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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 曾秀如 | zh_TW |
dc.contributor.advisor | Shiou-Ru Tzeng | en |
dc.contributor.author | 王奕翔 | zh_TW |
dc.contributor.author | Yi-Shiang Wang | en |
dc.date.accessioned | 2024-02-20T16:27:49Z | - |
dc.date.available | 2024-02-21 | - |
dc.date.copyright | 2024-02-20 | - |
dc.date.issued | 2024 | - |
dc.date.submitted | 2024-02-05 | - |
dc.identifier.citation | Tsuzuki, T., Mita, S., Maeda, S., Araki, S. & Shimada, K. Structure of the human prealbumin gene. J Biol Chem 260, 12224-12227 (1985).
2. Sasaki, H., Yoshioka, N., Takagi, Y. & Sakaki, Y. Structure of the chromosomal gene for human serum prealbumin. Gene 37, 191-197 (1985). 3. Serot, J.M., Christmann, D., Dubost, T. & Couturier, M. Cerebrospinal fluid transthyretin: aging and late onset Alzheimer's disease. J Neurol Neurosurg Psychiatry 63, 506-508 (1997). 4. Makover, A., et al. Plasma transthyretin. Tissue sites of degradation and turnover in the rat. J Biol Chem 263, 8598-8603 (1988). 5. Soprano, D.R., Herbert, J., Soprano, K.J., Schon, E.A. & Goodman, D.S. Demonstration of transthyretin mRNA in the brain and other extrahepatic tissues in the rat. J Biol Chem 260, 11793-11798 (1985). 6. Martone, R.L., Herbert, J., Dwork, A. & Schon, E.A. Transthyretin Is Synthesized in the Mammalian Eye. Biochem Bioph Res Co 151, 905-912 (1988). 7. Liz, M.A., et al. A Narrative Review of the Role of Transthyretin in Health and Disease. Neurol Ther 9, 395-402 (2020). 8. Magalhaes, J., Eira, J. & Liz, M.A. The role of transthyretin in cell biology: impact on human pathophysiology. Cell Mol Life Sci 78, 6105-6117 (2021). 9. Adams, D., Koike, H., Slama, M. & Coelho, T. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol 15, 387-404 (2019). 10. Lai, Z., Colon, W. & Kelly, J.W. The acid-mediated denaturation pathway of transthyretin yields a conformational intermediate that can self-assemble into amyloid. Biochemistry 35, 6470-6482 (1996). 11. Oppenheimer, J.H. Role of plasma proteins in the binding, distribution and metabolism of the thyroid hormones. N Engl J Med 278, 1153-1162 (1968). 12. Refetoff, S. Thyroid Hormone Serum Transport Proteins. in Endotext (eds. Feingold, K.R., et al.) (South Dartmouth (MA), 2000). 13. Mendel, C.M. The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev 10, 232-274 (1989). 14. Pappa, T., Ferrara, A.M. & Refetoff, S. Inherited defects of thyroxine-binding proteins. Best Pract Res Clin Endocrinol Metab 29, 735-747 (2015). 15. Richardson, S.J., Wijayagunaratne, R.C., D'Souza, D.G., Darras, V.M. & Van Herck, S.L.J. Transport of thyroid hormones via the choroid plexus into the brain: the roles of transthyretin and thyroid hormone transmembrane transporters. Front Neurosci-Switz 9(2015). 16. Moses, A.C., Lawlor, J., Haddow, J. & Jackson, I.M. Familial euthyroid hyperthyroxinemia resulting from increased thyroxine binding to thyroxine-binding prealbumin. N Engl J Med 306, 966-969 (1982). 17. Refetoff, S., et al. A new family with hyperthyroxinemia caused by transthyretin Val109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone--a clinical research center study. J Clin Endocrinol Metab 81, 3335-3340 (1996). 18. Refetoff, S., Dwulet, F.E. & Benson, M.D. Reduced affinity for thyroxine in two of three structural thyroxine-binding prealbumin variants associated with familial amyloidotic polyneuropathy. J Clin Endocrinol Metab 63, 1432-1437 (1986). 19. Episkopou, V., et al. Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone. Proc Natl Acad Sci U S A 90, 2375-2379 (1993). 20. Palha, J.A., et al. Transthyretin regulates thyroid hormone levels in the choroid plexus, but not in the brain parenchyma: study in a transthyretin-null mouse model. Endocrinology 141, 3267-3272 (2000). 21. Mayerl, S., et al. Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. J Clin Invest 124, 1987-1999 (2014). 22. Kono, N. & Arai, H. Intracellular transport of fat-soluble vitamins A and E. Traffic 16, 19-34 (2015). 23. O'Byrne, S.M. & Blaner, W.S. Retinol and retinyl esters: biochemistry and physiology. J Lipid Res 54, 1731-1743 (2013). 