Branched Ubiquitination: Detection Methods, Biological Functions and Chemical Synthesis
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Versatile Roles of K63-Linked Ubiquitin Chains in Trafficking
Cells 2014, 3, 1027-1088; doi:10.3390/cells3041027 OPEN ACCESS cells ISSN 2073-4409 www.mdpi.com/journal/cells Review Versatile Roles of K63-Linked Ubiquitin Chains in Trafficking Zoi Erpapazoglou 1,2, Olivier Walker 3 and Rosine Haguenauer-Tsapis 1,* 1 Institut Jacques Monod-CNRS, UMR 7592, Université-Paris Diderot, Sorbonne Paris Cité, F-75205 Paris, France; E-Mail: [email protected] 2 Current address: Brain and Spine Institute, CNRS UMR 7225, Inserm, U 1127, UPMC-P6 UMR S 1127, 75013 Paris, France 3 Institut des Sciences Analytiques, UMR5280, Université de Lyon/Université Lyon 1, 69100 Villeurbanne, France; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]. External Editor: Hanjo Hellmann Received: 14 July 2014; in revised form: 14 October 2014 / Accepted: 21 October 2014 / Published: 12 November 2014 Abstract: Modification by Lys63-linked ubiquitin (UbK63) chains is the second most abundant form of ubiquitylation. In addition to their role in DNA repair or kinase activation, UbK63 chains interfere with multiple steps of intracellular trafficking. UbK63 chains decorate many plasma membrane proteins, providing a signal that is often, but not always, required for their internalization. In yeast, plants, worms and mammals, this same modification appears to be critical for efficient sorting to multivesicular bodies and subsequent lysosomal degradation. UbK63 chains are also one of the modifications involved in various forms of autophagy (mitophagy, xenophagy, or aggrephagy). Here, in the context of trafficking, we report recent structural studies investigating UbK63 chains assembly by various E2/E3 pairs, disassembly by deubiquitylases, and specifically recognition as sorting signals by receptors carrying Ub-binding domains, often acting in tandem. -
The HECT Domain Ubiquitin Ligase HUWE1 Targets Unassembled Soluble Proteins for Degradation
OPEN Citation: Cell Discovery (2016) 2, 16040; doi:10.1038/celldisc.2016.40 ARTICLE www.nature.com/celldisc The HECT domain ubiquitin ligase HUWE1 targets unassembled soluble proteins for degradation Yue Xu1, D Eric Anderson2, Yihong Ye1 1Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; 2Advanced Mass Spectrometry Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA In eukaryotes, many proteins function in multi-subunit complexes that require proper assembly. To maintain complex stoichiometry, cells use the endoplasmic reticulum-associated degradation system to degrade unassembled membrane subunits, but how unassembled soluble proteins are eliminated is undefined. Here we show that degradation of unassembled soluble proteins (referred to as unassembled soluble protein degradation, USPD) requires the ubiquitin selective chaperone p97, its co-factor nuclear protein localization protein 4 (Npl4), and the proteasome. At the ubiquitin ligase level, the previously identified protein quality control ligase UBR1 (ubiquitin protein ligase E3 component n-recognin 1) and the related enzymes only process a subset of unassembled soluble proteins. We identify the homologous to the E6-AP carboxyl terminus (homologous to the E6-AP carboxyl terminus) domain-containing protein HUWE1 as a ubiquitin ligase for substrates bearing unshielded, hydrophobic segments. We used a stable isotope labeling with amino acids-based proteomic approach to identify endogenous HUWE1 substrates. Interestingly, many HUWE1 substrates form multi-protein com- plexes that function in the nucleus although HUWE1 itself is cytoplasmically localized. Inhibition of nuclear entry enhances HUWE1-mediated ubiquitination and degradation, suggesting that USPD occurs primarily in the cytoplasm. -
A Family of Mammalian E3 Ubiquitin Ligases That Contain the UBR Box Motif and Recognize N-Degrons Takafumi Tasaki,1 Lubbertus C
