scholarly journals Ube2W conjugates ubiquitin to α-amino groups of protein N-termini

2013 ◽  
Vol 453 (1) ◽  
pp. 137-145 ◽  
Author(s):  
Michael H. Tatham ◽  
Anna Plechanovová ◽  
Ellis G. Jaffray ◽  
Helena Salmen ◽  
Ronald T. Hay
Keyword(s):  
Ring Finger ◽  
Specific Protein ◽  
Cysteine Residue ◽  
Cellular Systems ◽  
Covalent Attachment ◽  
Amino Group ◽  
Ubiquitin Conjugating Enzyme ◽  
E2 Enzymes ◽  
Almost All ◽  
Conjugating Enzyme

The covalent attachment of the protein ubiquitin to intracellular proteins by a process known as ubiquitylation regulates almost all major cellular systems, predominantly by regulating protein turnover. Ubiquitylation requires the co-ordinated action of three enzymes termed E1, E2 and E3, and typically results in the formation of an isopeptide bond between the C-terminal carboxy group of ubiquitin and the ϵ-amino group of a target lysine residue. However, ubiquitin is also known to conjugate to the thiol of cysteine residue side chains and the α-amino group of protein N-termini, although the enzymes responsible for discrimination between different chemical groups have not been defined. In the present study, we show that Ube2W (Ubc16) is an E2 ubiquitin-conjugating enzyme with specific protein N-terminal mono-ubiquitylation activity. Ube2W conjugates ubiquitin not only to its own N-terminus, but also to that of the small ubiquitin-like modifier SUMO (small ubiquitin-related modifier) in a manner dependent on the SUMO-targeted ubiquitin ligase RNF4 (RING finger protein 4). Furthermore, N-terminal mono-ubiquitylation of SUMO-2 primes it for poly-ubiquitylation by the Ubc13–UEV1 (ubiquitin-conjugating enzyme E2 variant 1) heterodimer, showing that N-terminal ubiquitylation regulates protein fate. The description in the present study is the first of an E2-conjugating enzyme with N-terminal ubiquitylation activity, and highlights the importance of E2 enzymes in the ultimate outcome of E3-mediated ubiquitylation.

scholarly journals Targeting neddylation E2s: a novel therapeutic strategy in cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yi-Chao Zheng ◽  
Yan-Jia Guo ◽  
Bo Wang ◽  
Chong Wang ◽  
M. A. A. Mamun ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Therapeutic Strategy ◽  
Neural Precursor Cell ◽  
Catalytic Core Domain ◽  
Catalytic Core ◽  
Core Domain ◽  
E3 Ligases ◽  
Ubiquitin Conjugating Enzyme ◽  
E2 Enzymes ◽  
Conjugating Enzyme

AbstractUbiquitin-conjugating enzyme E2 M (UBE2M) and ubiquitin-conjugating enzyme E2 F (UBE2F) are the two NEDD8-conjugating enzymes of the neddylation pathway that take part in posttranslational modification and change the activity of target proteins. The activity of E2 enzymes requires both a 26-residue N-terminal docking peptide and a conserved E2 catalytic core domain, which is the basis for the transfer of neural precursor cell-expressed developmentally downregulated 8 (NEDD8). By recruiting E3 ligases and targeting cullin and non-cullin substrates, UBE2M and UBE2F play diverse biological roles. Currently, there are several inhibitors that target the UBE2M-defective in cullin neddylation protein 1 (DCN1) interaction to treat cancer. As described above, this review provides insights into the mechanism of UBE2M and UBE2F and emphasizes these two E2 enzymes as appealing therapeutic targets for the treatment of cancers.

scholarly journals OTUB1 non-catalytically stabilizes the E2 ubiquitin-conjugating enzyme UBE2E1 by preventing its autoubiquitination

2018 ◽  
Vol 293 (47) ◽  
pp. 18285-18295 ◽  
Author(s):  
Nagesh Pasupala ◽  
Marie E. Morrow ◽  
Lauren T. Que ◽  
Barbara A. Malynn ◽  
Averil Ma ◽  
...  
Keyword(s):  
Polyubiquitin Chains ◽  
Protein Ubiquitination ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzymes ◽  
E2 Enzymes ◽  
Ubiquitin Conjugating Enzymes ◽  
In Cells ◽  
Conjugating Enzyme