24. van Bennekum, A.M., et al. Biochemical basis for depressed serum retinol levels in transthyretin-deficient mice. J Biol Chem 276, 1107-1113 (2001). 25. Bellovino, D., Morimoto, T., Tosetti, F. & Gaetani, S. Retinol binding protein and transthyretin are secreted as a complex formed in the endoplasmic reticulum in HepG2 human hepatocarcinoma cells. Exp Cell Res 222, 77-83 (1996). 26. Naylor, H.M. & Newcomer, M.E. The structure of human retinol-binding protein (RBP) with its carrier protein transthyretin reveals an interaction with the carboxy terminus of RBP. Biochemistry 38, 2647-2653 (1999). 27. White, J.T. & Kelly, J.W. Support for the multigenic hypothesis of amyloidosis: the binding stoichiometry of retinol-binding protein, vitamin A, and thyroid hormone influences transthyretin amyloidogenicity in vitro. Proc Natl Acad Sci U S A 98, 13019-13024 (2001). 28. Fex, G., Albertsson, P.A. & Hansson, B. Interaction between Pre-Albumin and Retinol-Binding Protein Studied by Affinity Chromatography, Gel-Filtration and 2-Phase Partition. Eur J Biochem 99, 353-360 (1979). 29. Monaco, H.L. The transthyretin-retinol-binding protein complex. Biochim Biophys Acta 1482, 65-72 (2000). 30. Zanotti, G., et al. Structural and mutational analyses of protein-protein interactions between transthyretin and retinol-binding protein. Febs J 275, 5841-5854 (2008). 31. Chou, C.M., et al. Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease. Cell 161, 634-646 (2015). 32. Kawaguchi, R., Zhong, M., Kassai, M., Ter-Stepanian, M. & Sun, H. Vitamin A Transport Mechanism of the Multitransmembrane Cell-Surface Receptor STRA6. Membranes (Basel) 5, 425-453 (2015). 33. Zhong, M., et al. Regulatory mechanism for the transmembrane receptor that mediates bidirectional vitamin A transport. Proc Natl Acad Sci U S A 117, 9857-9864 (2020). 34. Wei, S., et al. Retinyl ester hydrolysis and retinol efflux from BFC-1beta adipocytes. J Biol Chem 272, 14159-14165 (1997). 35. Fedders, R., et al. Liver-secreted RBP4 does not impair glucose homeostasis in mice. Journal of Biological Chemistry 293, 15269-15276 (2018). 36. Zhong, M., Kawaguchi, R., Kassai, M. & Sun, H. How Free Retinol Behaves Differently from RBP-Bound Retinol in RBP Receptor-Mediated Vitamin A Uptake. Mol Cell Biol 34, 2108-2110 (2014). 37. Rask, L., Vahlquist, A. & Peterson, P.A. Studies on two physiological forms of the human retinol-binding protein differing in vitamin A and arginine content. J Biol Chem 246, 6638-6646 (1971). 38. Waits, R.P., Yamada, T., Uemichi, T. & Benson, M.D. Low plasma concentrations of retinol-binding protein in individuals with mutations affecting position 84 of the transthyretin molecule. Clin Chem 41, 1288-1291 (1995). 39. Liz, M.A., Faro, C.J., Saraiva, M.J. & Sousa, M.M. Transthyretin, a new cryptic protease. J Biol Chem 279, 21431-21438 (2004). 40. Navab, M., et al. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J Lipid Res 41, 1495-1508 (2000). 41. Liz, M.A., et al. Substrate specificity of transthyretin: identification of natural substrates in the nervous system. Biochem J 419, 467-474 (2009). 42. Liz, M.A., et al. Transthyretin is a metallopeptidase with an inducible active site. Biochemical Journal 443, 769-778 (2012). 43. Fleming, C.E., Saraiva, M.J. & Sousa, M.M. Transthyretin enhances nerve regeneration. J Neurochem 103, 831-839 (2007). 44. Fleming, C.E., Mar, F.M., Franquinho, F., Saraiva, M.J. & Sousa, M.M. Transthyretin internalization by sensory neurons is megalin mediated and necessary for its neuritogenic activity. J Neurosci 29, 3220-3232 (2009). 45. Li, X., et al. Mechanisms of transthyretin inhibition of beta-amyloid aggregation in vitro. J Neurosci 33, 19423-19433 (2013). 46. Gimeno, A., et al. Insights on the Interaction between Transthyretin and Aβ in Solution. A Saturation Transfer Difference (STD) NMR Analysis of the Role of lododiflunisal. Journal of Medicinal Chemistry 60, 5749-5758 (2017). 47. Buxbaum, J.N., et al. Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Abeta toxicity. Proc Natl Acad Sci U S A 105, 2681-2686 (2008). 48. Hornberg, A., Eneqvist, T., Olofsson, A., Lundgren, E. & Sauer-Eriksson, A.E. A comparative analysis of 23 structures of the amyloidogenic protein transthyretin. J Mol Biol 302, 649-669 (2000). 