scholarly journals Molecular Basis for the Association of Human E4B U Box Ubiquitin Ligase with E2-Conjugating Enzymes UbcH5c and Ubc4

Structure ◽  
2010 ◽  
Vol 18 (8) ◽  
pp. 955-965 ◽  
Author(s):  
Robert C. Benirschke ◽  
James R. Thompson ◽  
Yves Nominé ◽  
Emeric Wasielewski ◽  
Nenad Juranić ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Molecular Basis ◽  
Conjugating Enzymes

scholarly journals The Molecular Basis of CRL4DDB2/CSA Ubiquitin Ligase Architecture, Targeting, and Activation

Cell ◽  
2011 ◽  
Vol 147 (5) ◽  
pp. 1024-1039 ◽  
Author(s):  
Eric S. Fischer ◽  
Andrea Scrima ◽  
Kerstin Böhm ◽  
Syota Matsumoto ◽  
Gondichatnahalli M. Lingaraju ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Molecular Basis

scholarly journals Sequential Poly-ubiquitylation by Specialized Conjugating Enzymes Expands the Versatility of a Quality Control Ubiquitin Ligase

2016 ◽  
Vol 63 (5) ◽  
pp. 827-839 ◽  
Author(s):  
Annika Weber ◽  
Itamar Cohen ◽  
Oliver Popp ◽  
Gunnar Dittmar ◽  
Yuval Reiss ◽  
...  
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Conjugating Enzymes

scholarly journals UBE2G1 governs the destruction of cereblon neomorphic substrates

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Gang Lu ◽  
Stephanie Weng ◽  
Mary Matyskiela ◽  
Xinde Zheng ◽  
Wei Fang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Antitumor Activities ◽  
Fundamental Interest ◽  
Myeloma Cells ◽  
Ubiquitin Ligase Complex ◽  
Clinical Resistance ◽  
Conjugating Enzymes ◽  
Ubiquitin Conjugating Enzymes

The cereblon modulating agents (CMs) including lenalidomide, pomalidomide and CC-220 repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the K48-linked polyubiquitination of CRL4CRBN neomorphic substrates via a sequential ubiquitination mechanism. Blockade of UBE2G1 diminishes the ubiquitination and degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested CMs. For example, UBE2G1 inactivation significantly attenuated the degradation of myeloma survival factors IKZF1 and IKZF3 induced by lenalidomide and pomalidomide, hence conferring drug resistance. UBE2G1-deficient myeloma cells, however, remained sensitive to a more potent IKZF1/3 degrader CC-220. Collectively, it will be of fundamental interest to explore if loss of UBE2G1 activity is linked to clinical resistance to drugs that hijack the CRL4CRBN to eliminate disease-driving proteins.

scholarly journals Mammalian DET1 Regulates Cul4A Activity and Forms Stable Complexes with E2 Ubiquitin-Conjugating Enzymes

2007 ◽  
Vol 27 (13) ◽  
pp. 4708-4719 ◽  
Author(s):  
Elah Pick ◽  
On-Sun Lau ◽  
Tomohiko Tsuge ◽  
Suchithra Menon ◽  
Yingchun Tong ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Associated Factors ◽  
Cultured Cells ◽  
Negative Regulator ◽  
Polyubiquitin Chain ◽  
Light Responses ◽  
E3 Ligases ◽  
Conjugating Enzymes ◽  
Ubiquitin Conjugating Enzymes

ABSTRACT DET1 (de-etiolated 1) is an essential negative regulator of plant light responses, and it is a component of the Arabidopsis thaliana CDD complex containing DDB1 and COP10 ubiquitin E2 variant. Human DET1 has recently been isolated as one of the DDB1- and Cul4A-associated factors, along with an array of WD40-containing substrate receptors of the Cul4A-DDB1 ubiquitin ligase. However, DET1 differs from conventional substrate receptors of cullin E3 ligases in both biochemical behavior and activity. Here we report that mammalian DET1 forms stable DDD-E2 complexes, consisting of DDB1, DDA1 (DET1, DDB1 associated 1), and a member of the UBE2E group of canonical ubiquitin-conjugating enzymes. DDD-E2 complexes interact with multiple ubiquitin E3 ligases. We show that the E2 component cannot maintain the ubiquitin thioester linkage once bound to the DDD core, rendering mammalian DDD-E2 equivalent to the Arabidopsis CDD complex. While free UBE2E-3 is active and able to enhance UbcH5/Cul4A activity, the DDD core specifically inhibits Cul4A-dependent polyubiquitin chain assembly in vitro. Overexpression of DET1 inhibits UV-induced CDT1 degradation in cultured cells. These findings demonstrate that the conserved DET1 complex modulates Cul4A functions by a novel mechanism.

scholarly journals F-Box Proteins and Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1249 ◽  
Author(s):  
Kanae Yumimoto ◽  
Yuhei Yamauchi ◽  
Keiichi I. Nakayama
Keyword(s):  
Ubiquitin Ligase ◽  
Molecular Basis ◽  
Cancer Therapeutics ◽  
S Phase ◽  
Cancer Development ◽  
Tumor Promoters ◽  
Cellular Processes ◽  
Novel Targets ◽  
Scf Ubiquitin Ligase ◽  
F Box Protein

Controlled protein degradation is essential for the operation of a variety of cellular processes including cell division, growth, and differentiation. Identification of the relations between ubiquitin ligases and their substrates is key to understanding the molecular basis of cancer development and to the discovery of novel targets for cancer therapeutics. F-box proteins function as the substrate recognition subunits of S-phase kinase-associated protein 1 (SKP1)−Cullin1 (CUL1)−F-box protein (SCF) ubiquitin ligase complexes. Here, we summarize the roles of specific F-box proteins that have been shown to function as tumor promoters or suppressors. We also highlight proto-oncoproteins that are targeted for ubiquitylation by multiple F-box proteins, and discuss how these F-box proteins are deployed to regulate their cognate substrates in various situations.

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