Components and mechanisms of cytoplasmic protein quality control and elimination of regulatory enzymes [Elektronische Ressource] / Frederik Eisele. Betreuer: Dieter H. Wolf
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Components and mechanisms of cytoplasmic protein quality control and elimination of regulatory enzymes [Elektronische Ressource] / Frederik Eisele. Betreuer: Dieter H. Wolf

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Components and mechanisms of cytoplasmic protein quality control and elimination of regulatory enzymes Von der Fakultät Energie-, Verfahrens- und Biotechnik der Universität Stuttgart zur Erlangung der Würde eines Doktors der Naturwissenschaften (Dr. rer. nat.) genehmigte AbhandlungVorgelegt von Dipl.-Biol. (t.o.) Frederik Eisele aus WaiblingenHauptberichter: Prof. Dr. Dieter H. Wolf Mitberichter: Priv. Doz. Dr. Wolfgang HiltTag der mündlichen Prüfung: 24. Mai 2011Institut für Biochemie der Universität Stuttgart2011Eidesstattliche ErklärungHiermit versichere ich, dass ich diese Arbeit selbst verfasst und dabei keine anderen als die angegebenen Quellen und Hilfsmittel verwendet habe.Stuttgart, 12. Januar 2011Frederik EiseleTable of contentsAbbreviations!6Abstract!9Zusammenfassung!101. Introduction!131.1. Folding of proteins!131.1.1. Hsp70 chaperone family!141.1.2. Hsp40 chaperone family!161.1.3. Hsp110 chaperone family!171.1.4. Hsp100 chaperone family!171.1.5. Hsp60 chaperone family!181.1.6. Hsp90 chaperone family!181.1.7. Small Heat Shock Proteins!191.2. Degradation of proteins!191.2.1. Lysosomal or vacuolar protein degradation via autophagocytosis and endocytosis!211.2.2. The ubiquitin proteasome system!221.2.2.1. Polyubiquitylation as signal for proteasomal degradation!231.2.2.2. The 26S proteasome!271.2.2.2.1. The 19S regulatory particle!271.2.2.2.2. The 20S proteolytic core particle!281.2.2.2.3. Proteasomal degradation!2931.2.

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Published 01 January 2011
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Language English
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Components and mechanisms of
cytoplasmic protein quality control and
elimination of regulatory enzymes
Von der Fakultät Energie-, Verfahrens- und Biotechnik der Universität Stuttgart zur
Erlangung der Würde eines Doktors der Naturwissenschaften (Dr. rer. nat.)
genehmigte Abhandlung
Vorgelegt von
Dipl.-Biol. (t.o.) Frederik Eisele
aus Waiblingen
Hauptberichter: Prof. Dr. Dieter H. Wolf
Mitberichter: Priv. Doz. Dr. Wolfgang Hilt
Tag der mündlichen Prüfung: 24. Mai 2011
Institut für Biochemie der Universität Stuttgart
2011Eidesstattliche Erklärung
Hiermit versichere ich, dass ich diese Arbeit selbst verfasst und dabei keine anderen
als die angegebenen Quellen und Hilfsmittel verwendet habe.