49. Yokoyama, T. & Mizuguchi, M. Transthyretin Amyloidogenesis Inhibitors: From Discovery to Current Developments. J Med Chem 63, 14228-14242 (2020). 50. Guo, X., et al. Review on the Structures and Activities of Transthyretin Amyloidogenesis Inhibitors. Drug Des Devel Ther 14, 1057-1081 (2020). 51. Ciccone, L., Tonali, N., Nencetti, S. & Orlandini, E. Natural compounds as inhibitors of transthyretin amyloidosis and neuroprotective agents: analysis of structural data for future drug design. J Enzym Inhib Med Ch 35, 1145-1162 (2020). 52. Schmidt, M., et al. Cryo-EM structure of a transthyretin-derived amyloid fibril from a patient with hereditary ATTR amyloidosis. Nat Commun 10, 5008 (2019). 53. Iakovleva, I., et al. Structural basis for transthyretin amyloid formation in vitreous body of the eye. Nat Commun 12, 7141 (2021). 54. Nguyen, B.A., et al. Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy. Nat Commun 15, 581 (2024). 55. Saelices, L., et al. Uncovering the Mechanism of Aggregation of Human Transthyretin. J Biol Chem 290, 28932-28943 (2015). 56. Blake, C.C., Geisow, M.J., Oatley, S.J., Rerat, B. & Rerat, C. Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 A. J Mol Biol 121, 339-356 (1978). 57. McLean, T.R., Rank, M.M., Smooker, P.M. & Richardson, S.J. Evolution of thyroid hormone distributor proteins. Mol Cell Endocrinol 459, 43-52 (2017). 58. Ueda, M., et al. Aged vervet monkeys developing transthyretin amyloidosis with the human disease-causing Ile122 allele: a valid pathological model of the human disease. Lab Invest 92, 474-484 (2012). 59. Khwanmunee, J., Leelawatwattana, L. & Prapunpoj, P. Gene structure and evolution of transthyretin in the order Chiroptera. Genetica 144, 71-83 (2016). 60. Hennebry, S.C., Wright, H.M., Likic, V.A. & Richardson, S.J. Structural and functional evolution of transthyretin and transthyretin-like proteins. Proteins 64, 1024-1045 (2006). 61. Richardson, S.J. Tweaking the structure to radically change the function: the evolution of transthyretin from 5-hydroxyisourate hydrolase to triiodothyronine distributor to thyroxine distributor. Front Endocrinol (Lausanne) 5, 245 (2014). 62. Wojtczak, A., Cody, V., Luft, J.R. & Pangborn, W. Structures of human transthyretin complexed with thyroxine at 2.0 angstrom resolution and 3',5'-dinitro-N-acetyl-L-thyronine at 2.2 angstrom resolution. Acta Crystallographica Section D-Biological Crystallography 52, 758-765 (1996). 63. Hamilton, J.A., et al. The x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolution. J Biol Chem 268, 2416-2424 (1993). 64. Ferguson, R.N., Edelhoch, H., Saroff, H.A., Robbins, J. & Cahnmann, H.J. Negative cooperativity in the binding of thyroxine to human serum prealbumin. Preparation of tritium-labeled 8-anilino-1-naphthalenesulfonic acid. Biochemistry 14, 282-289 (1975). 65. Monaco, H.L., Rizzi, M. & Coda, A. Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science 268, 1039-1041 (1995). 66. Perduca, M., Nicolis, S., Mannucci, B., Galliano, M. & Monaco, H.L. Human plasma retinol-binding protein (RBP4) is also a fatty acid-binding protein. Biochim Biophys Acta Mol Cell Biol Lipids 1863, 458-466 (2018). 67. Ronne, H., et al. Ligand-dependent regulation of intracellular protein transport: effect of vitamin a on the secretion of the retinol-binding protein. J Cell Biol 96, 907-910 (1983). 68. Sanguinetti, C., et al. The Journey of Human Transthyretin: Synthesis, Structure Stability, and Catabolism. Biomedicines 10(2022). 69. Peterson, S.A., et al. Inhibiting transthyretin conformational changes that lead to amyloid fibril formation. Proc Natl Acad Sci U S A 95, 12956-12960 (1998). 70. Miroy, G.J., et al. Inhibiting transthyretin amyloid fibril formation via protein stabilization. Proc Natl Acad Sci U S A 93, 15051-15056 (1996). 71. Mangione, P.P., et al. Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis. Proc Natl Acad Sci U S A 111, 1539-1544 (2014). 72. Mangione, P.P., et al. Plasminogen activation triggers transthyretin amyloidogenesis in vitro. J Biol Chem 293, 14192-14199 (2018). 73. Zhao, L., Buxbaum, J.N. & Reixach, N. Age-related oxidative modifications of transthyretin modulate its amyloidogenicity. Biochemistry 52, 1913-1926 (2013). 