scholarly journals Chain reactions: molecular mechanisms of RBR ubiquitin ligases

2020 ◽  
Vol 48 (4) ◽  
pp. 1737-1750 ◽  
Author(s):  
Thomas R. Cotton ◽  
Bernhard C. Lechtenberg
Keyword(s):  
Molecular Mechanisms ◽  
Catalytic Mechanism ◽  
Ubiquitin Ligases ◽  
Post Translational Modification ◽  
E3 Ligases ◽  
Chain Reactions ◽  
The Family ◽  
Domain Organisation ◽  
Almost All ◽  
Unique Domain

Ubiquitination is a fundamental post-translational modification that regulates almost all aspects of cellular signalling and is ultimately catalysed by the action of E3 ubiquitin ligases. The RING-between-RING (RBR) family of E3 ligases encompasses 14 distinct human enzymes that are defined by a unique domain organisation and catalytic mechanism. Detailed characterisation of several RBR ligase family members in the last decade has revealed common structural and mechanistic features. At the same time these studies have highlighted critical differences with respect to autoinhibition, activation and catalysis. Importantly, the majority of RBR E3 ligases remain poorly studied, and thus the extent of diversity within the family remains unknown. In this mini-review we outline the current understanding of the RBR E3 mechanism, structure and regulation with a particular focus on recent findings and developments that will shape the field in coming years.

scholarly journals Ubiquitin in regulation of spindle apparatus and its positioning: implications in development and disease

2015 ◽  
Vol 93 (4) ◽  
pp. 273-281 ◽  
Author(s):  
Devika Srivastava ◽  
Oishee Chakrabarti
Keyword(s):  
Cell Division ◽  
Developmental Disorders ◽  
Ubiquitin Ligases ◽  
Pivotal Role ◽  
Direct Connection ◽  
Post Translational Modification ◽  
E3 Ligases ◽  
Cellular Events ◽  
Spindle Apparatus

Emerging data implicates ubiquitination, a post-translational modification, in regulating essential cellular events, one of them being mitosis. In this review we discuss how various E3 ligases modulate the cortical proteins such as dynein, LGN, NuMa, Gα, along with polymerization, stability, and integrity of spindles. These are responsible for regulating symmetric cell division. Some of the ubiquitin ligases regulating these proteins include PARK2, BRCA1/BARD1, MGRN1, SMURF2, and SIAH1; these play a pivotal role in the correct positioning of the spindle apparatus. A direct connection between developmental or various pathological disorders and the ubiquitination mediated cortical regulation is rather speculative, though deletions or mutations in them lead to developmental disorders and disease conditions.

scholarly journals E3 ubiquitin ligases: styles, structures and functions

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Quan Yang ◽  
Jinyao Zhao ◽  
Dan Chen ◽  
Yang Wang
Keyword(s):  
Cancer Progression ◽  
Large Family ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Therapeutic Approaches ◽  
E3 Ligases ◽  
Promising Target ◽  
Stress Signal ◽  
Ubiquitin Conjugating Enzyme ◽  
Almost All

AbstractE3 ubiquitin ligases are a large family of enzymes that join in a three-enzyme ubiquitination cascade together with ubiquitin activating enzyme E1 and ubiquitin conjugating enzyme E2. E3 ubiquitin ligases play an essential role in catalyzing the ubiquitination process and transferring ubiquitin protein to attach the lysine site of targeted substrates. Importantly, ubiquitination modification is involved in almost all life activities of eukaryotes. Thus, E3 ligases might be involved in regulating various biological processes and cellular responses to stress signal associated with cancer development. Thanks to their multi-functions, E3 ligases can be a promising target of cancer therapy. A deeper understanding of the regulatory mechanisms of E3 ligases in tumorigenesis will help to find new prognostic markers and accelerate the growth of anticancer therapeutic approaches. In general, we mainly introduce the classifications of E3 ligases and their important roles in cancer progression and therapeutic functions.

scholarly journals HERC Ubiquitin Ligases in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1653
Author(s):  
Joan Sala-Gaston ◽  
Arturo Martinez-Martinez ◽  
Leonardo Pedrazza ◽  
L. Francisco Lorenzo-Martín ◽  
Rubén Caloto ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tumor Suppressors ◽  
Molecular Mechanisms ◽  
Ubiquitin Ligases ◽  
Tumor Type ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Damage Response ◽  
Herc Proteins

HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3–HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type. We include a discussion of both the molecular mechanisms involved and the potential therapeutic strategies.

scholarly journals Polyphosphate-dependent synthesis of ATP and ADP by the family-2 polyphosphate kinases in bacteria

