Structural investigations of coagulation factors:
Gespeichert in:
| 1. Verfasser: | |
|---|---|
| Format: | Buch |
| Sprache: | English |
| Veröffentlicht: |
2001
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| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | München, Techn. Univ., Diss., 2001 |
| Beschreibung: | 222 S. Ill., graph. Darst. |
Internformat
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Datensatz im Suchindex
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| adam_text |
INDEX
L
ABBREVIATIONS COMMONLY USED 4
CHAPTER 1: THE COAGULATION CASCADE 5
1.1. THE COAGULATION CASCADE - AN OVERVIEW 7
1.2. THE PROTEINASES 13
1.2.1. GLA DOMAINS MEDIATE BINDING TO PHOSPHOLIPID MEMBRANES 15
1.2.2. EGF-LIKE DOMAINS ARE INVOLVED IN PROTEIN-PROTEIN INTERACTIONS 19
1.2.3. KRINGLE DOMAINS POSSESS LYSINE BINDING SITES
YY
, 22
1.2.4. THE PROTEINASES INVOLVED IN THROMBOSIS AND FIBRINOLYSIS BELONG
TO THE TRYPSIN FAMILY 25
1.2.4.1. ZYMOGEN ACTIVATION FOLLOWS CLEAVAGE OF A SINGLE PEPTIDE BOND 27
1.2.5. PROTHROMBIN, MEIZOTHROMBIN, THROMBIN 28
1.2.5.1. EXOSITE BINDING INDUCES ALLOSTERIC REARRANGEMENTS 34
1.2.6. FACTOR XA: AT THE CROSS-POINT OF THE INTRINSIC AND
EXTRINSIC PATHWAYS 35
1.2.7. FACTOR IXA: AN AGE-REGULATED FACTOR 37
1.2.8. FACTOR VII, FACTOR VILA AND TISSUE FACTOR ^ 40
1.2.9. PROTEIN C, THROMBOMODULIN AND THE REGULATION OF THE
COAGULATION CASCADE 43
1.2.10. FACTOR XI, FACTOR XII AND THE CONTACT PHASE OF COAGULATION 46
1.3. THE SOLUBLE COFACTORS 47
1.3.1. FACTORS VA AND VILLA ARE COFACTORS OF THE SERINE PROTEINASES
XA AND IXA 47
1.3.2. THE A DOMAINS ARE HOMOLOGOUS TO SEVERAL METAL-BINDING PROTEINS 48
1.3.3. THE C DOMAINS ARE HOMOLOGOUS TO A FUNGAL LECTIN, DISCOIDIN 49
1.3.4. FACTOR V IS FOUND BOTH IN PLASMA AND IN PLATELETS 51
1.3.5. FACTOR VIII CIRCULATES IN COMPLEX WITH VON WILLEBRAND FACTOR 52
1.3.6. PROTEIN S IS THE COFACTOR FOR INACTIVATION OF FACTOR VA AND
FACTOR VILLA BY ACTIVATED PROTEIN C 56
1.4. OTHER INTEGRAL MEMBRANE PROTEINS 57
1.4.1. G-PROTEIN-COUPLED PROTEASE ACTIVATED RECEPTORS 58
1.4.2. INTEGRINS AND OTHER PLATELET RECEPTORS 60
1.4.3. ENDOTHELIAL PROTEIN C RECEPTOR 65
1.5. OTHER SOLUBLE PROTEINS ' 66
1.5.1. FIBRINOGEN, FIBRIN AND BLOOD CLOT FORMATION 66
1.5.2. THE TRANSGLUTAMINASE FACTOR XHIA STABILIZES THE FIBRIN CLOT 68
1.5.3. PLASMA CARBOXYPEPTIDASE B AND THE INHIBITION OF FIBRINOLYSIS 70
1.5.4. TISSUE FACTOR PATHWAY INHIBITOR 71
1.5.5. SERPINS INHIBITION OF SERINE PROTEINASES: A 'SUICIDE' SUBSTRATE
MECHANISM 72
BIBLIOGRAFISCHE INFORMATIONEN
HTTP://D-NB.INFO/962740632
INDEX
2
CHAPTER 2: STRUCTURAL BASIS FOR THE MEMBRANE BINDING ABILITY OF
COAGULATION FACTOR V: CRYSTAL STRUCTURES OF HUMAN FACTOR V C2 DOMAIN
2.1. THE C2 DOMAINS OF FACTOR VA AND FACTOR VILLA MEDIATE BINDING TO
PHOSPHOLIPID MEMBRANES
2.2. STRUCTURE DETERMINATION
2.2.1. PURIFICATION AND CRYSTALLIZATION
2.2.2. SEARCH FOR HEAVY ATOM DERIVATIVES
2.2.3. DATA COLLECTION
2.2.4. PHASING AND REFINEMENT
2.3. THE CRYSTAL STRUCTURE OF FVA-C2
2.3. STRUCTURAL HOMOLOGY WITH THE N-TERMINAL DOMAIN OF
GALACTOSE OXIDASE
2.5. CONFORMATIONAL FLEXIBILITY OF THE FIRST 'SPIKE' OF FVA-C2
2.6. EXPERIMENTAL EVIDENCE SUGGESTS THAT THE CLOSED FORM IS
FAVORED IN SOLUTION
2.7. PUTATIVE STEREOSPECIFIC P
LS-BINDING SITES ARE ENCLOSED BY THE
C2 SPIKES
2.8. IMPLICATIONS FOR MEMBRANE ASSOCIATION
2.9. A KINETIC MECHANISM FOR FACTOR VA MEMBRANE BINDING
2.10. COMPARISON WITH OTHER PERIPHERAL MEMBRANE PROTEINS
2.11. COMPARISON WITH THE STRUCTURE OF FVIIIA-C2: IMPLICATIONS FOR
