1;Preface;5 2;Contents;5 3;Contributors;5 4;1: Mechanisms of Molecular Recognition: Structural Characteristics of Transthyretin Ligand Interactions;14 4.1;1.1 Introduction;15 4.2;1.2 TTR Monomer Assembly and Stability;18 4.3;1.3 Negative Cooperativity in TTR Binding;21 4.4;1.4 Ligand Binding Architecture;23 4.5;1.5 TTR Variants and Amyloid Disease;27 4.6;1.6 Summary;29 4.7;Acknowledgement;30 4.8;References;30 5;2: TTR Synthesis During Development and Evolution: What the Marsupials Revealed;35 5.1;2.1 Marsupials Marsupialand Other Mammals;36 5.1.1;2.1.1 Eutherians, Marsupials and MonotremesMonotreme;36 5.1.2;2.1.2 Evolutionary History of the Marsupials;36 5.1.3;2.1.3 Development of Marsupials;38 5.2;2.2 TTR as a Thyroid Hormone Distributor Protein (THDP);38 5.2.1;2.2.1 The Role of THDPs in Blood;38 5.2.2;2.2.2 TTR as a THDP in the CSF;39 5.2.3;2.2.3 THDPs Thyroid hormone distributor protein (THDP)Differ Between Species: Mammalian TTR is the Exception, not the Rule;39 5.3;2.3 Sites of TTR Synthesis in Eutherian EutherianMammals;40 5.3.1;2.3.1 LiverLiver;40 5.3.2;2.3.2 Choroid PlexusChoroid plexus;40 5.3.3;2.3.3 Visceral Yolk Sac and Placenta;40 5.3.4;2.3.4 Retinal and Ciliary Pigment Epithelia;41 5.3.5;2.3.5 Intestine, Pancreas and Meninges;41 5.4;2.4 Sites of TTR Synthesis During Development in Vertebrates;41 5.4.1;2.4.1 LiverLiver;41 5.4.2;2.4.2 Onset of Hepatic TTR Synthesis in Juveniles Only Could be Related to the Developmental Surge of Thyroid Hormones in Bloo;43 5.4.3;2.4.3 Choroid PlexusChoroid plexus;43 5.4.4;2.4.4 Visceral Yolk Sac and Placenta;44 5.4.5;2.4.5 Other Tissues;45 5.5;2.5 TTR Synthesis During Evolution (Adult Animals);45 5.5.1;2.5.1 LiverLiver;45 5.5.1.1;2.5.1.1 Albumin is the Oldest THDP in Vertebrates;45 5.5.1.2;2.5.1.2 No Clear Phylogeny for TBGThyroxine-binding globulin (TBG) in Vertebrates;45 5.5.1.3;2.5.1.3 Hepatic TTR Synthesis in Adult Birds, Diprotodont Marsupials and Eutherians;45 5.5.1.4;2.5.1.4 Hepatic TTR Synthesis and the Increase in Lipid Pool to Body Mass Ratio: Consider Marsupials;46 5.5.1.5;2.5.1.5 Hepatic TTR Synthesis and Homeothermy: Marsupials Fall between the Cracks;46 5.5.1.6;2.5.1.6 The TTR-RBP Retinol-binding protein (RBP)Complex: Marsupials Raise a Question;47 5.5.2;2.5.2 Choroid PlexusChoroid plexus;47 5.5.3;2.5.3 Other Tissues;48 5.6;2.6 Evolution of TTR Structure and Function: MarsupialMarsupials are a `Missing Link´;48 5.7;2.7 Marsupial Models for Studying TTR Amyloid Formation;50 5.8;2.8 Conclusions;51 5.9;References;52 6;3: Evolution of Transthyretin Gene Structure;56 6.1;3.1 Genomic Structure of the Transthyretin Gene;57 6.1.1;3.1.1 General;57 6.1.2;3.1.2 Genomic Structure of Human TTR;57 6.1.3;3.1.3 Genomic Structure of TTR from Rodents;58 6.2;3.2 Evolution of the TTR Gene Structure and the Stepwise Shift of the Splicing Mechanism;59 6.3;3.3 Influence of Changes in Gene Structure on Function of TTR;63 6.4;3.4 Conclusion;65 6.5;References;66 7;4: Evolutionary Insights from Fish Transthyretin;70 7.1;4.1 Introduction;71 7.2;4.2 Thyroid Axis;72 7.3;4.3 Thyroid Hormones Distributor Proteins;72 7.4;4.4 Structure and Hormone Binding Characteristics;74 7.5;4.5 Evolution;75 7.5.1;4.5.1 TTR Tissue Distribution and Function;75 7.5.2;4.5.2 TTR and TLP Transthyretin-like protein (TLP)Evolution in Fish;76 7.6;Acknowledgements;82 7.7;References;82 8;5: The Salmonella sp. TLP: A Periplasmic 5-Hydroxyisourate Hydrolase;87 8.1;5.1 Introduction;88 8.2;5.2 The Identification of Non-Vertebrate TTR Homologs;88 8.2.1;5.2.1 The Relative Distributions of TTR and TLP Genes;88 8.2.2;5.2.2 Motifs Characterising TLP and TTR Sequences;89 8.2.3;5.2.3 Structural Significance of Motifs;90 8.2.4;5.2.4 Variations in the Predicted Subcellular Localisation of TLPs;91 8.3;5.3 Structural Characterisation of the S. dublin TLP;92 8.3.1;5.3.1 Synthesis and Characterisation of Recombinant S. dublin TLP;92 8.3.2;5.3.2 The X-Ray Crystal StructureCrystal structure of the S. dublin TLP;92 8.3.3;5.3.3 Comparison of the