Structural and functional investigation of the innate immune receptor MDA5 and its inhibition by paramyxoviral V proteins:
Gespeichert in:
| 1. Verfasser: | |
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| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
2013
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| Schlagworte: | |
| Online-Zugang: | kostenfrei http://d-nb.info/104158413X/34 kostenfrei Inhaltsverzeichnis |
| Beschreibung: | III, 99 Blatt Ill., graph. Darst. |
| Format: | Langzeitarchivierung gewährleistet, LZA |
Internformat
MARC
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| 100 | 1 | |a Motz, Carina Beate |d 1983- |e Verfasser |0 (DE-588)1042546681 |4 aut | |
| 245 | 1 | 0 | |a Structural and functional investigation of the innate immune receptor MDA5 and its inhibition by paramyxoviral V proteins |c Carina Beae Motz |
| 264 | 1 | |c 2013 | |
| 300 | |a III, 99 Blatt |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 502 | |a München, Univ., Diss., 2013 | ||
| 538 | |a Langzeitarchivierung gewährleistet, LZA | ||
| 655 | 7 | |0 (DE-588)4113937-9 |a Hochschulschrift |2 gnd-content | |
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Datensatz im Suchindex
| _version_ | 1804151440991584256 |
|---|---|
| adam_text | IMAGE 1
TABLE OF CONTENTS
TABLE OF CONTENTS
1 INTRODUCTION 1-23
1.1 PATTERN RECOGNITION RECEPTORS ARE KEY SENTINELS OF THE INNATE IMMUNE
SYSTEM 1-5 1.1.1 UNIVERSALITY VERSUS SPECIFICITY 1
1.1.2 TOLL-LIKE RECEPTORS (TLRS) 2
1.1.3 NOD-LIKE RECEPTORS (NLRS) 2-3
1.1.4 THE AIM2 INFLAMMASOME 3
1.1.5 OTHER DNA SENSORS 3
1.1.6 RIG-I LIKE RECEPTORS (RLRS) 3-4
1.1.7 COMPONENTS OF THE INNATE IMMUNE SYSTEM DO NOT ACT IN ISOLATION 4-5
1.2 THE RIG-I LIKE RECEPTOR FAMILY SENSES VIRUSES BY RECOGNIZING RNA
PATTERNS 5-10
1.2.1 RLRS SHARE A SIMILAR DOMAIN ORGANIZATION BUT FILNCTION DIVERGENTLY
IN ANTIVIRAL IMMUNITY 5-8
1.2.2 THE RD DETERMINES THE SPECIFICITY OF RLRS FOR DIFFERENT RNA
LIGANDS 8-10
1.3 THE STRUCTURAL BASIS FOR ANTIVIRAL SIGNAL ACTIVATION BY RLRS 10-15
1.3.1 RIG-I IS ACTIVATED BY A CONFORMATIONAL SWITCH THAT TRIGGERS
SIGNALING 10-12
1.3.2 THE ACTIVATION OF MDA5 SHOWS MECHANISTIC SIMILARITIES AND
DIFFERENCES TO RIG-I 12-14
1.3.3 THE FUNCTION OF ATP HYDROLYSIS IN THE ACTIVATION OF RLRS IS
UNKNOWN 14-15
1.4 RIG-I AND MDA5 USE THE ADAPTOR MAVS TO INDUCE CYTOKINE PRODUCTION
15-19
1.4.1 UBIQUITIN AND THE POLYMERIZATION OF MAVS PROPAGATE THE ANTIVIRAL
SIGNALING CASCADE 15-16
1.4.2 THE ACTIVATED TRANSCRIPTION FACTORS NF-KB, IRF3 AND IRF7 DRIVE THE
CYTOKINE PRODUCTION 16-17
1.4.3 CARDLESS LGP2 REGULATES THE ANTIVIRAL ACTIVITY OF RIG-I AND MDA5
17-19
1 .5 THE PARAMYXOVIRAL V PROTEIN IS A POTENT CYTOKINE ANTAGONIST 19-23
1.5.1 THE V PROTEIN IS A NON-STRUCTURAL PROTEIN REQUIRED FOR VIRAL
PATHOGENESIS 19-20