MOLECULAR AND CELLULAR BIOLOGY, Aug. 2005, p. 7120–7136 Vol. 25, No. 16 0270-7306/05/$08.00ϩ0 doi:10.1128/MCB.25.16.7120–7136.2005 Copyright © 2005, American Society for Microbiology. All Rights Reserved. A Family of Mammalian E3 Ubiquitin Ligases That Contain the UBR Box Motif and Recognize N-Degrons Takafumi Tasaki,1 Lubbertus C. F. Mulder,2 Akihiro Iwamatsu,3 Min Jae Lee,1 Ilia V. Davydov,4† Alexander Varshavsky,4 Mark Muesing,2 and Yong Tae Kwon1* Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 152611; Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 100162; Protein Research Network, Inc., Yokohama, Kanagawa 236-0004, Japan3; and Division of Biology, California Institute of Technology, Pasadena, California 911254 Received 15 March 2005/Returned for modification 27 April 2005/Accepted 13 May 2005 A subset of proteins targeted by the N-end rule pathway bear degradation signals called N-degrons, whose determinants include destabilizing N-terminal residues. Our previous work identified mouse UBR1 and UBR2 as E3 ubiquitin ligases that recognize N-degrons. Such E3s are called N-recognins. We report here that while double-mutant UBR1؊/؊ UBR2؊/؊ mice die as early embryos, the rescued UBR1؊/؊ UBR2؊/؊ fibroblasts still retain the N-end rule pathway, albeit of lower activity than that of wild-type fibroblasts. An affinity assay for proteins that bind to destabilizing N-terminal residues has identified, in addition to UBR1 and UBR2, a huge (570 kDa) mouse protein, termed UBR4, and also the 300-kDa UBR5, a previously characterized mammalian E3 known as EDD/hHYD. -
Amino Acid Building Block Models – in Brief
Amino Acid Building Block Models – In Brief Key Teaching Points for Amino Acid Building Block Models© Overall Student Learning Objective: What Dictates How a Protein Folds? Amino acids are the building blocks of proteins. All amino acids have an identical core structure consisting of an alpha-carbon, carboxyl group, amino group and R-group (sidechain). A linear chain of amino acids is a polypeptide. The primary sequence of a protein is the linear sequence of amino acids in a polypeptide. Proteins are made up of amino acid monomers linked together by peptide bonds. Peptide bond formation between amino acids results in the release of water (dehydration synthesis or condensation reaction). The protein backbone is characterized by the “N-C-C-N-C-C. .” pattern. The “ends” of the protein can be identified by the N-terminus (amino group) end and the C-terminus (carboxyl group) end. For a more complete lesson guide, please visit: http://www.3dmoleculardesigns.com/3DMD-Files/AABB/ContentsandAssembly.pdf Amino Acid Core Structure Build an amino acid according to the diagram to the right: 1. Identify the alpha carbon, amino group, carboxyl group and R-group (sidechain representation) in the structure you have constructed. Two amino acids can be chemically linked by a reaction called “condensation” or “dehydration synthesis” to form a dipeptide bond linking the two amino acids. A chain of amino acid units (monomers) linked together by peptide bonds is called a polypeptide. General Dipeptide Structure Construct a model of a dipeptide using the amino acid models previously built. 2. What are the products of the condensation reaction (dehydration synthesis)? 3. -
The Ubiquitin Proteasome System and Its Involvement in Cell Death Pathways
Cell Death and Differentiation (2010) 17, 1–3 & 2010 Macmillan Publishers Limited All rights reserved 1350-9047/10 $32.00 www.nature.com/cdd Editorial The ubiquitin proteasome system and its involvement in cell death pathways F Bernassola1, A Ciechanover2 and G Melino1,3 Cell Death and Differentiation (2010) 17, 1–3; doi:10.1038/cdd.2009.189 Following the awarding of the 2004 Nobel Prize in Chemistry Inactivation of the proteasome following caspase-mediated to Aaron Ciechanover, Avram Hershko, and Irwin A Rose cleavage may disable the proteasome, interfering with its for the discovery of ubiquitin (Ub)-mediated degradation, role in the regulation of key cellular processes and thereby Cell Death and Differentiation has drawn the attention of facilitating induction of apoptosis. The noted recent develop- its readers to the Ub Proteasome System (UPS) and its ments show how understanding of these functions is just involvement in regulating cell death pathways.1–4 The current starting to emerge. For example, why does dIAP1 associate set of reviews is an update on this theme.5–16 with multiple E2s via its RING finger? Does dIAP1 also interact From previous review articles published in Cell Death and with the E3 – the F-box protein Morgue, which is a part of an Differentiation, it was apparent that the UPS has a major SCF E3 complex? Why does dIAP1, which is an E3, have to mechanistic role in regulating cell death via modification and interact with other ligases such as the N-end rule UBR1 and degradation of key regulatory proteins involved in -