74. Duan, G., et al. The Regulatory Mechanism of Transthyretin Irreversible Aggregation through Liquid-to-Solid Phase Transition. Int J Mol Sci 24(2023). 75. Connors, L.H., Lim, A., Prokaeva, T., Roskens, V.A. & Costello, C.E. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid 10, 160-184 (2003). 76. Cornwell, G.G., 3rd, Murdoch, W.L., Kyle, R.A., Westermark, P. & Pitkanen, P. Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation. Am J Med 75, 618-623 (1983). 77. Ruberg, F.L. & Berk, J.L. Transthyretin (TTR) cardiac amyloidosis. Circulation 126, 1286-1300 (2012). 78. Pomerance, A. Senile cardiac amyloidosis. Br Heart J 27, 711-718 (1965). 79. Cassidy, J.T. Cardiac amyloidosis. Two cases with digitalis sensitivity. Ann Intern Med 55, 989-994 (1961). 80. Briggs, G.W. Amyloidosis. Ann Intern Med 55, 943-957 (1961). 81. Storkel, S., Bohl, J. & Schneider, H.M. Senile amyloidosis: principles of localization in a heterogeneous form of amyloidosis. Virchows Arch B Cell Pathol Incl Mol Pathol 44, 145-161 (1983). 82. Westermark, P., Sletten, K., Johansson, B. & Cornwell, G.G. Fibril in Senile Systemic Amyloidosis Is Derived from Normal Transthyretin. P Natl Acad Sci USA 87, 2843-2845 (1990). 83. Westermark, P., Bergstrom, J., Solomon, A., Murphy, C. & Sletten, K. Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations. Amyloid 10 Suppl 1, 48-54 (2003). 84. Ng, B., Connors, L.H., Davidoff, R., Skinner, M. & Falk, R.H. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med 165, 1425-1429 (2005). 85. Tanskanen, M., et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 40, 232-239 (2008). 86. Sekijima, Y., et al. High prevalence of wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome: a common cause of carpal tunnel syndrome in the elderly. Hum Pathol 42, 1785-1791 (2011). 87. Banypersad, S.M., Moon, J.C., Whelan, C., Hawkins, P.N. & Wechalekar, A.D. Updates in cardiac amyloidosis: a review. J Am Heart Assoc 1, e000364 (2012). 88. Picken, M.M. New insights into systemic amyloidosis: the importance of diagnosis of specific type. Curr Opin Nephrol Hy 16, 196-203 (2007). 89. Masri, A., et al. Efficient 1-Hour Technetium-99 m Pyrophosphate Imaging Protocol for the Diagnosis of Transthyretin Cardiac Amyloidosis. Circ Cardiovasc Imaging 13, e010249 (2020). 90. Yee, A.W., et al. A molecular mechanism for transthyretin amyloidogenesis. Nat Commun 10, 925 (2019). 91. Carr, A.S., et al. A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK. J Neurol Neurosurg Psychiatry 87, 620-627 (2016). 92. Jacobson, D.R., Alexander, A.A., Tagoe, C. & Buxbaum, J.N. Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans. Amyloid 22, 171-174 (2015). 93. Jacobson, D.R., et al. The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa. Mol Genet Genomic Med 4, 548-556 (2016). 94. Shah, K.B., et al. Transthyretin Cardiac Amyloidosis in Black Americans. Circ Heart Fail 9, e002558 (2016). 95. Carr, A.S., et al. Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy. Neuromuscul Disord 25, 511-515 (2015). 96. Ruberg, F.L., et al. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J 164, 222-228 e221 (2012). 97. Damas, A.M., Ribeiro, S., Lamzin, V.S., Palha, J.A. & Saraiva, M.J. Structure of the Val122Ile variant transthyretin - a cardiomyopathic mutant. Acta Crystallogr D Biol Crystallogr 52, 966-972 (1996). 98. Jiang, X., Buxbaum, J.N. & Kelly, J.W. The V122I cardiomyopathy variant of transthyretin increases the velocity of rate-limiting tetramer dissociation, resulting in accelerated amyloidosis. Proc Natl Acad Sci U S A 98, 14943-14948 (2001). 99. Leach, B.I., Zhang, X., Kelly, J.W., Dyson, H.J. & Wright, P.E. NMR Measurements Reveal the Structural Basis of Transthyretin Destabilization by Pathogenic Mutations. Biochemistry 57, 4421-4430 (2018). 100. Cendron, L., et al. Amyloidogenic potential of transthyretin variants: insights from structural and computational analyses. J Biol Chem 284, 25832-25841 (2009). 101. Andrade, C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 75, 408-427 (1952). 102. Andersson, R. Familial amyloidosis with polyneuropathy. A clinical study based on patients living in northern Sweden. Acta Med Scand Suppl 590, 1-64 (1976). 