OTUB1 is a deubiquitinating enzyme that cleaves Lys-48–linked polyubiquitin chains and also regulates ubiquitin signaling through a unique, noncatalytic mechanism. OTUB1 binds to a subset of E2 ubiquitin-conjugating enzymes and inhibits their activity by trapping the E2∼ubiquitin thioester and preventing ubiquitin transfer. The same set of E2s stimulate the deubiquitinating activity of OTUB1 when the E2 is not charged with ubiquitin. Previous studies have shown that, in cells, OTUB1 binds to E2-conjugating enzymes of the UBE2D (UBCH5) and UBE2E families, as well as to UBE2N (UBC13). Cellular roles have been identified for the interaction of OTUB1 with UBE2N and members of the UBE2D family, but not for interactions with UBE2E E2 enzymes. We report here a novel role for OTUB1–E2 interactions in modulating E2 protein ubiquitination. We observe that Otub1−/− knockout mice exhibit late-stage embryonic lethality. We find that OTUB1 depletion dramatically destabilizes the E2-conjugating enzyme UBE2E1 (UBCH6) in both mouse and human OTUB1 knockout cell lines. Of note, this effect is independent of the catalytic activity of OTUB1, but depends on its ability to bind to UBE2E1. We show that OTUB1 suppresses UBE2E1 autoubiquitination in vitro and in cells, thereby preventing UBE2E1 from being targeted to the proteasome for degradation. Taken together, we provide evidence that OTUB1 rescues UBE2E1 from degradation in vivo.

scholarly journals Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A

2005 ◽  
Vol 170 (5) ◽  
pp. 745-755 ◽  
Author(s):  
Parker L. Andersen ◽  
Honglin Zhou ◽  
Landon Pastushok ◽  
Trevor Moraes ◽  
Sean McKenna ◽  
...  
Keyword(s):  
Nuclear Factor Κb ◽  
Cysteine Residue ◽  
Physical Interaction ◽  
Polyubiquitin Chains ◽  
Active Site Cysteine ◽  
Cellular Processes ◽  
Damage Repair ◽  
Ubiquitin Conjugating Enzyme ◽  
Active Site Cysteine Residue ◽  
Conjugating Enzyme

Ubc13, a ubiquitin-conjugating enzyme (Ubc), requires the presence of a Ubc variant (Uev) for polyubiquitination. Uevs, although resembling Ubc in sequence and structure, lack the active site cysteine residue and are catalytically inactive. The yeast Uev (Mms2) incites noncanonical Lys63-linked polyubiquitination by Ubc13, whereas the increased diversity of Uevs in higher eukaryotes suggests an unexpected complication in ubiquitination. In this study, we demonstrate that divergent activities of mammalian Ubc13 rely on its pairing with either of two Uevs, Uev1A or Mms2. Structurally, we demonstrate that Mms2 and Uev1A differentially modulate the length of Ubc13-mediated Lys63-linked polyubiquitin chains. Functionally, we describe that Ubc13–Mms2 is required for DNA damage repair but not nuclear factor κB (NF-κB) activation, whereas Ubc13–Uev1A is involved in NF-κB activation but not DNA repair. Our finding suggests a novel regulatory mechanism in which different Uevs direct Ubcs to diverse cellular processes through physical interaction and alternative polyubiquitination.

scholarly journals A Giant Ubiquitin-conjugating Enzyme Related to IAP Apoptosis Inhibitors

1998 ◽  
Vol 141 (6) ◽  
pp. 1415-1422 ◽  
Author(s):  
Hans-Peter Hauser ◽  
Michael Bardroff ◽  
George Pyrowolakis ◽  
Stefan Jentsch
Keyword(s):  
Covalent Attachment ◽  
Protein Protein Interaction ◽  
Small Proteins ◽  
The Family ◽  
Golgi Compartment ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzymes ◽  
And Function ◽  
Ubiquitin Conjugating Enzymes ◽  
Conjugating Enzyme

Ubiquitin-conjugating enzymes (UBC) catalyze the covalent attachment of ubiquitin to target proteins and are distinguished by the presence of a UBC domain required for catalysis. Previously identified members of this enzyme family are small proteins and function primarily in selective proteolysis pathways. Here we describe BRUCE (BIR repeat containing ubiquitin-conjugating enzyme), a giant (528-kD) ubiquitin-conjugating enzyme from mice. BRUCE is membrane associated and localizes to the Golgi compartment and the vesicular system. Remarkably, in addition to being an active ubiquitin-conjugating enzyme, BRUCE bears a baculovirus inhibitor of apoptosis repeat (BIR) motif, which to this date has been exclusively found in apoptosis inhibitors of the IAP-related protein family. The BIR motifs of IAP proteins are indispensable for their anti–cell death activity and are thought to function through protein–protein interaction. This suggests that BRUCE may combine properties of IAP-like proteins and ubiquitin-conjugating enzymes and indicates that the family of IAP-like proteins is structurally and functionally more diverse than previously expected.