PGC-1A Protects from Notch-Induced Kidney Fibrosis Development
BASIC RESEARCH www.jasn.org PGC-1a Protects from Notch-Induced Kidney Fibrosis Development † ‡ ‡ Seung Hyeok Han,* Mei-yan Wu, § Bo Young Nam, Jung Tak Park,* Tae-Hyun Yoo,* ‡ † † † † Shin-Wook Kang,* Jihwan Park, Frank Chinga, Szu-Yuan Li, and Katalin Susztak *Department of Internal Medicine, Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Korea; †Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; ‡Severance Biomedical Science Institute, Brain Korea 21 PLUS, Yonsei University College of Medicine, Seoul, Korea; and §Department of Nephrology, The First Hospital of Jilin University, Changchun, China ABSTRACT Kidney fibrosis is the histologic manifestation of CKD. Sustained activation of developmental pathways, such as Notch, in tubule epithelial cells has been shown to have a key role in fibrosis development. The molecular mechanism of Notch-induced fibrosis, however, remains poorly understood. Here, we show that, that expression of peroxisomal proliferation g-coactivator (PGC-1a) and fatty acid oxidation-related genes are lower in mice expressing active Notch1 in tubular epithelial cells (Pax8-rtTA/ICN1) compared to littermate controls. Chromatin immunoprecipitation assays revealed that the Notch target gene Hes1 directly binds to the regulatory region of PGC-1a. Compared with Pax8-rtTA/ICN1 transgenic animals, Pax8-rtTA/ICN1/Ppargc1a transgenic mice showed improvement of renal structural alterations (on his- tology) and molecular defect (expression of profibrotic genes). Overexpression of PGC-1a restored mi- tochondrial content and reversed the fatty acid oxidation defect induced by Notch overexpression in vitro in tubule cells. Furthermore, compared with Pax8-rtTA/ICN1 mice, Pax8-rtTA/ICN1/Ppargc1a mice exhibited improvement in renal fatty acid oxidation gene expression and apoptosis. -
The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression
International Journal of Molecular Sciences Review The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression Tingting Zou and Zhenghong Lin * School of Life Sciences, Chongqing University, Chongqing 401331, China; [email protected] * Correspondence: [email protected] Abstract: The cell cycle is a collection of events by which cellular components such as genetic materials and cytoplasmic components are accurately divided into two daughter cells. The cell cycle transition is primarily driven by the activation of cyclin-dependent kinases (CDKs), which activities are regulated by the ubiquitin-mediated proteolysis of key regulators such as cyclins, CDK inhibitors (CKIs), other kinases and phosphatases. Thus, the ubiquitin-proteasome system (UPS) plays a pivotal role in the regulation of the cell cycle progression via recognition, interaction, and ubiquitination or deubiquitination of key proteins. The illegitimate degradation of tumor suppressor or abnormally high accumulation of oncoproteins often results in deregulation of cell proliferation, genomic instability, and cancer occurrence. In this review, we demonstrate the diversity and complexity of the regulation of UPS machinery of the cell cycle. A profound understanding of the ubiquitination machinery will provide new insights into the regulation of the cell cycle transition, cancer treatment, and the development of anti-cancer drugs. Keywords: cell cycle regulation; CDKs; cyclins; CKIs; UPS; E3 ubiquitin ligases; Deubiquitinases (DUBs) Citation: Zou, T.; Lin, Z. The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression. 1. Introduction Int. J. Mol. Sci. 2021, 22, 5754. https://doi.org/10.3390/ijms22115754 The cell cycle is a ubiquitous, complex, and highly regulated process that is involved in the sequential events during which a cell duplicates its genetic materials, grows, and di- Academic Editors: Kwang-Hyun Bae vides into two daughter cells. -
TRAIP Modulates the IGFBP3/AKT Pathway to Enhance the Invasion