103. Araki, S., Mawatari, S., Ohta, M., Nakajima, A. & Kuroiwa, Y. Polyneuritic amyloidosis in a Japanese family. Arch Neurol 18, 593-602 (1968). 104. Ando, Y., Nakamura, M. & Araki, S. Transthyretin-related familial amyloidotic polyneuropathy. Arch Neurol 62, 1057-1062 (2005). 105. Waddington-Cruz, M., et al. Characteristics of Patients with Late- vs. Early-Onset Val30Met Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS). Neurol Ther 10, 753-766 (2021). 106. Plante-Bordeneuve, V. & Said, G. Familial amyloid polyneuropathy. Lancet Neurol 10, 1086-1097 (2011). 107. Sebastiao, M.P., Saraiva, M.J. & Damas, A.M. The crystal structure of amyloidogenic Leu → Pro transthyretin variant reveals a possible pathway for transthyretin polymerization into amyloid fibrils. Journal of Biological Chemistry 273, 24715-24722 (1998). 108. Lashuel, H.A., Wurth, C., Woo, L. & Kelly, J.W. The most pathogenic transthyretin variant, L55P, forms amyloid fibrils under acidic conditions and protofilaments under physiological conditions. Biochemistry 38, 13560-13573 (1999). 109. Jacobson, D.R., McFarlin, D.E., Kane, I. & Buxbaum, J.N. Transthyretin Pro55, a variant associated with early-onset, aggressive, diffuse amyloidosis with cardiac and neurologic involvement. Hum Genet 89, 353-356 (1992). 110. Hsieh, S.T. Amyloid neuropathy with transthyretin mutations: overview and unique Ala97Ser in Taiwan. Acta Neurol Taiwan 20, 155-160 (2011). 111. Hsu, H.C., Liao, M.F., Hsu, J.L., Lee, Y.L. & Ro, L.S. Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis. J Vis Exp (2018). 112. Lachmann, H.J., Booth, D.R., Bybee, A. & Hawkins, P.N. Transthyretin Ala97Ser is associated with familial amyloidotic polyneuropathy in a Chinese-Taiwanese family. Hum Mutat 16, 180 (2000). 113. Lai, H.J., et al. The Temporal Profiles of Changes in Nerve Excitability Indices in Familial Amyloid Polyneuropathy. PLoS One 10, e0141935 (2015). 114. Liu, Y.T., Lee, Y.C., Yang, C.C., Chen, M.L. & Lin, K.P. Transthyretin Ala97Ser in Chinese-Taiwanese patients with familial amyloid polyneuropathy: genetic studies and phenotype expression. J Neurol Sci 267, 91-99 (2008). 115. Low, S.C., et al. Ala97Ser mutation is common among ethnic Chinese Malaysians with transthyretin familial amyloid polyneuropathy. Amyloid 26, 7-8 (2019). 116. Pasutharnchat, N., Taychargumpoo, C., Vorasettakarnkij, Y. & Amornvit, J. Ala97Ser transthyretin amyloidosis-associated polyneuropathy, clinical and neurophysiological profiles in a Thai cohort. BMC Neurol 21, 206 (2021). 117. Du, K., et al. Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study. Ann Clin Transl Neurol 8, 831-841 (2021). 118. Chao, H.C., et al. Clinical and genetic profiles of hereditary transthyretin amyloidosis in Taiwan. Ann Clin Transl Neurol 6, 913-922 (2019). 119. Chao, C.C., et al. Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy. Ann Neurol 85, 560-573 (2019). 120. Lai, H.J., et al. Cardiac manifestations and prognostic implications of hereditary transthyretin amyloidosis associated with transthyretin Ala97Ser. J Formos Med Assoc 119, 693-700 (2020). 121. Hsueh, H.W., et al. Unique Phenotypes With Corresponding Pathology in Late-Onset Hereditary Transthyretin Amyloidosis of A97S vs. V30M. Front Aging Neurosci 13, 786322 (2021). 122. Ibrahim, R.B., et al. Cellular secretion and cytotoxicity of transthyretin mutant proteins underlie late-onset amyloidosis and neurodegeneration. Cell Mol Life Sci 77, 1421-1434 (2020). 123. Kan, H.W., et al. Sensory nerve degeneration in a mouse model mimicking early manifestations of familial amyloid polyneuropathy due to transthyretin Ala97Ser. Neuropathol Appl Neurobiol 44, 673-686 (2018). 124. Liu, Y.T., et al. Biophysical characterization and modulation of Transthyretin Ala97Ser. Ann Clin Transl Neurol 6, 1961-1970 (2019). 125. Qin, Q., et al. Current Review of Leptomeningeal Amyloidosis Associated With Transthyretin Mutations. Neurologist 26, 189-195 (2021). 126. Llull, L., Berenguer, J., Yagüe, J. & Graus, F. Leptomeningeal amyloidosis due to A25T TTR mutation: a case report. Neurologia 29, 382-384 (2014). 