The Proteasome — Ubiquitin Protein Degradation Pathway PDF
Preview The Proteasome — Ubiquitin Protein Degradation Pathway
Current Topics in Microbiology 268 and Immunology Editors R.W. Compans. Atlanta/Georgia M.D. Cooper. Birmingham/Alabama· Y. Ito, Kyoto H. Koprowski, Philadelphia/Pennsylvania· F. Melchers, Basel M.B.A. Oldstone, La lolla/California . S. Olsnes. Oslo M. Potter, Bethesda/Maryland P.K. Vogt, La lolla/California . H. Wagner, Munich Springer Berlin Heidelberg New York Barcelona Hong Kong London Milan Paris Tokyo The Proteasome - Ubiquitin Protein Degradation Pathway Edited by P. Zwickl and W. Baumeister With 17 Figures and 6 Tables , Springer Dr. PETER ZWICKL Professor Dr. WOLFGANG BAUMEISTER Department of Molecular Structural Biology Max-Planck-Institute for Biochemistry Am Klopferspitz 18 a 82152 Martinsried Germany e-mail: [email protected] [email protected] Cover Illustration: Schematic representation of the MHC class I-antigen processing and presentation pathway (G. Niedermann, this volume). ISSN 0070-217X ISBN-13: 978-3-642-63971-5 e-ISBN-13: 978-3-642-59414-4 DOT: 10.1007/978-3-642-59414-4 This work is subject to copyright. All rights are reserved. whether the whole or part of the material is concerned. specifically the rights of translation, reprinting. reuse of illustrations. recitation. broadcasting. reproduction on microfilm or in any other way. and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer-Verlag is a company in the specialist publishing group BertelsmannSpringer http://www.springer.de ~C:' Springer-Verlag Berlin Heidelberg 2002 Softcover reprint of the hardcover 1st edition 2002 Library of Congress Catalog Card Number 15-12910 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting other i'e!evant literature. Production Editor: Christiane Messerschmidt. Rheinau Cover Design: design & production GmbH. Heidelberg Typesetting: Scientific Publishing Services (P) Ltd, Madras Printed on acid-free paper SPIN: 10718401 27/30205432 I 0 Preface This volume gives an overview of pro tea some-mediated protein degradation and the regulatory role of the ubiquitin system in cellular proteolysis. The first chapter describes the molecular evolution of the proteasome and its associated activators, i.e., the 20S core, the base and the lid of the 19S cap, and the 11 S regulator. The ensuing chapter gives an overview of the structure and assembly of the 20S proteasome and the regulation of the archaeal proteasome by PAN. The third contribution summarizes our knowledge on the eukaryotic 26S proteasome and its regulation by the 19S regu lator, followed by a chapter devoted to the llS regulator, which elucidates the structural basis for the 11 S-mediated activation of the 20S proteasome. The fifth chapter reviews in detail the role of the proteasome in the immune response. The subsequent chapter gives a comprehensive description of the natural substrates of the proteasome and their recognition by the enzymes of the ubiqui tination machinery. The penultimate chapter rounds up the in formation on intracellular distribution of proteasomes in yeast and mammalian cells, while the last contribution highlights proteasome inhibitors, tools which proved to be very valuable for dissecting the cellular roles of the proteasome and which might turn out to be of pharmacological importance. In summary, this volume gives a complete overview of the structure and function of the proteasome, its regulators and inhibitors, and its cellular importance, in conjunction with the ubiquitin system, for the degradation of regulatory proteins and the generation of immu nogenic peptides. January 2002 PETER ZWICKL WOLFGANG BAUMEISTER List of Contents C. VOLKER and A.N. LUPAS Molecular Evolution of Pro tea somes .............. . P. ZWICKL The 20S Proteasome. . . . . . . . . . . . . . . . . . . . . . . . . . . 23 M.H. GLICKMAN and V. MAYTAL Regulating the 26S Proteasome . . . . . . . . . . . . . . . . . . . 43 c.P. HILL, E.I. MASTERS, and F.G. WHITBY The lIS Regulators of 20S Proteasome Activity. . . . . . . 73 G. NIEDERMANN Immunological Functions of the Proteasome 91 H.D. ULRICH Natural Substrates of the Proteasome and Their Recognition by the Ubiquitin System. . . . . .. 137 C. GORDON The Intracellular Localization of the Proteasome 175 M. BOGYO and E.W. WANG Proteasome Inhibitors: Complex Tools for a Complex Enzyme 185 Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 209 List of Contributors (Their addresses can be found at the beginning of their respective chapters.) BOGYO, M. 185 NIEDERMANN, G. 91 GLICKMAN, M.H. 43 ULRICH, H.D. 137 GORDON, C. 175 VOLKER, C. HILL, c.P. 73 WANG, E.W. 185 LUPAS, A.N. WHITBY, F.G. 73 MASTERS, E.I. 73 ZWICKL, P. 23 MAYTAL, V. 43 Molecular Evolution of Proteasomes C. VOLKER and A.N. LUPAS* Introduction 2 Molecular Evolution of the 20S Proteolytic Core Complex 2 2.1 The Ntn Hydrolase Family. 2 2.2 Evolution of Self-Compartmentalization. 2.3 Subunit Differentiation in Eukaryotes .. 7 2.4 Problems in the Phylogenetic Reconstruction of Proteasome Evolution 9 Molecular Evolution of the lIS Regulator (PA28) . 10 4 Molecular Evolution of the 19S Cap Complex II 4.1 The Base Subcomplex: ATPase Subunits . 