Protein Degradation in Health and Disease

135 Pages·2002·3.019 MB·English

by  Takumi Kamura, Joan W. Conaway (auth.), Michèle Reboud-Ravaux (eds.)

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Springer-Verlag Berlin Heidelberg GmbH
Michele Reboud-Ravaux (Ed.)
Protein Degradation
in Health and Disease
With 12 Figures
Springer
Professor Dr. MICHELE REBOUD-RAVAUX
Laboratoire d'Enzymologie Moleculaire et Fonctionnelle
Departement de Biologie Cellulaire
Institut Jacques Monod
Universites Paris VI & VII
2, Place Jussieu
75251 Paris Cedex 05
France
ISSN 0079-6484
ISBN 978-3-642-62714-9 ISBN 978-3-642-56373-7 (eBook)
DOI 10.1007/978-3-642-56373-7
Library of Congress Cataloging-in-Publication Data
Protein degradation in health and disease 1 Michele Reboud-Ravaux (ed.).
p. cm. - (Progress in molecular and subcellular biology, ISSN 0079-6484; 29)
Includes bibliographical references and index.
ISBN 3540425942 (hbk.)
1. Proteins - Metabolism. 2. Proteins - Metabolism - Disorders. 3. Proteins - Pathophysiology.
4. Brain - Aging - Molecular aspects. 1. Reboud - Ravaux, Michele, 1945- II. Ser ies.
QP551 .P6958176 2002
612.3'98 - dc21
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Preface
Proteolytic processes occur in all cell compartments. These processes involve
breaking one or more peptide bonds to unmask or suppress a physiological
function, or to promote intracellular traffic. Proteolytic degradation can also
lead to total protein hydrolysis and the release of amino acids. Proteases, which
selectively catalyze the hydrolysis of peptide bonds, are implicated in protein
turnover (synthesis and degradation) and protein function. Therefore, they
playa major role in the dynamic processes that maintain cellular homeosta
sis, as well as in fundamental biological processes such as cell migration, tissue
differentiation, and development. Research into protein degradation, and into
the structure-function and regulation of proteases, has a long history. The
world of proteolysis and protein turnover research is expanding very rapidly,
and it would be quite impossible to cover all the new aspects of this field. This
book concentrates on giving an idea of the current thinking about protein
degradation via intracellular proteolysis, focusing on the effects of aging and
the links with diseases.
The multitude of biological processes regulated by proteolytic enzymes,
includes (I) the rapid elimination of key regulatory proteins (such as cyclins)
and rate-limiting enzymes that are required for regulating the cell cycle, gene
transcription and metabolic pathways; and (2) the rapid degradation of cell
proteins with abnormal conformations, whose accumulation could be damag
ing. Eukaryotic cells contain several proteolytic systems, including lysosomal
proteases, calpains, and proteasome. The crucial role of the proteasome will be
discussed in particular. Its importance in cellular responses is demonstrated
using selective inhibitors. Protein degradation by proteasomes is also crucial
in the propagation of diseases such as neurological and metabolic disorders,
cancers, and viral escape from immune surveillance. The buildup of damaged
proteins with age indicates the importance of the impairment of proteasome
housekeeping in the aging process. The enormous progress in the methodol
ogy of proteomics, by mapping the relationships between whole proteins
and their changes in aging and diseases, will considerably facilitate the
investigation of the mechanisms implicated in the age-related decline of
protein degradation, and how it is altered in various diseases such as
Alzheimer's disease.