127. Shimizu, Y., Takeuchi, M., Matsumura, M., Tokuda, T. & Iwata, M. A case of biopsy-proven leptomeningeal amyloidosis and intravenous Ig-responsive polyneuropathy associated with the Ala25Thr transthyretin gene mutation. Amyloid 13, 37-41 (2006). 128. Fan, K., et al. The identification of a transthyretin variant p.D38G in a Chinese family with early-onset leptomeningeal amyloidosis. J Neurol 266, 232-241 (2019). 129. Sekijima, Y., et al. Energetic characteristics of the new transthyretin variant A25T may explain its atypical central nervous system pathology. Lab Invest 83, 409-417 (2003). 130. Sekijima, Y., et al. The biological and chemical basis for tissue-selective amyloid disease. Cell 121, 73-85 (2005). 131. Azevedo, E.P., et al. Dissecting the structure, thermodynamic stability, and aggregation properties of the A25T transthyretin (A25T-TTR) variant involved in leptomeningeal amyloidosis: identifying protein partners that co-aggregate during A25T-TTR fibrillogenesis in cerebrospinal fluid. Biochemistry 50, 11070-11083 (2011). 132. Hammarström, P., et al. D18G transthyretin is monomeric, aggregation prone, and not detectable in plasma and cerebrospinal fluid:: A prescription for central nervous system amyloidosis? Biochemistry 42, 6656-6663 (2003). 133. Buck, T.M. & Brodsky, J.L. Escaping the endoplasmic reticulum: why does a molecular chaperone leave home for greener pastures? EMBO J 34, 1-3 (2015). 134. Sato, T., et al. Endoplasmic reticulum quality control regulates the fate of transthyretin variants in the cell. EMBO J 26, 2501-2512 (2007). 135. Sekijima, Y., et al. R104H may suppress transthyretin amyloidogenesis by thermodynamic stabilization, but not by the kinetic mechanism characterizing T119 interallelic trans-suppression. Amyloid 13, 57-66 (2006). 136. Almeida, M.R., Alves, I.L., Terazaki, H., Ando, Y. & Saraiva, M.J. Comparative studies of two transthyretin variants with protective effects on familial amyloidotic polyneuropathy: TTR R104H and TTR T119M. Biochem Biophys Res Commun 270, 1024-1028 (2000). 137. Sant'Anna, R., et al. Cavity filling mutations at the thyroxine-binding site dramatically increase transthyretin stability and prevent its aggregation. Sci Rep-Uk 7(2017). 138. Terazaki, H., et al. A novel compound heterozygote (FAP ATTR Arg104His/ATTR Val30Met) with high serum transthyretin (TTR) and retinol binding protein (RBP) levels. Biochem Biophys Res Commun 264, 365-370 (1999). 139. Neto-Silva, R.M., et al. X-ray crystallographic studies of two transthyretin variants: further insights into amyloidogenesis. Acta Crystallogr D 61, 333-339 (2005). 140. Kim, J.H., Oroz, J. & Zweckstetter, M. Structure of Monomeric Transthyretin Carrying the Clinically Important T119M Mutation. Angew Chem Int Ed Engl 55, 16168-16171 (2016). 141. Chandrashekar, P., Desai, A.K. & Trachtenberg, B.H. Targeted treatments of AL and ATTR amyloidosis. Heart Fail Rev 27, 1587-1603 (2022). 142. Aimo, A., et al. RNA-targeting and gene editing therapies for transthyretin amyloidosis. Nat Rev Cardiol 19, 655-667 (2022). 143. Holmgren, G., et al. Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet 40, 242-246 (1991). 144. Ericzon, B.G., et al. Liver Transplantation for Hereditary Transthyretin Amyloidosis: After 20 Years Still the Best Therapeutic Alternative? Transplantation 99, 1847-1854 (2015). 145. Hornsten, R., Suhr, O.B., Jensen, S.M. & Wiklund, U. Outcome of heart rate variability and ventricular late potentials after liver transplantation for familial amyloidotic polyneuropathy. Amyloid 15, 187-195 (2008). 146. Carvalho, A., Rocha, A. & Lobato, L. Liver Transplantation in Transthyretin Amyloidosis: Issues and Challenges. Liver Transplant 21, 282-292 (2015). 147. Tomasoni, D., et al. Treating amyloid transthyretin cardiomyopathy: lessons learned from clinical trials. Front Cardiovasc Med 10, 1154594 (2023). 148. Adams, D., et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med 379, 11-21 (2018). 149. Adams, D., et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid 30, 1-9 (2023). 150. Benson, M.D., et al. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med 379, 22-31 (2018). 151. Coelho, T., et al. Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-L(Rx) (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy. Neurol Ther 10, 375-389 (2021). 