
Products: -
?
[RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[RCR-type E3 ubiquitin transferase]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
Substrates: -
Products: -
Products: -
?
[RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[RCR-type E3 ubiquitin transferase]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
Substrates: -
Products: -
Products: -
?
[RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [F-box protein FBXW7]-L-threonine
[RCR-type E3 ubiquitin transferase]-L-cysteine + [F-box protein FBXW7]-3-O-ubiquitinyl-L-threonine
Substrates: -
Products: -
Products: -
?
[RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [F-box protein FBXW7]-L-threonine
[RCR-type E3 ubiquitin transferase]-L-cysteine + [F-box protein FBXW7]-3-O-ubiquitinyl-L-threonine
Substrates: -
Products: -
Products: -
?
additional information
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Substrates: MYCBP2 contains two essential catalytic cysteine residues that relay ubiquitin to its substrate via thioester intermediates. It shows esterification activity and intrinsic selectivity for threonine over serine
Products: -
Products: -
?
additional information
?
-
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Substrates: MYCBP2 contains two essential catalytic cysteine residues that relay ubiquitin to its substrate via thioester intermediates. It shows esterification activity and intrinsic selectivity for threonine over serine
Products: -
Products: -
?
additional information
?
-
Substrates: F-box protein FBXW7 protein levels markedly decline during extended mitotic arrest. F-box/SPRY domain-containing protein FBXO45 binds to a conserved acidic N-terminal motif of FBXW7 specifically under a prolonged delay in mitosis, leading to ubiquitylation and subsequent proteasomal degradation of FBXW7 by the FBXO45-MYCBP2 E3 ubiquitin ligase
Products: -
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additional information
?
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Substrates: MYCBP2 shows autoubiquitination activity on Lys residue
Products: -
Products: -
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [RCR-type E3 ubiquitin transferase]-L-cysteine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine
[RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[RCR-type E3 ubiquitin transferase]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
Substrates: -
Products: -
Products: -
?
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
Substrates: overall reaction
Products: -
Products: -
?
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [RCR-type E3 ubiquitin transferase]-L-cysteine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine
Substrates: -
Products: -
Products: -
?
[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [RCR-type E3 ubiquitin transferase]-L-cysteine
[E2 ubiquitin-conjugating enzyme]-L-cysteine + [RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine
Substrates: -
Products: -
Products: -
?
[RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[RCR-type E3 ubiquitin transferase]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
Substrates: -
Products: -
Products: -
?
[RCR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine
[RCR-type E3 ubiquitin transferase]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine
Substrates: -
Products: -
Products: -
?
additional information
?
-
Substrates: MYCBP2 contains two essential catalytic cysteine residues that relay ubiquitin to its substrate via thioester intermediates. It shows esterification activity and intrinsic selectivity for threonine over serine
Products: -
Products: -
?
additional information
?
-
-
Substrates: MYCBP2 contains two essential catalytic cysteine residues that relay ubiquitin to its substrate via thioester intermediates. It shows esterification activity and intrinsic selectivity for threonine over serine
Products: -
Products: -
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Colonic Neoplasms
Epigenetically regulated miR-1247 functions as a novel tumour suppressor via MYCBP2 in methylator colon cancers.
Hyperalgesia
MYCBP2 Is a Guanosine Exchange Factor for Ran Protein and Determines Its Localization in Neurons of Dorsal Root Ganglia.
Hyperalgesia
The ubiquitin ligase MYCBP2 regulates transient receptor potential vanilloid receptor 1 (TRPV1) internalization through inhibition of p38 MAPK signaling.
Infections
A Chimeric Pneumovirus Fusion Protein Carrying Neutralizing Epitopes of Both MPV and RSV.
Melanoma
miR-92a-3p and MYCBP2 are involved in MS-275-induced and c-myc-mediated TRAIL-sensitivity in melanoma cells.
Neoplasms
Epigenetically regulated miR-1247 functions as a novel tumour suppressor via MYCBP2 in methylator colon cancers.
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Clinical significance of high c-MYC and low MYCBP2 expression and their association with Ikaros dysfunction in adult acute lymphoblastic leukemia.