1.5.2 THE V PROTEIN SABOTAGES THE INNATE IMMUNE RESPONSE AT SEVERAL
LEVELS 20-21
1.5.3 THE V PROTEIN SPECIFICALLY BINDS AND INHIBITS MDA5 22-23
1.6 OBJECTIVES 23
HTTP://D-NB.INFO/1042546835
IMAGE 2
TABLE OF CONTENTS
2 MATERIAL AND METHODS 24-42
2.1 MATERIALS 24
2.2 METHODS 24-42
2.2.1 GENERAL MOLECULAR BIOLOGY METHODS 24-25
2.2.1.1 CLONING 24
2.2.1.2 SITE-DIRECTED MUTAGENESIS 24
2.2.1.3 HEAT SHOCK TRANSFORMATION OF ESCHERICHIA COLI XLL-BLUE (K12) 25
2.2.1.4 ISOLATION OF PLASMID DNA FROM ESCHERICHIA COLI XLL-BLUE (K12) 25
2.2.1.5 DETERMINATION OF NUCLEIC ACID AND PROTEIN CONCENTRATIONS 25
2.2.2 GENERAL BIOINFORMATICS METHODS 25
2.2.2.1 PROTEIN SEQUENCE ALIGNMENTS AND SECONDARY STRUCTURE PREDICTIONS
25
2.2.2.2 STRUCTURE VISUALIZATION AND ANALYSIS 25
2.2.3 SMALL SCALE PROTEIN TESTEXPRESSION 26
2.2.4 LARGE SCALE PROTEIN EXPRESSION 27
2.2.5 LARGE SCALE PURIFICATION OF MDA5 AND PIV5 V PROTEINS AND THEIR
COMPLEXES 28-29
2.2.6 ATPASE ASSAYS 29
2.2.7 STATIC LIGHT SCATTERING (SLS) MEASUREMENTS 30-31
2.2.8 SMALL-ANGLE X-RAY SCATTERING (SAXS) OF PROTEIN SOLUTIONS 31
2.2.9 REDUCTIVE METHYLATION 32
2.2.10 LARGE SCALE PURIFICATION OF FAB FRAGMENTS AND TRIPLE COMPLEX
FORMATION 32
2.2.11 CRYSTALLIZATION OF THE SSMDA5:PIV5 V PROTEIN CORE COMPLEX 32-33
2.2.12 STRUCTURE DETERMINATION 33-41
2.2.12.1 PRINCIPLES OF X-RAY STRUCTURE ANALYSIS 33-34
2.2.12.2 PRINCIPLES OF SAD PAHSING 35-40
2.2.12.3 STRUCTURE DETERMINATION OF THE SSMDA5:PIV5 V PROTEIN CORE
COMPLEX 40-41
2.2.13 ANALYTICAL SIZE EXCLUSION CHROMATOGRAPHY 41
2.2.14 DIFFERENTIAL SCANNING FLUORIMETRY EXPERIMENTS 41
2.2.15 ELECTROPHORETIC MOBILITY SHIFT ASSAYS (EMSAS) 41-42
2.2.16 ELECTRON MICROSCOPY 42
IMAGE 3
TABLE OF CONTENTS
3 RESULTS 43-65
3.1 RECOMBINANTLY EXPRESSED FULL LENGTH MDA5 IS A FUNCTIONAL PROTEIN
43-45
3.2 OPTIMIZATION OF PROTEIN CONSTRUCTS FOR CRYSTALLIZATION 46-49
3.3 CRYSTALLIZATION OF THE SSMDA5:PIV5 V PROTEIN CORE COMPLEX 49-52
3.4 THE PARAMYXOVIRAL V PROTEIN DISRUPTS THE FOLD OF THE MDA5 SF2 ATPASE
DOMAIN 52-56
3.5 DIFFERENCES IN RESIDUE CONSERVATION ENABLE RIG-I TO EVADE V PROTEIN
RECOGNITION 57-59
3.6 THE PIV5 V PROTEIN HAS TO UNFOLD ITSELF TO DISRUPT THE FOLD OF MDA5
59-62
3.7 V PROTEIN BINDING HAS DUAL IMPACT ON THE FUNCTION OF MDA5 63-65
4 DISCUSSION 66-80
4.1 A STRUCTURE-DERIVED MODEL FOR MDA5 INHIBITION BY PARAMYXOVIRAL V
PROTEINS 66-72 4
4.1.1 WHICH ENERGY SOURCE DRIVES THE UNFOLDING PROCESSES THAT ACCOMPANY
V PROTEIN BINDING? 69-70
4.1.2 KNOWN P-STRAND DISPLACEMENT MECHANISMS IN OTHER BIOLOGICAL
PROCESSES 70-72
4.2 IS THE RD OF RLRS ABLE TO SWITCH BETWEEN TWO BINDING MODES? 72-73
4.3 V PROTEIN BINDING TO OTHER RLR FAMILY MEMBERS AND ITS FUNCTIONAL
IMPACT 73-78
4.3.1 ENGINEERING OF RIG-I INHIBITION BY PARAMYXOVIRAL V PROTEINS 75-77
4.3.2 INDIRECT INHIBITION BY PARAMYXOVIRAL V PROTEINS VIA LGP2 78
