Recent Advances in Transthyretin Evolution, Structure and Biological Functions (eBook)

Samantha J. Richardson, Vivian Cody (Herausgeber)

eBook Download: PDF

2009 | 2009
XIII, 362 Seiten
Springer Berlin (Verlag)
978-3-642-00646-3 (ISBN)

Infos

Since its ?rst description in 1942 in both serum and cerebrospinal ?uid, transthyretin (TTR) has had an eventful history, including changes in name from 'prealbumin' to 'thyroxine-binding prealbumin' to 'transthyretin' as knowledge increased about its functions. TTR is synthesised in a wide range of tissues in humans and other eutherian mammals: the liver, choroid plexus (blood- cerebrospinal ?uid barrier), retinal pigment epithelium of the eye, pancreas, intestine and meninges. However, its sites of synthesis are more restricted in other vertebrates. This implies that the number of tissues synthesising TTR during vertebrate evolution has increased, and raises questions about the selection pressures governing TTR synthesis. TTR is most widely known as a distributor of thyroid hormones. In addition, TTR binds retinol-binding protein, which binds retinol. In this way, TTR is also involved with retinoid distribution. More recently, TTR has been demonstrated to bind a wide variety of endocrine disruptors including drugs, pollutants, industrial compounds, heavy metals, and some naturally occurring plant ?avonoids. These not only interfere with thyroid hormone delivery in the body, but also transport such endocrine disruptors into the brain, where they have the potential to accumulate.

