scholarly journals E3 ubiquitin ligase components in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Elena Faccenda ◽  
Robert Layfield
Keyword(s):  
Cell Cycle Progression ◽  
Protein Complexes ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Post Translational Modification ◽  
Protein Substrates ◽  
Cellular Processes ◽  
Ubiquitin Molecule ◽  
E2 Enzymes ◽  
Ubiquitin Conjugating Enzymes

Ubiquitination (a.k.a. ubiquitylation) is a protein post-translational modification that typically requires the sequential action of three enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases) [19]. Ubiquitination of proteins can target them for proteasomal degradation, or modulate cellular processes including cell cycle progression, transcriptional regulation, DNA repair and signal transduction. E3 ubiquitin ligases, of which there are >600 in humans, are a family of highly heterogeneous proteins and protein complexes that recruit ubiquitin-loaded E2 enzymes to mediate transfer of the ubiquitin molecule from the E2 to protein substrates. Target substrate specificity is determined by a substrate recognition subunit within the E3 complex.

scholarly journals E3 ubiquitin ligase components (version 2019.5) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (5) ◽  
Author(s):  
Elena Faccenda ◽  
Robert Layfield
Keyword(s):  
Cell Cycle Progression ◽  
Protein Complexes ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Post Translational Modification ◽  
Protein Substrates ◽  
Cellular Processes ◽  
Ubiquitin Molecule ◽  
E2 Enzymes ◽  
Ubiquitin Conjugating Enzymes

Ubiquitination (a.k.a. ubiquitylation) is a protein post-translational modification that typically requires the sequential action of three enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases) [16]. Ubiquitination of proteins can target them for proteasomal degradation, or modulate cellular processes including cell cycle progression, transcriptional regulation, DNA repair and signal transduction. E3 ubiquitin ligases, of which there are >600 in humans, are a family of highly heterogeneous proteins and protein complexes that recruit ubiquitin-loaded E2 enzymes to mediate transfer of the ubiquitin molecule from the E2 to protein substrates. Target substrate specificity is determined by a substrate recognition subunit within the E3 complex.

scholarly journals Functional Significance of the E3 Ubiquitin Ligases in Disease and Therapeutics

2021 ◽  
Author(s):  
Julius Tieroyaare Dongdem ◽  
Cletus Adiyaga Wezena
Keyword(s):  
Therapeutic Potential ◽  
Protein Complexes ◽  
Ring Finger ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Phd Finger ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Future Drug ◽  
Ubiquitin Conjugating Enzyme

E3 ubiquitin ligases of which there are >600 putative in humans, constitute a family of highly heterogeneous proteins and protein complexes that are the ultimate enzymes responsible for the recruitment of an ubiquitin loaded E2 ubiquitin-conjugating enzyme, recognise the appropriate protein substrate and directly or indirectly transfer the ubiquitin load onto the substrate. The aftermath of an E3 ligase activity is usually the formation of an isopeptide bond between the free carboxylate group of ubiquitin’s C-terminal Gly76 and an ε-amino group of the substrate’s Lys, even though non-canonical ubiquitylation on non-amine groups of target proteins have been observed. E3 ligases are grouped into four distinct families: HECT, RING-finger/U-box, RBR and PHD-finger. E3 ubiquitin ligases play critical roles in subcellular signalling cascades in eukaryotes. Dysfunctional E3 ubiquitin ligases therefore tend to inflict dramatic effects on human health and may result in the development of various diseases including Parkinson’s, Amyotrophic Lateral Sclerosis, Alzheimer’s, cancer, etc. Being regulators of numerous cellular processes, some E3 ubiquitin ligases have become potential targets for therapy. This chapter will present a comprehensive review of up-to-date findings in E3 ligases, their role in the pathology of disease and therapeutic potential for future drug development.

scholarly journals The p97 cofactor Ubxn7 facilitates replisome disassembly during S-phase

