Faculty Opinions recommendation of The RAG1 N-terminal domain is an E3 ubiquitin ligase.

Proteolysis-targeting chimeras mediate the degradation of bromodomain and extra-terminal domain proteins

Future Medicinal Chemistry ◽

10.4155/fmc-2017-0264 ◽

2020 ◽

Vol 12 (18) ◽

pp. 1669-1683

Author(s):

Yifei Yang ◽

Zhenwei Wu ◽

Pan Chen ◽

Peiyuan Zheng ◽

Huibin Zhang ◽

...

Keyword(s):

Clinical Trials ◽

Side Effects ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Drug Discovery And Development ◽

Terminal Domain ◽

Super Enhancer ◽

Bet Inhibitors ◽

Subsequent Degradation ◽

Bet Protein

Bromodomain and extra-terminal domain (BET) protein family plays an important role in regulating gene transcription preferentially at super-enhancer regions and has been involved with several types of cancers as a candidate. Up to now, there are 16 pan-BET inhibitors in clinical trials, however, most of them have undesirable off-target and side-effects. The proteolysis-targeting chimeras technology through a heterobifunctional molecule to link the target protein and E3 ubiquitin ligase, causes the target’s ubiquitination and subsequent degradation. By using this technology, the heterobifunctional small-molecule BET degraders can induce BET protein degradation. In this review, we discuss the advances in the drug discovery and development of BET-targeting proteolysis-targeting chimeras.

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Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics

Molecular Biology of the Cell ◽

10.1091/mbc.e16-04-0208 ◽

2017 ◽

Vol 28 (3) ◽

pp. 396-410 ◽

Cited By ~ 37

Author(s):

Edward Cherok ◽

Shan Xu ◽

Sunan Li ◽

Shweta Das ◽

W. Alex Meltzer ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Critical Role ◽

E3 Ubiquitin Ligase ◽

Mitochondrial Morphology ◽

Ubiquitinated Proteins ◽

Terminal Domain ◽

Degradation Rates ◽

And Control

MARCH5, an OMM-associated E3 ubiquitin ligase, controls mitochondrial function. Despite its importance, the mechanism and factors controlling MARCH5 activity are largely unknown. Here we report that the MARCH5 C-terminal domain plays a critical role in degradation of MARCH5 substrates, likely by facilitating release of ubiquitinated proteins from the OMM. We also found that the mitochondrial fission proteins Drp1 and Mff negatively regulate MARCH5’s activity toward MiD49 and Mcl1. Knockouts of either Drp1 or Mff led to reduced expression, shorter half-lives, and increased ubiquitination of MiD49 and Mcl1. Effects of Mff and Drp1 depletion on degradation rates and ubiquitination of Mcl1 and MiD49 were eliminated in Drp1−/−/MARCH5−/− and Mff−/−/MARCH5−/− cells. Our data show that it is not mitochondrial morphology per se but rather Mff and Drp1 that directly control MARCH5. Consistently, we find that Mff is an integral component of the MARCH5/p97/Npl4 complex, which is also controlled by MARCH5’s C-terminal domain. Furthermore, not only mitochondrial fission but also fusion is regulated through Mff and Drp1 protein activities. Thus, in addition to their canonical roles in mitochondrial fission, Mff and Drp1 also act as regulatory factors that control mitochondrial fission and fusion.

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Nonhost Resistance of Tomato to the Bean Pathogen Pseudomonas syringae pv. syringae B728a Is Due to a Defective E3 Ubiquitin Ligase Domain in AvrPtoBB728a

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-08-12-0190-r ◽

2013 ◽

Vol 26 (4) ◽

pp. 387-397 ◽

Cited By ~ 8

Author(s):

Ching-Fang Chien ◽

Johannes Mathieu ◽

Chun-Hua Hsu ◽

Patrick Boyle ◽

Gregory B. Martin ◽

...

Keyword(s):

Pseudomonas Syringae ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

E3 Ligase ◽

Amino Acid Identity ◽

Nonhost Resistance ◽

Plant Host ◽

Terminal Domain ◽

Tomato Cultivars

The bean pathogen Pseudomonas syringae pv. syringae B728a expresses homologs of the type III effectors AvrPto and AvrPtoB, either of which can trigger resistance in tomato cultivars expressing Pto and Prf genes. We found that strain B728a also elicits nonhost resistance in tomato cultivars VFNT Cherry and Moneymaker that lack Pto but express other members of the Pto family (e.g., SlFen and SlPtoC). Here, we show that the AvrPtoB homolog from B728a, termed AvrPtoBB728a (also known as HopAB1), is recognized by ‘VFNT Cherry’ and ‘Moneymaker’ when the effector is expressed in P. syringae pv. syringae 61, a strain lacking the avrPto or avrPtoB homolog. Using a gene-silencing approach, this recognition was shown to involve one or more Pto family members and Prf. AvrPtoBB728a interacted with SlFen, SlPtoC, and SlPtoD, in addition to Pto, in a yeast two-hybrid assay. In P. syringae pv. tomato DC3000, the C-terminal domain of AvrPtoB is an E3 ubiquitin ligase that ubiquitinates Fen, causing its degradation and leading to disease susceptibility. Although the C-terminal domain of AvrPtoBB728a shares 69% amino acid identity with that of AvrPtoB, we found that it has greatly reduced E3 ligase activity and is unable to ubiquitinate Fen in an in vitro ubiquitination assay. Thus, the nonhost resistance of ‘VFNT Cherry’ and ‘Moneymaker’ to B728a appears to be due to recognition of AvrPtoBB728 as a result of the effector's reduced E3 ligase activity, which prevents it from facilitating degradation of a Pto family member. We speculate that the primary plant host of B728a lacks a Fen-like protein and that, therefore, the E3 ligase of AvrPtoBB728 was unnecessary for pathogenicity and has diverged and become ineffective.

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