12 4.2 The Base Subcomplex: Non-ATPase Subunits 15 4.3 The Lid Subcomplex and Its Relationship to COP9 and eIF3 17 Conclusion 18 6 Summary 18 References . 19 1 Introduction Because of the potential damage to the cell, intracellular protein degradation is one of the most tightly regulated processes in living systems. As a consequence, all protein breakdown in the cell is energy dependent, even though proteolysis is fundamentally exergonic. The basic regulatory strategy has been the confinement of proteolytic active sites to internal compartments with tightly controlled access. In eukaryotes this has eventually led to the evolution of a dedicated organelle, the lysosome, in which the primary energy-dependent step is the translocation of substrates across the membrane. The oldest solution, however (which still handles the bulk of intracellular proteolysis even in eukaryotes) is a set of proteases that form barrel-shaped complexes through self-association, enclosing a central Bioinformatics. Smith Kline Beecham Pharmaceuticals. UP 1345. 1250 South Collegeville Road. Collegeville, PA 19426-0989. USA * Presellf address: Department of Protein Evolution. Max Planck Institute for Developmental Biology. Spemannstr. 35. 72076 Tuebingen. Germany 2 C. Volker and A.N. Lupas proteolytic cavity (LUPAS et al. 1997b). Access to this cavity is provided by polar pores guarded by ring-shaped ATPases, which unfold and translocate substrate proteins in an energy-dependent manner. Prokaryotes contain several such prote ases, including Lon, ClpAP, ClpXP, FtsH, and proteasomes, but the only one present outside of organelles in eukaryotes is the proteasome. Proteasomes are, in one form or another, ubiquitous to life (for reviews see Coux et al. 1996; BAUMEISTER et al. 1998; PETERS et al. 1998). The simplest form is found in bacteria and consists of two rings of core subunits (HsIV), which associate with ATPase rings of the Clp/HSPIOO subfamily (HsIU). This complex is induced during heat shock and is not essential under normal growth conditions. Archaea contain a more elaborate version, formed by four rings of core subunits (the 20S proteasome) that interact with ATPase rings of the AAA subfamily. This form is also found in one branch of the bacteria, the actinomycetes, where it was pre sumably acquired by horizontal transfer. In the archaeon Thermoplasma acido phi/um the proteasome is essential under stress conditions, but not during normal growth, whereas in the actinomycete Mycobacterium smegma tis its knock-out does not have a phenotype under any of the conditions tested. The most complicated form occurs in eukaryotes, where a 20S proteasome complex forms the core of a much larger protease, the 26S proteasome. In this form, the 20S core complex is capped by two 19S complexes containing ATPases of the AAA subfamily. The 26S proteasome is the central protease of ubiquitin-dependent protein degradation and is essential for cell survival. It is found free in the cytosol, attached to the endo plasmic reticulum (ER), and in the nucleus, and is involved in the removal of abnormal proteins, antigen processing, signal transduction, transcription, cell cycle progression, and apoptosis. In this chapter we discuss the evolution of proteasomes from simple mono meric precursors to structures of increasing complexity (Fig. \), leading up to the highly complicated 26S proteasome, a molecular machine of 32 subunits and 2.2MDa. 2 Molecular Evolution of the 20S Proteolytic Core Complex 2.1 The Ntn Hydrolase Family The protease subunits of energy-dependent proteases appear to have originated from a number of unrelated hydrolase families, most of which are not typically associated with proteolysis (LuPAs et al. 1997b). Only FtsH, a Zn-dependent metalloprotease, belongs to one of the classic protease families (clan MB, family M41 in the MEROPS classification; http://merops.iapc.bbsrc.ac.uk). The proteo lytic subunits of proteasomes belong to the N-terminal nucleophile (Ntn) hydro lases, a group of proteins that also encompasses penicillin acylases, class II glutamine amidotransferases, and glycosylasparaginase (BRANNIGAN et al. 1995; s:: o ii> (") '" ~ m "' o S o· ::l .., o "" (3 " e; o 3 ~ ? y Other Vertebrates 115re9· ·I-interferon-inducible core subunits and S regulator (PA28afl) 11 core 20S Plants Y Animals Fungi 205 complex Rhodococcus lIS reg. Protists Actinomycetes Other I I Paralogous core subunits SubstrateClade-specific cap subunits ./ ./ ~ HslU PA28 y/PA26 _ ././ HstV COP9 Eukaryotes Archaea Bacteria HslU Subunil dlfferenllation ----------... 19Scap . Ubiquilin HslVU Escherichia al"'/~ Sevenfold core symmetry Sixfold core symmetry ~ ~ I nactive a -subunit ring s Clp/Hspl00 ATPase ~ AAAATPase a 20S complex Thermoplasma Oligomeric rings Slacked double rings Protease-ATPase proto-complexes? Ntn hydrolase RecA-like ·unfotda~e· olution. The branchpoints represent the most likely sequence of events. as discussed in the text. (Images courtesy of - ev 265 complex Xenopus /"~/ elF3 ~ / \ / _-\{ / /" t : I Oligomerization I I PCl/PINT-domain protein MPN/JAB-domain protein Schematic representation of proteasome meister laboratory) 195 cap 205 core cap 195 I. Fig. the Bau
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