Paris, February 200 I MICHELE REBOUD-RAVAUX
Contents
Roles of SCF and VHL Ubiquitin Ligases in Regulation
of Cell Growth
Takumi Kamura, Joan W. Conaway, and Ronald C. Conaway
1 Introduction ...................................... . 1
2 Architectures of the SCF and VHL E3 Ubiquitin Ligases .... . 2
2.1 The Cullin Proteins ................................. . 3
2.2 The RING Finger Protein Rbxl ....................... . 4
3 Targets of the SCF Ubiquitin Ligase .................... . 4
3.1 The S. cerev;s;ae SCFld<4 Complex ..................... . 4
3.2 The S. cerev;s;ae SCF(;rrl Complex ..................... . 5
3.3 The S. cerev;s;ae SCF~lft\O Complex ..................... . 6
3.4 The Mammalian SCFSkp2 Complex ..................... . 6
3.5 The Mammah•a n SCF 1l·IRC.P Complex .................... . 7
4 The von Hippel-Lindau Ubiquitin Ligase ............... . 7
4.1 The VHL Tumor Suppressor Protein ................... . 7
4.2 Hypoxia-Inducible Transcription Factors Are Targets
of the VHL Ubiquitin Ligase .......................... . 8
5 Regulation of SCF and VHL Ubiquitin Ligase Activities .... . 9
5.1 Stimulation of SCF and VHL Ubiquitin Ligase Activities
by NEDD8 Modification of Cullin Proteins .............. . 9
5.2 Autocatalytic Ubiquitylation and Degradation
of F-box Proteins ................................... . 9
References ......................................... 10
Aging of Proteins and the Proteasome
Bertrand Friguet
1 Introduction ...................................... . 17
2 Proteins: Cellular Targets for Oxidative Damage .......... . 18
3 Proteins: Cellular Targets for Other Damaging
Processes ......................................... . 21
4 Oxidized Proteins Degradation by the Proteasome ........ . 22
5 Proteasome and Oxidative Stress ...................... . 24
6 Proteasome and Aging .............................. . 25
References ........................................ . 28
VIII Contents
Protein Degradation in the Aging Organism
Walter F. Ward
Introduction .................... .................. . 35
2 Pathways of Protein Degradation and How They
Are Affected by Age ................................ . 36
2.1 The Heterophagic Pathway of Protein Degradation ........ . 36
2.2 Pathways of Autophagic Protein Degradation .......... .. . 37
2.2.1 Macroautophagy ................................... . 37
2.2.2 Microautophagy ................................... . 38
2.2.3 Chaperone-Mediated Autophagy ...................... . 38
2.2.4 Crinophagy ....................................... . 39
3 Cytosolic Pathways of Protein Degradation .............. . 39
3.1 The Proteasome .................................... . 39
3.2 The Cal pains ....... ............... ................ . 40
4 Summary ... ...................................... . 41
References ........................................ . 41
Protein Degradation in Alzheimer's Disease and Aging of the Brain
Teruyuki Tsuji and Shun Shimohama
1 Introduction .................................. .... . 43
2 Amyloid and Presenilin ............................. . 44
3 PS Mutant Activity ................................. . 44
3.1 Proteolytic Maturation of PS ......................... . 45
3.2 The Role of PS in AP Metabolism ..................... . 46
4 Tau Phosphorylation and Filamentous Aggregation ....... . 47
4.1 Tau Protein in AD .................................. . 48
5 Alpha-Synuclin in Lewy Body Disease .................. . 49
6 Ubiquitin ......................................... . 50
6.1 Ubiquitin and AD .................................. . 52
6.2 Ubiquitin and PD .................................. . 53
7 Calpain and AD .................................... . 54
8 Other Protein Degradation Mechanisms
and Future Directions ............................... . 55
References ......................................... 56
Protein Degradation in Human Disease
Richard K. Plemper and Anthea L. Hammond
1 Introduction ...................................... . 61
2 The Ubiquitin-Proteasome Degradation System .......... . 61
2.1 Diseases Associated with the Ubiquitin-
Proteasome Pathway ................................ . 67
2.l.l Neurological Disorders .............................. . 67
2.1.2 Malignancies ...................................... . 72
Contents IX
2.1.3 Metabolic Disorders ................................ . 73
2.1.4 Viral Escape from Immune Surveillance ................ . 76
3 Lysosomal Degradation ............................. . 78
References ........................................ . 79
The 26S Proteasome
Olivier Coux
Introduction ...................................... . 85
2 The Vb-Proteasome Pathway ......................... . 87
3 The 26S Proteasome, a Multi-enzymatic
Degradation Machine ............................... . 89
3.1 Enzymatic Activities of the 26S Proteasome ............. . 89
