Synthesis and Structural Analysis of the N-Terminal Domain of the Thyroid Hormone-Binding Protein Transthyretin
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Jackie A. Wilce
Abstract
Transthyretin (TTR) is a 55 kDa protein responsible for the transport of thyroid hormones and retinol in human serum. Misfolded forms of the protein are implicated in the amyloid diseases familial amyloidotic polyneuropathy and senile systemic amyloidosis. Its folding properties and stabilization by ligands are of current interest due to their importance in understanding and combating these diseases. To assist in such studies we developed a method for the solid phase synthesis of the monomeric unit of a TTR analogue and its folding to form a functional 55 kDa tetramer. The monomeric unit of the protein was chemically synthesized in three parts, comprising amino acid residues 1–51, 54–99 and 102–127, and ligated using chemoselective thioether ligation chemistry. The synthetic protein was folded and assembled to a tetrameric structure in the presence of the TTR's native ligand, thyroxine, as shown by gel filtration chromatography, native gel electrophoresis, TTR antibody recognition and thyroid hormone binding. In the current study the solution structure of the first of these fragment peptides, TTR(1–51) is examined to determine its intrinsic propensity to form β-sheet structure, potentially involved in amyloid fibril formation by TTR. Despite the presence of extensive β-structure in the native form of the protein, the N-terminal fragment adopts an essentially random coil conformation in solution.
Copyright © 2002 by Walter de Gruyter GmbH & Co. KG
Artikel in diesem Heft
- Author Index
- Subject Index
- Contents
- Historical Aspects and Perspectives in Transthyretin Research
- Transthyretin from Discovery to Now
- The Evolution of Transthyretin Synthesis in Vertebrate Liver, in Primitive Eukaryotes and in Bacteria
- The Evolution of Transthyretin Synthesis in the Choroid Plexus
- Hepatic Synthesis, Maturation and Complex Formation between Retinol-Binding Protein and Transthyretin
- Synthesis and Structural Analysis of the N-Terminal Domain of the Thyroid Hormone-Binding Protein Transthyretin
- Three-Dimensional Structure of the Transthyretin-Retinol-Binding Protein Complex
- Mechanisms of Molecular Recognition: Crystal Structure Analysis of Human and Rat Transthyretin Inhibitor Complexes
- Transthyretin in Fish: State of the Art
- The Effects of Endocrine-Disrupting Chemicals on Thyroid Hormone Binding to Xenopus laevis Transthyretin and Thyroid Hormone Receptor
- Clinical Picture and Outcome of Transthyretin-Related Familial Amyloid Polyneuropathy (FAP) in Japanese Patients
- Laboratory Assessment of Transthyretin Amyloidosis
- Amyloid: Morphology and Toxicity
- Historical Overview of Analytical Methods for the Measurement of Transthyretin
- Nutritional Regulation of Visceral Markers in Rat Liver and Cultured Hepatoma Cells
- Significance of Transthyretin in Protein Metabolism
- Transthyretin as a Thyroid Hormone Carrier: Function Revisited
- The Molar Ratio of Retinol-Binding Protein to Transthyretin in the Assessment of Vitamin A Status in Adults. Proposal of a Cut-off Point
- Observations with Regard to the National Kidney Foundation K/DOQI Clinical Practice Guidelines Concerning Serum Transthyretin in Chronic Renal Failure
- Metabolism and Clinical Interest of Serum Transthyretin (Prealbumin) in Dialysis Patients
- Protein Status in Pancreatitis – Transthyretin Is a Sensitive Biomarker of Malnutrition in Acute and Chronic Pancreatitis
- Assessment of Nutritional Status in Organ Transplant: Is Transthyretin a Reliable Indicator?
- Body Composition and Nutritional Parameters in HIV and AIDS Patients
- C-Reactive Protein to Transthyretin Ratio for the Early Diagnosis and Follow-up of Postoperative Infection
- The Prognostic Value of Nutritional and Inflammatory Indices in Critically Ill Patients with Acute Respiratory Failure
- Transthyretin: Its Response to Malnutrition and Stress Injury. Clinical Usefulness and Economic Implications
- Transthyretin Measurement as a Screening Tool for Protein Calorie Malnutrition in Emergency Hospital Admissions
- Outcomes of Continuous Process Improvement of a Nutritional Care Program Incorporating TTR Measurement
- The Role of Visceral Protein Markers in Protein Calorie Malnutrition
- Acknowledgement
- Meetings
Artikel in diesem Heft
- Author Index
- Subject Index
- Contents
- Historical Aspects and Perspectives in Transthyretin Research
- Transthyretin from Discovery to Now
- The Evolution of Transthyretin Synthesis in Vertebrate Liver, in Primitive Eukaryotes and in Bacteria
- The Evolution of Transthyretin Synthesis in the Choroid Plexus
- Hepatic Synthesis, Maturation and Complex Formation between Retinol-Binding Protein and Transthyretin
- Synthesis and Structural Analysis of the N-Terminal Domain of the Thyroid Hormone-Binding Protein Transthyretin
- Three-Dimensional Structure of the Transthyretin-Retinol-Binding Protein Complex
- Mechanisms of Molecular Recognition: Crystal Structure Analysis of Human and Rat Transthyretin Inhibitor Complexes
- Transthyretin in Fish: State of the Art
- The Effects of Endocrine-Disrupting Chemicals on Thyroid Hormone Binding to Xenopus laevis Transthyretin and Thyroid Hormone Receptor
- Clinical Picture and Outcome of Transthyretin-Related Familial Amyloid Polyneuropathy (FAP) in Japanese Patients
- Laboratory Assessment of Transthyretin Amyloidosis
- Amyloid: Morphology and Toxicity
- Historical Overview of Analytical Methods for the Measurement of Transthyretin
- Nutritional Regulation of Visceral Markers in Rat Liver and Cultured Hepatoma Cells
- Significance of Transthyretin in Protein Metabolism
- Transthyretin as a Thyroid Hormone Carrier: Function Revisited
- The Molar Ratio of Retinol-Binding Protein to Transthyretin in the Assessment of Vitamin A Status in Adults. Proposal of a Cut-off Point
- Observations with Regard to the National Kidney Foundation K/DOQI Clinical Practice Guidelines Concerning Serum Transthyretin in Chronic Renal Failure
- Metabolism and Clinical Interest of Serum Transthyretin (Prealbumin) in Dialysis Patients
- Protein Status in Pancreatitis – Transthyretin Is a Sensitive Biomarker of Malnutrition in Acute and Chronic Pancreatitis
- Assessment of Nutritional Status in Organ Transplant: Is Transthyretin a Reliable Indicator?
- Body Composition and Nutritional Parameters in HIV and AIDS Patients
- C-Reactive Protein to Transthyretin Ratio for the Early Diagnosis and Follow-up of Postoperative Infection
- The Prognostic Value of Nutritional and Inflammatory Indices in Critically Ill Patients with Acute Respiratory Failure
- Transthyretin: Its Response to Malnutrition and Stress Injury. Clinical Usefulness and Economic Implications
- Transthyretin Measurement as a Screening Tool for Protein Calorie Malnutrition in Emergency Hospital Admissions
- Outcomes of Continuous Process Improvement of a Nutritional Care Program Incorporating TTR Measurement
- The Role of Visceral Protein Markers in Protein Calorie Malnutrition
- Acknowledgement
- Meetings