Prostatic Neoplasms
MiR-1247-5p is overexpressed in castration resistant prostate cancer and targets MYCBP2.
Virus Diseases
A Chimeric Pneumovirus Fusion Protein Carrying Neutralizing Epitopes of Both MPV and RSV.
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
localizes to synaptic regions and the tip of the head motor neurons
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Phr1 is associated with the microtubule cytoskeleton within neurons and selectively localizes to axons
brenda
stimulation of neurons induces a GTPase-activating protein RanGAP1-dependent translocation of MYCBP2 to the nucleus
brenda
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
additional information
MYCBP2 transfers Ub to nonlysine substrates via a RING-Cys-relay mechanism, where Ub is relayed from an upstream cysteine to a downstream substrate esterification site. Transfer to the dynamic upstream cysteine, mitigates lysine activity, and requires a closed-like E2-Ub conjugate with tempered reactivity. Ub relay is facilitated by a helix-coil transition. The activity is required for normal neural development and programmed axon degeneration
physiological function
Magellan mutant embryos, having a truncated Phr1 protein, motor axons are error prone and wander inefficiently at choice points within embryos. Motor and sensory neurons from Magellan mutants display abnormal morphologies due to a breakdown in the polarized distribution of components that segregate between axons and growth cones. The Magellan phenotype can be reversed by stabilizing microtubules with taxol or inhibiting p38-MAPK activity
physiological function
mice with a MYCBP2-deficiency in peripheral sensory neurons show prolonged thermal hyperalgesia. Loss of MYCBP2 constitutively activates p38 MAPK and increases expression of several proteins involved in receptor trafficking. Loss of MYCBP2 inhibits internalization of transient receptor potential vanilloid receptor 1 (TRPV1) and prevents desensitization of capsaicin-induced calcium increases
physiological function
loss of MYCBP2 in peripheral sensory neurons inhibits the internalization of transient receptor potential vanilloid receptor 1 (TRPV1) in a p38 MAPK-dependent manner. This prevents desensitization of activity-induced calcium increases and prolongs formalin-induced thermal hyperalgesia
physiological function
Phr1 E3 ubiquitin ligase is a central component of degeneration program that drives the loss of damaged axons. Loss of Phr1 results in prolonged survival of severed axons both in the peripheral and central nervous systems, as well as preservation of motor and sensory nerve terminals. Phr1 depletion increases the axonal level of the axon survival molecule nicotinamide mononucleotide adenyltransferase 2 (NMNAT2), and NMNAT2 is necessary to mediate Phr1-dependent axon stability
physiological function
mice heterozygous for either Mycbp2 or receptor Robo2 are normal, mice double heterozygous for the two genes produce defects in dorsoventral topography in the olfactory bulb. Loss of Mycbp2 function leads to the loss of molecular identity of a subpopulation of olfactory sensory axons that normally express ROBO2. In addition, double heterozygous mice show complete absence of the hippocampal commissure
physiological function
loss of E3 ubiquitin ligase MYCBP2 causes the up-regulation of small GTPase Ran and GTPase-activating protein RanGAP1 in dorsal root ganglia under basal conditions and during inflammatory hyperalgesia. SUMOylated RanGAP1 physically interacts with MYCBP2 and inhibits its E3 ubiquitin ligase activity. Stimulation of neurons induces a RanGAP1-dependent translocation of MYCBP2 to the nucleus. In the nucleus of in dorsal root ganglia neurons MYCBP2 co-localizes with Ran and facilitates through its RCC1-like domain the GDP/GTP exchange of Ran. The nuclear localization of Ran is strongly increased in MYCBP2-deficient dorsal root ganglia
physiological function
the enzyme plays a central role in neural development and axon maintenance
Show AA Sequence and Transmembrane Helices (2717 entries)
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure of a covalently trapped E2-Ub:MYCBP2 transfer intermediate
covalently trapped E2-ubiquitin:enzyme transfer intermediate, hanging drop vapor diffusion method, using
structures of both the first and second PHR domains, displaying a beta sandwich fold composed of 11 anti-parallel beta-strands
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
G1092E
loss of function mutant. The residue is expected to disturb the topography of the conserved apical surface of RPM-1
C4572S
mutant retains activity and is able to form a discrete mono-ubiquitin adduct
C4520A
the mutation abolishes competition with native E2-E3 transthiolation, allowing assessment of enhanced rate of ububiquitin discharge to free lysine11. The mutation does not enhance lysine discharge activity
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
James, G.; Key, B.; Beverdam, A.