3.1.1 Proteolytic Activities ................................ . 89
3.1.2 Roles of the ATPases of the 19S Complex ............... . 92
3.1.2.1 Channel Opening ................................ . 93
3.1.2.2 Substrate Unfolding .............................. . 94
3.1.2.3 Substrate Translocation into the 20S Proteasome ......... . 95
3.1.3 Release from the Poly-Vb Chain and Vb Recycling ........ . 96
3.2 Assembly of the 26S Proteasome ...................... . 97
3.3 Substrate Recognition ............................... . 99
4 Perspectives ....................................... . 101
References ........................................ . 101
Proteasome Inhibitors
Michele Reboud-Ravaux
1 Introduction ....................................... 109
2 Molecular and Mechanistic Bases for Design. . . . . . . . . . . . . . 109
2.1 Crystallographic Structures of Inhibitor-
Proteasome Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
2.2 Mechanism of Peptide Hydrolysis ...................... 11 0
2.3 High Molecular Weight Inhibitors ...................... II 1
3 Low Molecular Weight Inhibitors of the Proteasome . . . . . . . . 112
3.1 Stable Acyl-Enzymes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
3.1.1 DCI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
3.1.2 Lactacystin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
3.2 Transition State Analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
3.2.1 Peptide Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
3.2.2 Peptide Boronic Acids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
3.3 Suicide Substrates ................................... 115
3.4 Non-covalent Inhibitors .............................. 117
3.5 Remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 7
4 Towards Therapeutic Applications. . . . . . . . . . . . . . . . . . . . . . 118
4.1 Inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
4.2 Various Cancers .................................... 11 8
x
Contents
4.2.1 Immune Diseases ................................... 119
4.2.2 Muscle Wasting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
4.2.3 Miscellaneous. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
5 Conclusion ........................................ 120
References ......................................... 120
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Roles of SCF and VHL Ubiquitin Ligases
in Regulation of Cell Growth
w.
Takumi Kamura\ Joan Conawar,3,\ and Ronald C. Conawar
1
I ntrod uction
Over the past few years, a growing body of evidence has brought to light
critical roles for ubiquitin-dependent protein degradation in controlling the
cellular levels of a large variety of proteins such as cyclins, cyclin-dependent
kinase inhibitors, oncogenes, and tumor suppressors, which play integral roles
in regulation of cell growth. Ubiquitin-dependent protein degradation is a
complex, multistep process that proceeds with the tagging of target proteins
with a poly-ubiquitin chain and culminates with the processive, ubiquitin
dependent degradation of tagged proteins by the 26S proteasome (Hershko et
al. 1983; Hochstrasser 1995,1996; Hershko and Ciechanover 1998). In the first
step, the C-terminus of ubiquitin is covalently linked through a thioester bond
to the active site cysteine residue of an El ubiquitin-activating enzyme. Ubiq
uitin is then transferred from the El via a thioester linkage to an active site
cysteine residue in one of a number of E2 ubiquitin-conjugating enzymes.
Ubiquitin is then either (l) conjugated directly via an isopeptide bond to the
f-amino group of a lysine in the target protein, (2) conjugated via an isopep
tide bond to another ubiquitin moiety on the target protein as part of synthe
sis of the poly-ubiquitin tag, or (3) transferred from the E2 via a thioester bond
to an active site cysteine residue in one of a growing family of E3 ubiquitin
ligases, which then conjugate ubiquitin to specific target proteins.
The E3 components of the ubiquitin cascade are responsible for
recognizing, binding specifically to, and recruiting target proteins for poly
ubiquitylation. E3s fall into two functional classes (Hershko and Ciechanover
1998; Joazeiro and Weissman 2000). One class includes the HECT {homologous
I Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu
University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
2 Program in Molecular and Cell Biology, Oklahoma Medical Research Foundation, 825 NE 13th
Street, Oklahoma City, Oklahoma 73104, USA
3 Howard Hughes Medical Institute, Oklahoma Medical Research Foundation, 825 NE 13th Street,
Oklahoma City, Oklahoma 73104, USA
4 Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences
Center, Oklahoma City, Oklahoma 73190, USA
Progress in Molecular and Subcellular Biology, Vol. 29
Michele Reboud-Ravaux (Ed.)
© Springer-Verlag Berlin Heidelberg 2002