Inhalt

Preface 5
Contents 5
Contributors 5
1: Mechanisms of Molecular Recognition: Structural Characteristics of Transthyretin Ligand Interactions 14
1.1 Introduction 15
1.2 TTR Monomer Assembly and Stability 18
1.3 Negative Cooperativity in TTR Binding 21
1.4 Ligand Binding Architecture 23
1.5 TTR Variants and Amyloid Disease 27
1.6 Summary 29
Acknowledgement 30
References 30
2: TTR Synthesis During Development and Evolution: What the Marsupials Revealed 35
2.1 Marsupials Marsupialand Other Mammals 36
2.1.1 Eutherians, Marsupials and MonotremesMonotreme 36
2.1.2 Evolutionary History of the Marsupials 36
2.1.3 Development of Marsupials 38
2.2 TTR as a Thyroid Hormone Distributor Protein (THDP) 38
2.2.1 The Role of THDPs in Blood 38
2.2.2 TTR as a THDP in the CSF 39
2.2.3 THDPs Thyroid hormone distributor protein (THDP)Differ Between Species: Mammalian TTR is the Exception, not the Rule 39
2.3 Sites of TTR Synthesis in Eutherian EutherianMammals 40
2.3.1 LiverLiver 40
2.3.2 Choroid PlexusChoroid plexus 40
2.3.3 Visceral Yolk Sac and Placenta 40
2.3.4 Retinal and Ciliary Pigment Epithelia 41
2.3.5 Intestine, Pancreas and Meninges 41
2.4 Sites of TTR Synthesis During Development in Vertebrates 41
2.4.1 LiverLiver 41
2.4.2 Onset of Hepatic TTR Synthesis in Juveniles Only Could be Related to the Developmental Surge of Thyroid Hormones in Bloo 43
2.4.3 Choroid PlexusChoroid plexus 43
2.4.4 Visceral Yolk Sac and Placenta 44
2.4.5 Other Tissues 45
2.5 TTR Synthesis During Evolution (Adult Animals) 45
2.5.1 LiverLiver 45
2.5.1.1 Albumin is the Oldest THDP in Vertebrates 45
2.5.1.2 No Clear Phylogeny for TBGThyroxine-binding globulin (TBG) in Vertebrates 45
2.5.1.3 Hepatic TTR Synthesis in Adult Birds, Diprotodont Marsupials and Eutherians 45
2.5.1.4 Hepatic TTR Synthesis and the Increase in Lipid Pool to Body Mass Ratio: Consider Marsupials 46
2.5.1.5 Hepatic TTR Synthesis and Homeothermy: Marsupials Fall between the Cracks 46
2.5.1.6 The TTR-RBP Retinol-binding protein (RBP)Complex: Marsupials Raise a Question 47
2.5.2 Choroid PlexusChoroid plexus 47
2.5.3 Other Tissues 48
2.6 Evolution of TTR Structure and Function: MarsupialMarsupials are a `Missing Link´ 48
2.7 Marsupial Models for Studying TTR Amyloid Formation 50
2.8 Conclusions 51
References 52
3: Evolution of Transthyretin Gene Structure 56
3.1 Genomic Structure of the Transthyretin Gene 57
3.1.1 General 57
3.1.2 Genomic Structure of Human TTR 57
3.1.3 Genomic Structure of TTR from Rodents 58
3.2 Evolution of the TTR Gene Structure and the Stepwise Shift of the Splicing Mechanism 59
3.3 Influence of Changes in Gene Structure on Function of TTR 63
3.4 Conclusion 65
References 66
4: Evolutionary Insights from Fish Transthyretin 70
4.1 Introduction 71
4.2 Thyroid Axis 72
4.3 Thyroid Hormones Distributor Proteins 72
4.4 Structure and Hormone Binding Characteristics 74
4.5 Evolution 75
4.5.1 TTR Tissue Distribution and Function 75
4.5.2 TTR and TLP Transthyretin-like protein (TLP)Evolution in Fish 76
Acknowledgements 82
References 82
5: The Salmonella sp. TLP: A Periplasmic 5-Hydroxyisourate Hydrolase 87
5.1 Introduction 88
5.2 The Identification of Non-Vertebrate TTR Homologs 88
5.2.1 The Relative Distributions of TTR and TLP Genes 88
5.2.2 Motifs Characterising TLP and TTR Sequences 89
5.2.3 Structural Significance of Motifs 90
5.2.4 Variations in the Predicted Subcellular Localisation of TLPs 91
5.3 Structural Characterisation of the S. dublin TLP 92
5.3.1 Synthesis and Characterisation of Recombinant S. dublin TLP 92
5.3.2 The X-Ray Crystal StructureCrystal structure of the S. dublin TLP 92