scholarly journals E3 ligase activity of RING finger proteins that interact with Hip-2, a human ubiquitin-conjugating enzyme

FEBS Letters ◽  
2001 ◽  
Vol 503 (1) ◽  
pp. 61-64 ◽  
Author(s):  
Sun-Joo Lee ◽  
Ju-Youn Choi ◽  
Yong-Mo Sung ◽  
Hyewon Park ◽  
Hyangshuk Rhim ◽  
...  
Keyword(s):  
Ring Finger ◽  
E3 Ligase ◽  
Human Ubiquitin ◽  
Ubiquitin Conjugating Enzyme ◽  
Ring Finger Proteins ◽  
Conjugating Enzyme

scholarly journals OTUB1 non-catalytically regulates the stability of the E2 ubiquitin conjugating enzyme UBE2E1

2018 ◽  
Author(s):  
Nagesh Pasupala ◽  
Marie E. Morrow ◽  
Lauren T. Que ◽  
Barbara A. Malynn ◽  
Averil Ma ◽  
...  
Keyword(s):  
Catalytic Mechanism ◽  
Polyubiquitin Chains ◽  
Protein Ubiquitination ◽  
Ubiquitin Conjugating Enzyme ◽  
E2 Enzymes ◽  
The Stability ◽  
In Cells ◽  
Conjugating Enzyme

AbstractOTUB1 is a deubiquitinating enzyme that cleaves K48-linked polyubiquitin chains and also regulates ubiquitin signaling through a unique, non-catalytic mechanism. OTUB1 binds to a subset of E2 ubiquitin conjugating enzymes and inhibits their activity by trapping the E2~ubiquitin thioester and preventing ubiquitin transfer. The same set of E2s stimulate the deubiquitinating activity of OTUB1 when the E2 is not charged with ubiquitin. Previous studies have shown that, in cells, OTUB1 binds to members of the UBE2D (UBCH5) and UBE2E families, as well as to UBC13 (UBE2N). Cellular roles have been identified for the interaction of OTUB1 with UBC13 and members of the UBE2D family, but not for UBE2E E2 enzymes. We report here a novel role for OTUB1-E2 interactions in modulating E2 protein ubiquitination. We find that depletion of OTUB1 dramatically destabilizes the E2 conjugating enzyme UBE2E1 (UBE2E1) in cells and that this effect is independent of the catalytic activity of OTUB1 but depends on the ability of OTUB1 to bind to UBE2E1. We show that OTUB1 suppresses UBE2E1 autoubiquitinationin vitroand in cells, thereby preventing UBE2E1 from being targeted to the proteasome for degradation. Taken together, we have found a new role for OTUB1 in rescuing specific E2s from degradationin vivo.

scholarly journals The ubiquitin-conjugating enzyme Ubc13-Mms2 cooperates with a family of FYVE-type-RING ubiquitin protein ligases in K63-polyubiquitylation at internal membranes

2019 ◽  
Author(s):  
Christian Renz ◽  
Vera Tröster ◽  
Thomas K. Albert ◽  
Olivier Santt ◽  
Susan C. Jacobs ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Budding Yeast ◽  
Ring Finger ◽  
Multivesicular Body ◽  
Phenotypic Analysis ◽  
Nuclear Ring ◽  
Ubiquitin Conjugating Enzyme ◽  
Ring Finger Proteins ◽  
Inflammatory Signalling ◽  
Conjugating Enzyme

AbstractThe heterodimeric ubiquitin-conjugating enzyme (E2), Ubc13-Mms2, catalyses K63-specific polyubiquitylation in genome maintenance and inflammatory signalling. In budding yeast, the only ubiquitin protein ligase (E3) known to cooperate with Ubc13-Mms2 so far is a nuclear RING finger protein, Rad5, involved in the replication of damaged DNA. We have now identified a family of membrane-associated FYVE-(type)-RING finger proteins as cognate E3s for Ubc13-Mms2 in several species. We show that budding yeast Pib1, a FYVE-RING finger E3 associated with internal membranes, exhibits exquisite selectivity for Ubc13-Mms2 and cooperates with the E2 in the multivesicular body pathway. Phenotypic analysis indicates that the contribution of Ubc13-Mms2 to membrane trafficking goes beyond its cooperation with Pib1, suggesting an involvement with additional E3s in the endocytic compartment. These results widely implicate Ubc13-Mms2 in the regulation of membrane protein sorting.

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