2008 ◽  
Vol 105 (46) ◽  
pp. 17730-17735 ◽  
Author(s):  
Boguslaw Nocek ◽  
Samvel Kochinyan ◽  
Michael Proudfoot ◽  
Greg Brown ◽  
Elena Evdokimova ◽  
...  
Keyword(s):  
Sinorhizobium Meliloti ◽  
Molecular Mechanisms ◽  
Catalytic Mechanism ◽  
Functional Characterization ◽  
High Energy ◽  
Inorganic Polyphosphate ◽  
The Family ◽  
Adp Crystal ◽  
Intracellular Energy

Inorganic polyphosphate (polyP) is a linear polymer of tens or hundreds of phosphate residues linked by high-energy bonds. It is found in all organisms and has been proposed to serve as an energy source in a pre-ATP world. This ubiquitous and abundant biopolymer plays numerous and vital roles in metabolism and regulation in prokaryotes and eukaryotes, but the underlying molecular mechanisms for most activities of polyP remain unknown. In prokaryotes, the synthesis and utilization of polyP are catalyzed by 2 families of polyP kinases, PPK1 and PPK2, and polyphosphatases. Here, we present structural and functional characterization of the PPK2 family. Proteins with a single PPK2 domain catalyze polyP-dependent phosphorylation of ADP to ATP, whereas proteins containing 2 fused PPK2 domains phosphorylate AMP to ADP. Crystal structures of 2 representative proteins, SMc02148 from Sinorhizobium meliloti and PA3455 from Pseudomonas aeruginosa, revealed a 3-layer α/β/α sandwich fold with an α-helical lid similar to the structures of microbial thymidylate kinases, suggesting that these proteins share a common evolutionary origin and catalytic mechanism. Alanine replacement mutagenesis identified 9 conserved residues, which are required for activity and include the residues from both Walker A and B motifs and the lid. Thus, the PPK2s represent a molecular mechanism, which potentially allow bacteria to use polyP as an intracellular energy reserve for the generation of ATP and survival.

scholarly journals Comparative analysis of the catalytic regulation of NEDD4-1 and WWP2 ubiquitin ligases

2019 ◽  
Vol 294 (46) ◽  
pp. 17421-17436 ◽  
Author(s):  
Hanjie Jiang ◽  
Stefani N. Thomas ◽  
Zan Chen ◽  
Claire Y. Chiang ◽  
Philip A. Cole
Keyword(s):  
Molecular Mechanisms ◽  
Ubiquitin Ligases ◽  
Product Distribution ◽  
Cellular Protein ◽  
Intramolecular Interactions ◽  
Interacting Protein ◽  
Ww Domain ◽  
E3 Ligases ◽  
Catalytic Activities ◽  
Tensin Homolog

NEDD4-1 E3 ubiquitin protein ligase (NEDD4-1) and WW domain-containing E3 ubiquitin ligase (WWP2) are HECT family ubiquitin E3 ligases. They catalyze Lys ubiquitination of themselves and other proteins and are important in cell growth and differentiation. Regulation of NEDD4-1 and WWP2 catalytic activities is important for controlling cellular protein homeostasis, and their dysregulation may lead to cancer and other diseases. Previous work has implicated noncatalytic regions, including the C2 domain and/or WW domain linkers in NEDD4-1 and WWP2, in contributing to autoinhibition of the catalytic HECT domains by intramolecular interactions. Here, we explored the molecular mechanisms of these NEDD4-1 and WWP2 regulatory regions and their interplay with allosteric binding proteins such as Nedd4 family-interacting protein (NDFIP1), engineered ubiquitin variants, and linker phosphomimics. We found that in addition to influencing catalytic activities, the WW domain linker regions in NEDD4-1 and WWP2 can impact product distribution, including the degree of polyubiquitination and Lys-48 versus Lys-63 linkages. We show that allosteric activation by NDFIP1 or engineered ubiquitin variants is largely mediated by relief of WW domain linker autoinhibition. WWP2-mediated ubiquitination of WW domain-binding protein 2 (WBP2), phosphatase and tensin homolog (PTEN), and p62 proteins by WWP2 suggests that substrate ubiquitination can also be influenced by WW linker autoinhibition, although to differing extents. Overall, our results provide a deeper understanding of the intricate and multifaceted set of regulatory mechanisms in the control of NEDD4-1–related ubiquitin ligases.

scholarly journals The functional landscape of the human phosphoproteome

2019 ◽  
Author(s):  
David Ochoa ◽  
Andrew F. Jarnuczak ◽  
Maja Gehre ◽  
Margaret Soucheray ◽  
Askar A. Kleefeldt ◽  
...  
Keyword(s):  
Protein Function ◽  
Molecular Mechanisms ◽  
State Of The Art ◽  
Functional Score ◽  
Post Translational Modification ◽  
Functional Sites ◽  
Cellular Processes ◽  
Major Bottleneck ◽  
Genomic Scale ◽  
Almost All