5.3.3 Comparison of the Structure of S. dublin TLP with TTRs from Human, Chicken, rat and Seabream 93
5.3.3.1 Comparison of the Overall Fold of S. dublin TLP with TTR 93
5.3.3.2 Comparison of the Putative Active Site of S. dublin TLP with the Thyroid Hormone Binding Site of Human TTR 95
5.3.3.3 Comparison of the X-Ray Crystal Structure Crystal structureof S. dublin TLP to TLP Structures from E. coli, B. subtili 97
5.4 The In Vitro Function of the S. dublin TLP 98
5.4.1 Binding of Thyroid Hormones by the S. dublin TLP 98
5.4.2 Examining the Role of the S. dublin TLP in Purine Metabolism 98
5.4.3 Hydrolysis of 5-HIU by the the S. dublin TLP 99
5.4.4 Characterisation of the Active Site of S. dublinSalmonella dublin TLP 101
5.5 Perspectives 101
References 103
6: Vertebrate HIU hydrolase: Identification, Function, Structure, and Evolutionary Relationship with Transthyretin 105
6.1 Introduction 106
6.2 Identification and Function of Vertebrate 5-Hydroxyisourate hydrolase (HIUase)HIUase 107
6.3 Molecular Evolution of the HIUase/Transthyretin Family 108
6.4 Crystal Structure Crystal structureof Zebra Fish HIUase 111
6.4.1 Comparison of the Structures of HIUase and Transthyretin 113
6.4.2 The HIUase Active Site 114
6.5 Conclusions 116
References 117
7: Transthyretin-Related and Transthyretin-like Proteins 119
7.1 Introduction 119
7.2 The Structure of TRP 121
7.2.1 Overall Structure 121
7.2.2 Composition of the Active site 124
7.3 The Amyloidogenic Properties of TRP 126
7.4 Structural Model of TLP 127
7.5 Conclusions 129
Acknowledgements 131
References 131
8: The Transthyretin-Retinol-Binding Protein Complex 133
8.1 The Complex 133
8.2 Plasma Retinol-Binding ProteinRetinol-binding protein (RBP) (RBP4) 135
8.3 Crystal Structures Crystal structureof the Complex 139
8.4 Experimental Evidence that Supports the X-Ray Models 147
Acknowledgements 148
References 148
9: TTR and RBP: Implications in Fish Physiology 153
9.1 Vitamin A Transport 154
9.2 Transthyretin in Fish 156
9.3 Piscine Retinol-Binding Protein 4 160
9.4 RBP/TTR Interaction in Fish 162
9.5 Conclusions 164
References 164
10: TTR and Endocrine Disruptors 168
10.1 Introduction 168
10.2 Chemicals That Interact with the TH-Binding Sites of TTR 169
10.3 Chemicals That Affect the Stability of the TTR Tetramer and the Formation of the TTR-RBP Complex 172
10.4 Application of Competitive TTR Binding Assay to Detect Potential TH-Disrupting Chemicals 174
10.5 Perspectives 176
References 177
11: Genetics: Clinical Implications of TTR Amyloidosis 181
11.1 Introduction 181
11.2 Clinical Picture of TTR Amyloidosis 182
11.3 Larger Kindreds 184
11.4 Clinical Aspects of Common TTR Mutations 185
11.5 Clinical Syndromes of FAP 187
11.5.1 Neuropathy 187
11.5.2 Cardiomyopathy 187
11.5.3 Gastroenteropathy 188
11.5.4 Leptomeningeal Amyloidosis 188
11.6 Pathogenesis of TTR Amyloidosis From a Clinical Aspect 190
11.7 Therapy 192
11.8 Conclusion 193
References 194
12: Molecular Pathogenesis Associated with Familial Amyloidotic Polyneuropathy 198
12.1 Introduction 198
12.2 Pathological Features in the Peripheral Nervous System in FAP 199
12.3 Early Deposition of TTR in an Asymptomatic Phase in a Nonfibrillar Fashion 200
12.3.1 Ex Vivo Analyses in Clinical Samples 200
12.3.2 Ex Vivo Analyses in Animal Models 201
12.4 Inflammation and Oxidative Stress Pathways in FAP and Involvement of the Receptor for Advanced Glycation-End Products (R 201
12.5 The Ubiquitin-Proteasome System in FAP 202
12.6 The Unfolded Protein Response in FAP 202
12.6.1 Activation of the Heat Shock Response 202
12.6.2 A Compromised Heat Shock Response Increases Systemic Extracellular Transthyretin Deposition and Affects the Peripheral 203