4.3.3 VIRAL PRESSURE ON THE EVOLUTION OF RLRS 78
4.4 THE PARAMYXOVIRAL V PROTEIN AS A UNIVERSAL IMMUNE TARGETING TOOL
79-80
5 SUMMARY 81-82
6 REFERENCES , 83-94
7 LIST OF ABBREVIATIONS 95-97
8 ACKNOWLEDGMENTS 98
9 CURRICULUM VITAE 99
|
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| spelling | Motz, Carina Beate 1983- Verfasser (DE-588)1042546681 aut Structural and functional investigation of the innate immune receptor MDA5 and its inhibition by paramyxoviral V proteins Carina Beae Motz 2013 III, 99 Blatt Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier München, Univ., Diss., 2013 Langzeitarchivierung gewährleistet, LZA (DE-588)4113937-9 Hochschulschrift gnd-content Erscheint auch als Online-Ausgabe urn:nbn:de:bvb:19-159843 https://nbn-resolving.org/urn:nbn:de:bvb:19-159843 Resolving-System kostenfrei Volltext http://d-nb.info/104158413X/34 Langzeitarchivierung Nationalbibliothek http://edoc.ub.uni-muenchen.de/15984/ Verlag kostenfrei DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=026806725&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Motz, Carina Beate 1983- Structural and functional investigation of the innate immune receptor MDA5 and its inhibition by paramyxoviral V proteins |
| subject_GND | (DE-588)4113937-9 |
| title | Structural and functional investigation of the innate immune receptor MDA5 and its inhibition by paramyxoviral V proteins |
| title_auth | Structural and functional investigation of the innate immune receptor MDA5 and its inhibition by paramyxoviral V proteins |
| title_exact_search | Structural and functional investigation of the innate immune receptor MDA5 and its inhibition by paramyxoviral V proteins |
| title_full | Structural and functional investigation of the innate immune receptor MDA5 and its inhibition by paramyxoviral V proteins Carina Beae Motz |
| title_fullStr | Structural and functional investigation of the innate immune receptor MDA5 and its inhibition by paramyxoviral V proteins Carina Beae Motz |
| title_full_unstemmed | Structural and functional investigation of the innate immune receptor MDA5 and its inhibition by paramyxoviral V proteins Carina Beae Motz |
| title_short | Structural and functional investigation of the innate immune receptor MDA5 and its inhibition by paramyxoviral V proteins |
| title_sort | structural and functional investigation of the innate immune receptor mda5 and its inhibition by paramyxoviral v proteins |
| topic_facet | Hochschulschrift |
| url | https://nbn-resolving.org/urn:nbn:de:bvb:19-159843 http://d-nb.info/104158413X/34 http://edoc.ub.uni-muenchen.de/15984/ http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=026806725&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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