AbstractProtein phosphorylation is a key post-translational modification regulating protein function in almost all cellular processes. While tens of thousands of phosphorylation sites have been identified in human cells to date, the extent and functional importance of the phosphoproteome remains largely unknown. Here, we have analyzed 6,801 publicly available phospho-enriched mass spectrometry proteomics experiments, creating a state-of-the-art phosphoproteome containing 119,809 human phosphosites. To prioritize functional sites, 59 features indicative of proteomic, structural, regulatory or evolutionary relevance were integrated into a single functional score using machine learning. We demonstrate how this prioritization identifies regulatory phosphosites across different molecular mechanisms and pinpoint genetic susceptibilities at a genomic scale. Several novel regulatory phosphosites were experimentally validated including a role in neuronal differentiation for phosphosites present in the SWI/SNF SMARCC2 complex member. The scored reference phosphoproteome and its annotations identify the most relevant phosphorylations for a given process or disease addressing a major bottleneck in cell signaling studies.

Analisis Perbandingan Manajemen Keuangan Ojek Online Dan Ojek Reguler Studi Kasus Kecamatan Duren Sawit Jakarta Timur

Liquidity ◽  
2018 ◽  
Vol 7 (1) ◽  
pp. 41-52
Author(s):  
M. Koesmawan ◽  
Darwin Erhandy ◽  
Dede Dahlan
Keyword(s):  
Financial Management ◽  
Average Income ◽  
Savings And Loans ◽  
Financial Difficulties ◽  
The Family ◽  
Family Finances ◽  
The Subject ◽  
Almost All

In order to meet the needs of living which consists of primary as well as secondary needs, human can work in either a formal or an informal job. One of the informal jobs that is became the subject of this research was to become an ojek driver. Ojek is a ranting motorcycle.  Revenue of ojek drivers, accordingly, should be well managed following the concept of financial management. This research was conducted for the driver of the online motorcycle drivers as well as the regular motorcycle drivers they are called “The Ojek”. Ojek’s location is in Kecamatan (subdistrict) Duren Sawit, East Jakarta with 70 drivers of ojeks. The online ojeks earn an average of Rp 100,000 per day, can save Rp 11,000 to 21,000 per day, while, the regular ojek has an average income per day slightly lower amounted to Rp 78,500, this kind of ojeks generally have other businesses and always record the outflow of theirs money. Both the online and regular ojeks feel a tight competition in getting passengers, but their income can help the family finances and both ojeks want a cooperative especially savings and loans, especially to overcome the urgent financial difficulties. Almost all rivers, do not dare to borrow money. They are afraid of can not refund the money as scheduled.

The Role of Ubiquitin E3 Ligase in Atherosclerosis

2020 ◽  
Vol 28 (1) ◽  
pp. 152-168
Author(s):  
Zhi-Xiang Zhou ◽  
Zhong Ren ◽  
Bin-Jie Yan ◽  
Shun-Lin Qu ◽  
Zhi-Han Tang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Protein Modification ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Atherosclerotic Cardiovascular Disease ◽  
E3 Ligases

: Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.

A Survey for Predicting Enzyme Family Classes Using Machine Learning Methods

2019 ◽  
Vol 20 (5) ◽  
pp. 540-550 ◽  
Author(s):  
Jiu-Xin Tan ◽  
Hao Lv ◽  
Fang Wang ◽  
Fu-Ying Dao ◽  
Wei Chen ◽  
...  
Keyword(s):  
Machine Learning ◽  
Catalytic Mechanism ◽  
Biological Function ◽  
Learning Methods ◽  
Biochemical Processes ◽  
Machine Learning Methods ◽  
Enzyme Family ◽  
The Family ◽  
Speed Up ◽  
Family Classification

Enzymes are proteins that act as biological catalysts to speed up cellular biochemical processes. According to their main Enzyme Commission (EC) numbers, enzymes are divided into six categories: EC-1: oxidoreductase; EC-2: transferase; EC-3: hydrolase; EC-4: lyase; EC-5: isomerase and EC-6: synthetase. Different enzymes have different biological functions and acting objects. Therefore, knowing which family an enzyme belongs to can help infer its catalytic mechanism and provide information about the relevant biological function. With the large amount of protein sequences influxing into databanks in the post-genomics age, the annotation of the family for an enzyme is very important. Since the experimental methods are cost ineffective, bioinformatics tool will be a great help for accurately classifying the family of the enzymes. In this review, we summarized the application of machine learning methods in the prediction of enzyme family from different aspects. We hope that this review will provide insights and inspirations for the researches on enzyme family classification.

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.

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