152. Finn, J.D., et al. A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing. Cell Rep 22, 2227-2235 (2018). 153. Bulawa, C.E., et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A 109, 9629-9634 (2012). 154. Coelho, T., et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 79, 785-792 (2012). 155. Alhamadsheh, M.M., et al. Potent Kinetic Stabilizers That Prevent Transthyretin-Mediated Cardiomyocyte Proteotoxicity. Sci Transl Med 3(2011). 156. Penchala, S.C., et al. AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci U S A 110, 9992-9997 (2013). 157. Miller, M., et al. Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis. Journal of Medicinal Chemistry 61, 7862-7876 (2018). 158. Judge, D.P., et al. Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy. J Am Coll Cardiol 74, 285-295 (2019). 159. Hammarstrom, P., Wiseman, R.L., Powers, E.T. & Kelly, J.W. Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299, 713-716 (2003). 160. Klabunde, T., et al. Rational design of potent human transthyretin amyloid disease inhibitors. Nat Struct Biol 7, 312-321 (2000). 161. Adamski-Werner, S.L., Palaninathan, S.K., Sacchettini, J.C. & Kelly, J.W. Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis. J Med Chem 47, 355-374 (2004). 162. Berk, J.L., et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 310, 2658-2667 (2013). 163. Ribeiro, C.A., et al. Transthyretin stabilization by iododiflunisal promotes amyloid-beta peptide clearance, decreases its deposition, and ameliorates cognitive deficits in an Alzheimer's disease mouse model. J Alzheimers Dis 39, 357-370 (2014). 164. Pinheiro, F., et al. Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis. Febs J 288, 310-324 (2021). 165. Sant'Anna, R., et al. Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity. Nat Commun 7, 10787 (2016). 166. Trivella, D.B., dos Reis, C.V., Lima, L.M., Foguel, D. & Polikarpov, I. Flavonoid interactions with human transthyretin: combined structural and thermodynamic analysis. J Struct Biol 180, 143-153 (2012). 167. Singh, B.N., Shankar, S. & Srivastava, R.K. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol 82, 1807-1821 (2011). 168. Ehrnhoefer, D.E., et al. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol 15, 558-566 (2008). 169. Ferreira, N., et al. Binding of epigallocatechin-3-gallate to transthyretin modulates its amyloidogenicity. FEBS Lett 583, 3569-3576 (2009). 170. Ferreira, N., Saraiva, M.J. & Almeida, M.R. Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation. FEBS Lett 585, 2424-2430 (2011). 171. Almeida, M.R. & Saraiva, M.J. Clearance of extracellular misfolded proteins in systemic amyloidosis: experience with transthyretin. FEBS Lett 586, 2891-2896 (2012). 172. Kristen, A.V., et al. Green tea halts progression of cardiac transthyretin amyloidosis: an observational report. Clin Res Cardiol 101, 805-813 (2012). 173. Cardoso, I. & Saraiva, M.J. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J 20, 234-239 (2006). 174. Macedo, B., Batista, A.R., Ferreira, N., Almeida, M.R. & Saraiva, M.J. Anti-apoptotic treatment reduces transthyretin deposition in a transgenic mouse model of Familial Amyloidotic Polyneuropathy. Biochim Biophys Acta 1782, 517-522 (2008). 175. Obici, L., et al. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid 19 Suppl 1, 34-36 (2012). 176. Hosoi, A., et al. Novel Antibody for the Treatment of Transthyretin Amyloidosis. Journal of Biological Chemistry 291, 25096-25105 (2016). 177. Ando, Y., et al. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid 29, 143-155 (2022). 178. Wang, T.T., Lewis, K.C. & Phang, J.M. Production of human plasma retinol-binding protein in Escherichia coli. Gene 133, 291-294 (1993). 179. Xie, Y., Lashuel, H.A., Miroy, G.J., Dikler, S. & Kelly, J.W. Recombinant human retinol-binding protein refolding, native disulfide formation, and characterization. Protein Expr Purif 14, 31-37 (1998). 180. Liebschner, D., et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr D Struct Biol 75, 861-877 (2019). 181. Emsley, P., Lohkamp, B., Scott, W.G. & Cowtan, K. Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66, 486-501 (2010). 