12.7 The ER Response 204
12.8 Activation of Extracellular Matrix Remodeling Genes 204
12.9 Antiapoptotic Treatments 205
12.10 Concluding Remarks 206
References 206
13: Histidine 31: The Achilles' Heel of Human Transthyretin. Microheterogeneity is Not Enough to Understand the Molecular Cause 208
13.1 Introduction 209
13.2 Microheterogeneity of Human TTR by Ligands and Amino Acid Substitutions 209
13.3 Microheterogeneity of Human TTR by Conformational Stabilities 210
13.4 The Achilles' Heel of Human TTR: His31 214
13.5 Conclusions 218
Acknowledgment 219
References 219
14: New Therapeutic Approaches for Familial Amyloidotic Polyneuropathy (FAP) 222
14.1 Introduction 222
14.2 Elimination of Variant TTR in Blood Circulation 224
14.3 Down regulation of Variant TTR 225
14.4 Inhibition of Amyloid Deposition in Tissues 225
14.4.1 Compounds Binding to Amyloid Fibrils 225
14.4.1.1 Congo Red 225
14.4.1.2 Congo Red Derivatives 226
14.4.1.3 BSB as a Valuable Therapeutic Drug 227
14.4.2 Drugs Disrupting Amyloid Fibrils 228
14.4.2.1 IDOX 228
14.4.2.2 Tetracycline and Its Derivatives 228
14.4.2.3 Immunotherapies to Promote Clearance of Amyloid Deposition 229
Antibody Therapy Against Amyloidogenic TTR 229
Vaccine Therapy 229
14.5 Stabilization of the Tetrameric Structure of TTR 230
14.5.1 Various Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Derivatives 231
14.5.2 Cr3+ 233
14.5.3 Fx-1006 233
14.5.4 Controlling Drugs for Endoplasmic Reticulum (ER) Stress 233
14.6 Gene Therapy 234
14.6.1 Gene Silencing Tools 234
14.6.2 Gene Conversion Therapy 235
14.7 Other Possible Therapies 237
14.7.1 Radical Scavengers 237
14.7.2 Tauroursodeoxycholic Acid (Tudca) 238
14.8 Summary 238
Acknowledgments 239
References 239
15: Liver Transplantation for Transthyretin Amyloidosis 246
15.1 Background 247
15.2 Patient Selection and Outcome After Transplantation 248
15.2.1 Demographic Data and ATTR-Mutation 249
15.2.2 Amyloid Deposits 250
15.2.3 Neuropathy 250
15.2.3.1 Peripheral Neuropathy 250
15.2.3.2 Autonomic Neuropathy 251
15.2.4 Heart Complications 252
15.2.5 Gastrointestinal Complications 254
15.2.6 Kidney Complications 255
15.2.7 Central Nervous and Eye Complications 256
15.2.8 Summary and a Proposed Algorithm for Patient Selection 256
15.3 The Transplantation Procedure 258
15.4 Domino Liver Transplantation 260
References 261
16: Mouse Models of Transthyretin Amyloidosis 268
16.1 Introduction 268
16.2 Transgenic Mice Carrying a Human Mutant TTR Gene 269
16.3 Disruption of the Ttr Gene in Mice 275
16.4 Transgenic Mouse Models of TTR-Associated Homozygous Amyloidosis 275
16.5 Analysis of the Role of Various Factors in Amyloid Deposition 277
16.5.1 Serum Amyloid P Component 277
16.5.1.1 Generation of Doubly Transgenic Mice Carrying Both a Human Mutant TTR Gene and the Human APCS Gene Encoding SAP 277
16.5.1.2 Induction of Mouse Sap Synthesis in a Transgenic Mouse Model of TTR Amyloidosis (MT-hTTRMet30 line) by Injection of 277
16.5.1.3 Induction of AA Amyloidosis in the Sap-Deficient Mice 279
16.5.1.4 Could Inhibition of Binding of SAP to Amyloid Fibrils be Effective as a Treatment For Human Amyloidoses? Contributio 280
16.5.2 Analysis of the Role of Factors Other than SAP in TTR Amyloid Deposition 282
16.5.2.1 TTR Amyloid Fibrils 282
16.5.2.2 Doxycycline 282
16.5.2.3 TTR Y78F 282
16.5.2.4 An Antiapoptotic Agent 283
16.6 Attempts to Generate a Closer Mouse Model of TTR Amyloidosis 283
16.7 Conclusions 284
Acknowledgments 284
References 284
17: What Have We Learned from TTR-Null Mice: Novel Functions for TTR? 288