2021 ◽  
Author(s):  
Zeynep Tarcan ◽  
Divyasree Poovathumkadavil ◽  
Aggeliki Skagia ◽  
Agnieszka Gambus
Keyword(s):  
Dna Replication ◽  
Molecular Mechanism ◽  
Protein Complexes ◽  
Ubiquitin Ligases ◽  
S Phase ◽  
E3 Ubiquitin Ligases ◽  
Replication Machinery ◽  
Replicative Helicase ◽  
Cellular Processes ◽  
Eukaryotic Dna

Complex cellular processes are driven by the regulated assembly and disassembly of large multi-protein complexes. In eukaryotic DNA replication, whilst we are beginning to understand the molecular mechanism for assembly of the replication machinery (replisome), we still know relatively little about the regulation of its disassembly at replication termination. Over recent years, the first elements of this process have emerged, revealing that the replicative helicase, at the heart of the replisome, is polyubiquitylated prior to unloading and that this unloading requires p97 segregase activity. Two different E3 ubiquitin ligases are now known to ubiquitylate the helicase under different conditions: Cul2Lrr1 and TRAIP. Here we have found two p97 cofactors, Ubxn7 and Faf1, which can interact with p97 during replisome disassembly in S-phase. Only Ubxn7 however facilitates efficient replisome disassembly through its interaction with both Cul2Lrr1 and p97. Our data therefore characterise Ubxn7 as the first substrate-specific p97 cofactor regulating replisome disassembly in vertebrates.

scholarly journals Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1015
Author(s):  
Utsa Bhaduri ◽  
Giuseppe Merla
Keyword(s):  
Drug Discovery ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
Genetic Disorders ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Post Translational Modification ◽  
Disease Biology ◽  
The Future

Ubiquitination is a post-translational modification that has pivotal roles in protein degradation and diversified cellular processes, and for more than two decades it has been a subject of interest in the biotech or biopharmaceutical industry. Tripartite motif (TRIM) family proteins are known to have proven E3 ubiquitin ligase activities and are involved in a multitude of cellular and physiological events and pathophysiological conditions ranging from cancers to rare genetic disorders. Although in recent years many kinds of E3 ubiquitin ligases have emerged as the preferred choices of big pharma and biotech startups in the context of protein degradation and disease biology, from a surface overview it appears that TRIM E3 ubiquitin ligases are not very well recognized yet in the realm of drug discovery. This article will review some of the blockbuster scientific discoveries and technological innovations from the world of ubiquitination and E3 ubiquitin ligases that have impacted the biopharma community, from biotech colossuses to startups, and will attempt to evaluate the future of TRIM family proteins in the province of E3 ubiquitin ligase-based drug discovery.

scholarly journals Regulation of cell cycle drivers by Cullin-RING ubiquitin ligases

2020 ◽  
Vol 52 (10) ◽  
pp. 1637-1651 ◽  
Author(s):  
Sang-Min Jang ◽  
Christophe E. Redon ◽  
Bhushan L. Thakur ◽  
Meriam K. Bahta ◽  
Mirit I. Aladjem
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Cycle Progression ◽  
Ubiquitin Ligases ◽  
Anaphase Promoting Complex ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Cellular Pathways ◽  
Regulation Of Cell Cycle ◽  
F Box Protein

Abstract The last decade has revealed new roles for Cullin-RING ubiquitin ligases (CRLs) in a myriad of cellular processes, including cell cycle progression. In addition to CRL1, also named SCF (SKP1-Cullin 1-F box protein), which has been known for decades as an important factor in the regulation of the cell cycle, it is now evident that all eight CRL family members are involved in the intricate cellular pathways driving cell cycle progression. In this review, we summarize the structure of CRLs and their functions in driving the cell cycle. We focus on how CRLs target key proteins for degradation or otherwise alter their functions to control the progression over the various cell cycle phases leading to cell division. We also summarize how CRLs and the anaphase-promoting complex/cyclosome (APC/C) ligase complex closely cooperate to govern efficient cell cycle progression.

scholarly journals Ubiquitin signaling in cell cycle control and tumorigenesis

2020 ◽  
Author(s):  
Fabin Dang ◽  
Li Nie ◽  
Wenyi Wei
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Cell Cycle Control ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Cycle Progression ◽  
Precise Control ◽  
Cycle Regulation