Stuttgart, 12. Januar 2011
Frederik EiseleTable of contents
Abbreviations!6
Abstract!9
Zusammenfassung!10
1. Introduction!13
1.1. Folding of proteins!13
1.1.1. Hsp70 chaperone family!14
1.1.2. Hsp40 chaperone family!16
1.1.3. Hsp110 chaperone family!17
1.1.4. Hsp100 chaperone family!17
1.1.5. Hsp60 chaperone family!18
1.1.6. Hsp90 chaperone family!18
1.1.7. Small Heat Shock Proteins!19
1.2. Degradation of proteins!19
1.2.1. Lysosomal or vacuolar protein degradation via autophagocytosis
and endocytosis!21
1.2.2. The ubiquitin proteasome system!22
1.2.2.1. Polyubiquitylation as signal for proteasomal degradation!23
1.2.2.2. The 26S proteasome!27
1.2.2.2.1. The 19S regulatory particle!27
1.2.2.2.2. The 20S proteolytic core particle!28
1.2.2.2.3. Proteasomal degradation!29
31.2.2.3. ER quality control and associated protein degradation (ERQD)
!30
1.2.2.4. The mammalian E3 ligase CHIP!31
1.2.2.5. Cytoplasmic protein quality control and degradation!32
1.2.2.6. N-end rule pathway and the ubiquitin ligase Ubr1!38
2. Results and discussion!43
2.1. Scope of this work!43
2.2. The Hsp70 chaperone machinery subjects misfolded proteins to
degradation via the ubiquitin-proteasome system!43
2.3. E3 ligases involved in the degradation of misfolded cytoplasmic proteins
!46
2.4. The Cdc48-Ufd1-Npl4 complex is central in ubiquitin-proteasome
dependent catabolite degradation of fructose-1,6-bisphosphatase!51
2.5. Mutants of the deubiquitylating enzyme Ubp14 decipher pathway
diversity of ubiquitin–proteasome linked protein degradation!53
3. Bibliography!55
4. Publications!74
4.1. The cytoplasmic Hsp70 chaperone machinery subjects misfolded and ER
import incompetent proteins to degradation via the ubiquitin-proteasome
system!74
4.2. Degradation of misfolded protein in the cytoplasm is mediated by the
ubiquitin ligase Ubr1!88
4.3. The Cdc48-Ufd1-Npl4 complex is central in ubiquitin-proteasome
triggered catabolite degradation of fructose-1,6-bisphosphatase!93
4Table of contents
4.4. Mutants of the deubiquitinating enzyme Ubp14 decipher pathway
diversity of ubiquitin–proteasome linked protein degradation!101
4.5. Ubiquitylation in the ERAD pathway!107
5. Acknowledgments!133
6. Curriculum vitae!134
5Abbreviations
Å Ångström
AAA ATPases associated with diverse cellular activities
ADP Adenosine 5ʼ-diphosphate
ALS Amyotrophic lateral sclerosis
APC Anaphase promoting complex
ATP Adenosine 5ʼ-triphosphate
AZC L-azetidine-2-carboxylic acid
BRR Basic rich region
C-terminal Carboxy-terminal
CP Core particle
Cvt Cytosol to vacuole targeting
DNA Desoxyribonucleic acid
DUB Deubiquitylating enzyme
E. coli Escherichia coli
ER Endoplasmic reticulum
ERAC ER-associated compartment
ERAD ER-associated protein degradation
ERQD ER quality control and associated protein degradation
Fig Figure
g Grams
GFP Green fluorescent protein
GID Glucose induced degradation deficient
HA Hemagglutinin
HECT Homologous to the E6-AP carboxyl terminus
Hsp Heat shock protein
HSR Heat shock response
IPOD Insoluble protein deposit
JUNQ Juxtanuclear quality control compartment
6Abbreviations
kDa Kilodalton
l Litre
mRNA Messenger RNA
N-terminal Amino-terminal
NAT N-terminal acetyltransferase
NBD Nucleotide-binding domain
NEF Nucleotide exchange factor
NMR Nuclear magnetic resonance
Ntn N-terminal nucleophile
ODC Ornithine decarboxylase
OST Oligosaccharyl transferase
PCNA Proliferating cell nuclear antigen
PDI Protein disulfide isomerase
PGK 3-phosphoglycerate kinase
RING Really interesting new gene
RNA Ribonucleic acid
S Svedberg
S. cerevisiae Saccharomyces cerevisiae
SBD Substrate-binding domain
SCF complex Skp, Cullin, F-box containing complex
SUMO Small ubiquitin-like modifier
TAP Tandem affinity purification
TM Transmembrane
TOP Thimet oligopeptidase
tRNA Transfer RNA
TS Temperature sensitive
UBA Ubiquitin-associated
UBD Ubiquitin-binding domain
UBL Ubiquitin-like
UBX Ubiquitin regulatory X
7UDP Uridine diphosphate
UFD Ubiquitin fusion degradation
UGGT UDP-glucose:glycoprotein glucosyl transferase
UIM Ubiquitin-interacting motif
UPR Unfolded protein response
UPS Ubiquitin proteasome system
VHL Von Hippel-Lindau tumor suppressor
WT Wild-type
8