MODELING OTHER MAMMALIAN DISCOIDIN DOMAINS
2.12. CONCLUSIONS
76
77
77
77
78
79
82
85
87
89
90
91
93
94
96
98
CHAPTER 3: THROMBIN INHIBITION: CRYSTAL STRUCTURE OF THE THROMBIN-
TRIABIN COMPLEX
3.1. TRIABIN IS A THROMBIN INHIBITOR WITH A UNIQUE INHIBITORY PROFILE
3.2. STRUCTURE DETERMINATION
3.2.1. PROTEIN PURIFICATION, CRYSTALLIZATION AND DATA COLLECTION
3.2.2. PHASING AND REFINEMENT
3.3. OVERALL STRUCTURE OF THE BOVINE THROMBIN-TRIABIN COMPLEX
3.4. TRIABIN STRUCTURE
3.5. THROMBIN-TRIABIN INTERACTION INTERFACE
3.6. COMPARISON WITH OTHER PROTEINACEOUS THROMBIN INHIBITORS
3.7. TRIABIN IS A DISTANT MEMBER OF THE LIPOCALIN FAMILY
3.8. A PUTATIVE EVOLUTIONARY MECHANISM CONVERTING A SMALL-LIGAND
BINDING PROTEIN INTO A THROMBIN INHIBITOR
3.9. CONCLUSIONS
100
101
101
104
106
109
112
115
117
123
126
CHAPTER 4: STRUCTURAL BASIS FOR THE ANTICOAGULANT ACTIVITY OF
THROMBOMODULIN-BOUND THROMBIN: CRYSTAL STRUCTURE OF THE HUMAN
OR
THROMBIN-TME456 COMPLEX
4.1. THREE CONSECUTIVE EGF-LIKE DOMAINS OF THROMBOMODULIN
CONFERS PROTEIN C COFACTOR ACTIVITY TO BOUND THROMBIN
4.2. STRUCTURE DETERMINATION
128
129
INDEX
3
4.2.1. PREPARATION OF PROTEINS 129
4.2.2. COMPLEX FORMATION, CRYSTALLIZATION AND DATA COLLECTION 129
4.2.3. PHASING AND REFINEMENT 130
4.3. OVERALL STRUCTURE OF THE THROMBIN-TME456 COMPLEX 130
4.4. ABSENCE OF ALLOSTERIC EFFECTS IN THROMBIN 132
4.5. STRUCTURE OF THE TME456 FRAGMENT 136
4.5.1. OVERALL ARRANGEMENT OF EGF-LIKE DOMAINS 136
4.5.2. STRUCTURE OF TME4 ' 139
4.5.3. AN ATYPICAL EGF-LIKE DOMAIN: TME5 140
4.5.4. TME6 AND CALCIUM BINDING 141
4.6. THE THROMBIN-THROMBOMODULIN INTERFACE 141
4.7. AN EXTENDED EXOSITE ON TME45 FACING THROMBIN 143
4.8. A DOCKING MECHANISM OF SUBSTRATE ACTIVATION 144
4.8.1. GENERATION OF A MODEL FOR THE ACTIVATION COMPLEX
PC-(MEIZO)THROMBIN-TME456 144
4.8.2. MANIFOLD INTERACTIONS BETWEEN THROMBIN AND PROTEIN CL
VALIDATE THE MODEL ' 146
4.8.3. TME45 PRESENTS THE SUBSTRATE PROTEIN C TO THE
ACTIVE SITE OF THROMBIN 148
4.9. ACTIVATION ON THE CELL MEMBRANE SURFACE 150
4.10. OTHER PHYSIOLOGICAL IMPLICATIONS 151
4.10.1. ACTIVATION OF TAFI 151
4.10.2. INACTIVATION BY THE SERPIN PROTEIN C INHIBITOR 152
4.11. CONCLUSIONS 152
APPENDICES
AL: RESULTS OF INVESTIGATIONS WITH KNOCKOUT MICE 154
A2: POSTTRANSLATIONAL MODIFICATIONS OF MAJOR HUMAN COAGULATION FACTORS
155
A3: STRUCTURE-BASED SEQUENCE ALIGNMENT OF THE CATALYTIC DOMAINS OF
SERINE PROTEINASES INVOLVED IN COAGULATION AND FIBRINOLYSIS 157
A4: MAJOR CLINICAL IMPLICATIONS OF DEFICIENCIES IN COAGULATION FACTORS
158
A5: STRUCTURAL BASIS OF HEMOPHILIA A MUTANTS MAPPED TO CL AND C2
DOMAINS OF FACTOR VIII 160
A6: PROGRAMS AND DATA BASES USED 161
/
REFERENCES 162
DANKSAGUNG 220
PALABRAS FINALES 221 |
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| subject_GND | (DE-588)4113937-9 |
| title | Structural investigations of coagulation factors |
| title_auth | Structural investigations of coagulation factors |
| title_exact_search | Structural investigations of coagulation factors |
| title_full | Structural investigations of coagulation factors Pablo Fuentes-Prior |
| title_fullStr | Structural investigations of coagulation factors Pablo Fuentes-Prior |
| title_full_unstemmed | Structural investigations of coagulation factors Pablo Fuentes-Prior |
| title_short | Structural investigations of coagulation factors |
| title_sort | structural investigations of coagulation factors |
| topic_facet | Hochschulschrift |
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