www.nature.com/cddis ARTICLE OPEN TRAIP modulates the IGFBP3/AKT pathway to enhance the invasion and proliferation of osteosarcoma by promoting KANK1 degradation ✉ ✉ Mi Li1,6, Wei Wu2,6, Sisi Deng3, Zengwu Shao2 and Xin Jin 4,5 © The Author(s) 2021 Osteosarcoma is one of the most common primary malignancies in bones and is characterized by high metastatic rates. Circulating tumor cells (CTCs) derived from solid tumors can give rise to metastatic lesions, increasing the risk of death in patients with cancer. Here, we used bioinformatics tools to compare the gene expression between CTCs and metastatic lesions in osteosarcoma to identify novel molecular mechanisms underlying osteosarcoma metastasis. We identified TRAIP as a key differentially expressed gene with prognostic significance in osteosarcoma. We demonstrated that TRAIP regulated the proliferation and invasion of osteosarcoma cells. In addition, we found that TRAIP promoted KANK1 polyubiquitination and subsequent degradation, downregulating IGFBP3 and activating the AKT pathway in osteosarcoma cells. These results support the critical role of the TRAIP/ KANK1/IGFBP3/AKT signaling axis in osteosarcoma progression and suggest that TRAIP may represent a promising therapeutic target for osteosarcoma. Cell Death and Disease (2021) 12:767 ; https://doi.org/10.1038/s41419-021-04057-0 INTRODUCTION mechanisms underlying osteosarcoma metastasis. We identified Mesenchymal stem cell-derived osteosarcoma is one of the most TRAIP as a differentially expressed gene (DEG) with prognostic and common primary malignancies in bones [1], and it is particularly diagnostic significance. We also found that TRAIP regulated the common in children and adolescents. With the recent progress in proliferation and invasion of osteosarcoma cells. -
Folding, Function and Subcellular Localization of Parkin
Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universtität München Folding, function and subcellular localization of parkin Julia Schlehe aus München 2008 Erklärung Diese Dissertation wurde im Sinne von §13 Abs. 3 der Promotionsordnung vom 29. Januar 1998 von PD Dr. Winklhofer betreut. Ehrenwörtliche Versicherung Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet. München, am 07.10.2008 …………………………………….. (Julia Schlehe) Dissertation eingereicht am 09.10.2008 1. Gutachter PD Dr. Konstanze Winklhofer 2. Gutachter Prof. Dr. Ulrich Hartl Mündliche Prüfung am 10.11.2008 Summary ...............................................................................................................................................................1 Introduction ..........................................................................................................................................................3 Parkinson’s Disease........................................................................................................................................3 History......................................................................................................................................................3 Clinical characteristics, symptoms and treatment ....................................................................................4 Neuropathological characteristics ............................................................................................................6 -
Introduction to Proteins and Amino Acids Introduction
Introduction to Proteins and Amino Acids Introduction • Twenty percent of the human body is made up of proteins. Proteins are the large, complex molecules that are critical for normal functioning of cells. • They are essential for the structure, function, and regulation of the body’s tissues and organs. • Proteins are made up of smaller units called amino acids, which are building blocks of proteins. They are attached to one another by peptide bonds forming a long chain of proteins. Amino acid structure and its classification • An amino acid contains both a carboxylic group and an amino group. Amino acids that have an amino group bonded directly to the alpha-carbon are referred to as alpha amino acids. • Every alpha amino acid has a carbon atom, called an alpha carbon, Cα ; bonded to a carboxylic acid, –COOH group; an amino, –NH2 group; a hydrogen atom; and an R group that is unique for every amino acid. Classification of amino acids • There are 20 amino acids. Based on the nature