Abstract Cell cycle progression is a tightly regulated process by which DNA replicates and cell reproduces. The major driving force underlying cell cycle progression is the sequential activation of cyclin-dependent kinases (CDKs), which is achieved in part by the ubiquitin-mediated proteolysis of their cyclin partners and kinase inhibitors (CKIs). In eukaryotic cells, two families of E3 ubiquitin ligases, anaphase-promoting complex/cyclosome and Skp1-Cul1-F-box protein complex, are responsible for ubiquitination and proteasomal degradation of many of these CDK regulators, ensuring cell cycle progresses in a timely and precisely regulated manner. In the past couple of decades, accumulating evidence have demonstrated that the dysregulated cell cycle transition caused by inefficient proteolytic control leads to uncontrolled cell proliferation and finally results in tumorigenesis. Based upon this notion, targeting the E3 ubiquitin ligases involved in cell cycle regulation is expected to provide novel therapeutic strategies for cancer treatment. Thus, a better understanding of the diversity and complexity of ubiquitin signaling in cell cycle regulation will shed new light on the precise control of the cell cycle progression and guide anticancer drug development.

scholarly journals Emerging roles of the HECT-type E3 ubiquitin ligases in hematological malignancies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Vincenza Simona Delvecchio ◽  
Claudia Fierro ◽  
Sara Giovannini ◽  
Gerry Melino ◽  
Francesca Bernassola
Keyword(s):  
Hematological Malignancies ◽  
Apoptotic Cell ◽  
Ubiquitin Ligases ◽  
Covalent Attachment ◽  
E3 Ubiquitin Ligases ◽  
Comprehensive Overview ◽  
Altered Expression ◽  
Hect Domain ◽  
Cellular Processes ◽  
Substrate Proteins

AbstractUbiquitination-mediated proteolysis or regulation of proteins, ultimately executed by E3 ubiquitin ligases, control a wide array of cellular processes, including transcription, cell cycle, autophagy and apoptotic cell death. HECT-type E3 ubiquitin ligases can be distinguished from other subfamilies of E3 ubiquitin ligases because they have a C-terminal HECT domain that directly catalyzes the covalent attachment of ubiquitin to their substrate proteins. Deregulation of HECT-type E3-mediated ubiquitination plays a prominent role in cancer development and chemoresistance. Several members of this subfamily are indeed frequently deregulated in human cancers as a result of genetic mutations and altered expression or activity. HECT-type E3s contribute to tumorigenesis by regulating the ubiquitination rate of substrates that function as either tumour suppressors or oncogenes. While the pathological roles of the HECT family members in solid tumors are quite well established, their contribution to the pathogenesis of hematological malignancies has only recently emerged. This review aims to provide a comprehensive overview of the involvement of the HECT-type E3s in leukemogenesis.

scholarly journals Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

2021 ◽  
Vol 14 (9) ◽  
pp. 848
Author(s):  
Lucas Cruz ◽  
Paula Soares ◽  
Marcelo Correia
Keyword(s):  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Cellular Targets ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
Ubiquitin Molecule

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.

scholarly journals The Roles of the Ubiquitin–Proteasome System in the Endoplasmic Reticulum Stress Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1526
Author(s):  
Junyan Qu ◽  
Tingting Zou ◽  
Zhenghong Lin
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Defense Mechanism ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
Cellular Processes ◽  
Ubiquitin Proteasome ◽  
Endoplasmic Reticulum Stress Pathway

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells, which is essential for synthesis, processing, sorting of protein and lipid metabolism. However, the cells activate a defense mechanism called endoplasmic reticulum stress (ER stress) response and initiate unfolded protein response (UPR) as the unfolded proteins exceed the folding capacity of the ER due to the environmental influences or increased protein synthesis. ER stress can mediate many cellular processes, including autophagy, apoptosis and senescence. The ubiquitin-proteasome system (UPS) is involved in the degradation of more than 80% of proteins in the cells. Today, increasing numbers of studies have shown that the two important components of UPS, E3 ubiquitin ligases and deubiquitinases (DUBs), are tightly related to ER stress. In this review, we summarized the regulation of the E3 ubiquitin ligases and DUBs in ER stress.

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