17.1 Transthyretin-Null Mice 289
17.2 Thyroid Hormones 289
17.3 Retinoids 292
17.4 Behavioral Disorders 293
17.4.1 Depression 293
17.4.2 Alzheimer's Disease, Aging, and Memory Impairment 294
17.5 Others: Energy Metabolism 297
17.6 Final Remarks 297
Acknowledgment 297
References 298
18: Transthyretin Null Mice: Developmental Phenotypes 303
18.1 Introduction 304
18.2 Thyroid Hormones and Development 304
18.2.1 Thyroid Hormones 304
18.2.2 Thyroid Hormones in Developing Vertebrates 305
18.3 Postnatal Development of Transthyretin Null Mice 306
18.3.1 Thyroid Hormone Levels in Plasma 306
18.3.2 Postnatal Development of Peripheral Tissues 306
18.3.2.1 Suckling-to-Weaning Transition 306
18.3.2.2 Onset of Rapid Growth 307
18.3.2.3 Bone Development 308
18.3.2.4 Maturation of the Ileum 310
18.3.3 Postnatal Development of Central Nervous Tissues 310
18.4 Perspectives 312
References 312
19: TTR Null Mice as a Model to Study the Involvement of TTR in Neurobiology: From Neuropeptide Processing to Nerve Regeneratio 317
19.1 Introduction 318
19.2 The TTR Knockout Mouse 318
19.2.1 T4 and Retinol Metabolism in TTR KO Mice: Absence of Major Effects on Thyroid Hormone Function and Retinol Metabolism 319
19.2.2 TTR KO Mice as a Tool to Address the Function of TTR in the Nervous System 319
19.2.2.1 TTR KO Mice have a Decreased Depressive-like Behavior and a Sensorimotor Impairment 320
19.2.2.2 TTR KO Mice and Age-related diseasesAge-related Disorders 322
19.3 TTR is Related to Differential Gene Expression in the Nervous System: PAM Upregulation in TTR KO Mice 323
19.3.1 Peptidylglycine a-Amidating Monooxygenase (PAM), a key Neuropeptide Processing Enzyme, is Increased in the Absenc 323
19.3.2 Increased PAM levels in the Absence of TTR are not Related to an Effect on PAM mRNA Stability 324
19.3.3 TTR KOs are a New Mouse Model for Increased Neuropeptide Y (NPY)Neuropeptide Y (NPY) 325
19.3.3.1 Amidated Neuropeptide Y is Increased in TTR KO Mice 325
19.3.3.2 Lipoprotein Lipase, a Gene Activated by NPY, is Increased in the Absence of TTR 326
19.3.3.3 NPY Overexpression in the Context of the Behavioral Phenotype of TTR KO Mice 326
19.3.3.4 The Use of TTR KO Mice as a NPY Overexpressor Model 327
19.4 TTR Enhances Nerve Regeneration 327
19.4.1 After Sciatic Nerve Crush, Lack of TTR is Related to a Delayed Regeneration Capacity 328
19.4.2 Assessment of the Cellular Mechanism Through Which TTR Enhances Nerve Regeneration 329
19.4.2.1 The Absence of TTR does not Affect Neuronal Survival Following Nerve Crush 329
19.4.2.2 TTR Increases Neurite Outgrowth 330
19.5 The Proteolytic Activity of TTR may Participate in the Biology of the Nervous System 331
19.6 Conclusions 331
References 332
20: Plasma Transthyretin Reflects the Fluctuations of Lean Body Mass in Health and Disease 335
20.1 Introduction 336
20.2 Body Composition Studies 336
20.3 Transthyretin in Health and Protein-Depleted States 339
20.4 Transthyretin in Acute and Chronic Stressful Disorders 342
20.5 The Transthyretin-Homocysteine Saga 346
20.6 Concluding Perspectives 352
Acknowledgments 354
References 354
Index 364

Produkt-Details

• Erscheint lt. Verlag: 9.8.2009
• Zusatzinfo: XIII, 362 p.
• Verlagsort: Berlin
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Innere Medizin
• Themenwelt: Medizin / Pharmazie ► Studium
• Themenwelt: Naturwissenschaften ► Biologie
• Themenwelt: Technik
• Schlagworte: Bacteria • Biology • growth • Hormone • Mutation • Neuropeptides • Physiology • Protein • proteins • Protein Structure • Proteomics • synthesis • thyroid hormone
• ISBN-10: 3-642-00646-9 / 3642006469
• ISBN-13: 978-3-642-00646-3 / 9783642006463