of their ‘R’ group, they are classified based on their polarity as: Classification based on essentiality: Essential amino acids are the amino acids which you need through your diet because your body cannot make them. Whereas non essential amino acids are the amino acids which are not an essential part of your diet because they can be synthesized by your body. Essential Non essential Histidine Alanine Isoleucine Arginine Leucine Aspargine Methionine Aspartate Phenyl alanine Cystine Threonine Glutamic acid Tryptophan Glycine Valine Ornithine Proline Serine Tyrosine Peptide bonds • Amino acids are linked together by ‘amide groups’ called peptide bonds. -
RING-Type E3 Ligases: Master Manipulators of E2 Ubiquitin-Conjugating Enzymes and Ubiquitination☆
Biochimica et Biophysica Acta 1843 (2014) 47–60 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamcr Review RING-type E3 ligases: Master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination☆ Meredith B. Metzger a,1, Jonathan N. Pruneda b,1, Rachel E. Klevit b,⁎, Allan M. Weissman a,⁎⁎ a Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, 1050 Boyles Street, Frederick, MD 21702, USA b Department of Biochemistry, Box 357350, University of Washington, Seattle, WA 98195, USA article info abstract Article history: RING finger domain and RING finger-like ubiquitin ligases (E3s), such as U-box proteins, constitute the vast Received 5 March 2013 majority of known E3s. RING-type E3s function together with ubiquitin-conjugating enzymes (E2s) to medi- Received in revised form 23 May 2013 ate ubiquitination and are implicated in numerous cellular processes. In part because of their importance in Accepted 29 May 2013 human physiology and disease, these proteins and their cellular functions represent an intense area of study. Available online 6 June 2013 Here we review recent advances in RING-type E3 recognition of substrates, their cellular regulation, and their varied architecture. Additionally, recent structural insights into RING-type E3 function, with a focus on im- Keywords: RING finger portant interactions with E2s and ubiquitin, are reviewed. This article is part of a Special Issue entitled: U-box Ubiquitin–Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf. Ubiquitin ligase (E3) Published by Elsevier B.V. Ubiquitin-conjugating enzyme (E2) Protein degradation Catalysis 1. -
1 the Functional Interplay Between the HIF Pathway and the Ubiquitin System
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2017 The functional interplay between the HIF pathway and the ubiquitin system – more than a one-way road Günter, Julia ; Ruiz-Serrano, Amalia ; Pickel, Christina ; Wenger, Roland H ; Scholz, Carsten C Abstract: The hypoxia inducible factor (HIF) pathway and the ubiquitin system represent major cellular processes that are involved in the regulation of a plethora of cellular signaling pathways and tissue func- tions. The ubiquitin system controls the ubiquitination of proteins, which is the covalent linkage of one or several ubiquitin molecules to specific targets. This ubiquitination is catalyzed by approximately 1000 different E3 ubiquitin ligases and can lead to different effects, depending on the type of internal ubiquitin chain linkage. The best-studied function is the targeting of proteins for proteasomal degradation. The activity of E3 ligases is antagonized by proteins called deubiquitinases (or deubiquitinating enzymes), which negatively regulate ubiquitin chains. This is performed in most cases by the catalytic removal of these chains from the targeted protein. The HIF pathway is regulated in an oxygen-dependent manner by oxygen-sensing hydroxylases. Covalent modification of HIF subunits leads to the recruitment ofan E3 ligase complex via the von Hippel-Lindau (VHL) protein and the subsequent polyubiquitination and proteasomal degradation of HIF subunits, demonstrating the regulation of the HIF pathway by the ubiq- uitin system. This unidirectional effect of an E3 ligase on the HIF pathway is the beststudied example for the interplay between these two important cellular processes. However, additional regulatory mechanisms of the HIF pathway through the ubiquitin system are emerging and, more recently, also the reciprocal regulation of the ubiquitin system through components of the HIF pathway.