The E3 ubiquitin ligase Mycbp2 genetically interacts with Robo2 to modulate axon guidance in the mouse olfactory system
Brain Struct. Funct.
219
861-874
2014
Mus musculus (Q7TPH6), Mus musculus
brenda
Richter, K.T.; Kschonsak, Y.T.; Vodicska, B.; Hoffmann, I.
FBXO45-MYCBP2 regulates mitotic cell fate by targeting FBXW7 for degradation
Cell Death Differ.
27
758-772
2019
Homo sapiens (O75592)
brenda
Babetto, E.; Beirowski, B.; Russler, E.; Milbrandt, J.; DiAntonio, A.
The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction
Cell Rep.
3
1422-1429
2013
Mus musculus (Q7TPH6)
brenda
Holland, S.; Scholich, K.
Regulation of neuronal functions by the E3-ubiquitinligase protein associated with MYC (MYCBP2)
Commun. Integr. Biol.
4
513-515
2011
Mus musculus (Q7TPH6)
brenda
Holland, S.; Coste, O.; Zhang, D.D.; Pierre, S.C.; Geisslinger, G.; Scholich, K.
The ubiquitin ligase MYCBP2 regulates transient receptor potential vanilloid receptor 1 (TRPV1) internalization through inhibition of p38 MAPK signaling
J. Biol. Chem.
286
3671-3680
2011
Mus musculus (Q7TPH6)
brenda
Doerr, A.; Pierre, S.; Zhang, D.D.; Henke, M.; Holland, S.; Scholich, K.
MYCBP2 Is a guanosine exchange factor for Ran rrotein and determines its localization in neurons of dorsal root ganglia
J. Biol. Chem.
290
25620-25635
2015
Mus musculus (Q7TPH6)
brenda
Sampathkumar, P.; Ozyurt, S.A.; Miller, S.A.; Bain, K.T.; Rutter, M.E.; Gheyi, T.; Abrams, B.; Wang, Y.; Atwell, S.; Luz, J.G.; Thompson, D.A.; Wasserman, S.R.; Emtage, J.S.; Park, E.C.; Rongo, C.; Jin, Y.; Klemke, R.L.; Sauder, J.M.; Burley, S.K.
Structures of PHR domains from Mus musculus Phr1 (Mycbp2) explain the loss-of-function mutation (Gly1092-->Glu) of the C. elegans ortholog RPM-1
J. Mol. Biol.
397
883-892
2010
Mus musculus (Q7TPH6), Mus musculus, Caenorhabditis elegans (Q17551), Caenorhabditis elegans
brenda
Pao, K.C.; Wood, N.T.; Knebel, A.; Rafie, K.; Stanley, M.; Mabbitt, P.D.; Sundaramoorthy, R.; Hofmann, K.; van Aalten, D.M.F.; Virdee, S.
Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity
Nature
556
381-385
2018
Homo sapiens (O75592), Homo sapiens
brenda
Lewcock, J.; Genoud, N.; Lettieri, K.; Pfaff, S.
The Ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics
Neuron
56
604-620
2007
Mus musculus (Q7TPH6)
brenda
Mabbitt, P.D.; Loreto, A.; Dery, M.A.; Fletcher, A.J.; Stanley, M.; Pao, K.C.; Wood, N.T.; Coleman, M.P.; Virdee, S.
Structural basis for RING-Cys-relay E3 ligase activity and its role in axon integrity
Nat. Chem. Biol.
16
1227-1236
2020
Homo sapiens (O75592), Mus musculus (Q7TPH6)
brenda
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