182. Groenning, M., Campos, R.I., Hirschberg, D., Hammarstrom, P. & Vestergaard, B. Considerably Unfolded Transthyretin Monomers Preceed and Exchange with Dynamically Structured Amyloid Protofibrils. Sci Rep 5, 11443 (2015). 183. Reixach, N., Deechongkit, S., Jiang, X., Kelly, J.W. & Buxbaum, J.N. Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc Natl Acad Sci U S A 101, 2817-2822 (2004). 184. Robinson, L.Z. & Reixach, N. Quantification of quaternary structure stability in aggregation-prone proteins under physiological conditions: the transthyretin case. Biochemistry 53, 6496-6510 (2014). 185. Wieczorek, E., et al. Destabilisation of the structure of transthyretin is driven by Ca(2). Int J Biol Macromol 166, 409-423 (2021). 186. Manning, M. & Colon, W. Structural basis of protein kinetic stability: resistance to sodium dodecyl sulfate suggests a central role for rigidity and a bias toward beta-sheet structure. Biochemistry 43, 11248-11254 (2004). 187. Wang, Y.S., et al. A molecular basis for tetramer destabilization and aggregation of transthyretin Ala97Ser. Protein Sci 32, e4610 (2023). 188. Ibrahim, R.B., Liu, Y.T., Yeh, S.Y. & Tsai, J.W. Contributions of Animal Models to the Mechanisms and Therapies of Transthyretin Amyloidosis. Front Physiol 10, 338 (2019). 189. Hammarstrom, P., Jiang, X., Hurshman, A.R., Powers, E.T. & Kelly, J.W. Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity. Proc Natl Acad Sci U S A 99 Suppl 4, 16427-16432 (2002). 190. Yang, M.F., Lei, M. & Huo, S.H. Why is Leu55→Pro55 transthyretin variant the most amyloidogenic:: Insights from molecular dynamics simulations of transthyretin monomers. Protein Sci 12, 1222-1231 (2003). 191. Lashuel, H.A., Lai, Z. & Kelly, J.W. Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation: implications for wild-type, V30M, and L55P amyloid fibril formation. Biochemistry 37, 17851-17864 (1998). 192. Wieczorek, E., Bezara, P. & Ozyhar, A. Deep blue autofluorescence reveals the instability of human transthyretin. Int J Biol Macromol 191, 492-499 (2021). 193. Xia, K., et al. Quantifying the kinetic stability of hyperstable proteins via time-dependent SDS trapping. Biochemistry 51, 100-107 (2012). 194. Ciccone, L., Tonali, N., Shepard, W., Nencetti, S. & Orlandini, E. Physiological Metals Can Induce Conformational Changes in Transthyretin Structure: Neuroprotection or Misfolding Induction? Crystals 11(2021). 195. Palmieri Lde, C., et al. Novel Zn2+-binding sites in human transthyretin: implications for amyloidogenesis and retinol-binding protein recognition. J Biol Chem 285, 31731-31741 (2010). 196. Ciccone, L., et al. Copper mediated amyloid-beta binding to Transthyretin. Sci Rep 8, 13744 (2018). 197. Cantarutti, C., et al. Calcium Binds to Transthyretin with Low Affinity. Biomolecules 12(2022). 198. Iakovleva, I., et al. Enthalpic Forces Correlate with the Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma. J Med Chem 58, 6507-6515 (2015). 199. Peterson, P.A. Studies on the interaction between prealbumin, retinol-binding protein, and vitamin A. J Biol Chem 246, 44-49 (1971). 200. Hyung, S.J., Deroo, S. & Robinson, C.V. Retinol and retinol-binding protein stabilize transthyretin via formation of retinol transport complex. ACS Chem Biol 5, 1137-1146 (2010). 201. Pinto, M.V., et al. Late-onset hereditary ATTR V30M amyloidosis with polyneuropathy: Characterization of Brazilian subjects from the THAOS registry. J Neurol Sci 403, 1-6 (2019). 202. Fernandez, A., Kardos, J., Scott, L.R., Goto, Y. & Berry, R.S. Structural defects and the diagnosis of amyloidogenic propensity. Proc Natl Acad Sci U S A 100, 6446-6451 (2003). 203. Fernandez, A. & Scott, L.R. Adherence of packing defects in soluble proteins. Phys Rev Lett 91, 018102 (2003). 204. Fernandez, A., Scott, R. & Berry, R.S. The nonconserved wrapping of conserved protein folds reveals a trend toward increasing connectivity in proteomic networks. Proc Natl Acad Sci U S A 101, 2823-2827 (2004). 205. Gomes, J.R., et al. Transthyretin provides trophic support via megalin by promoting neurite outgrowth and neuroprotection in cerebral ischemia. Cell Death Differ 23, 1749-1764 (2016). 206. Klimtchuk, E.S., et al. Unusual duplication mutation in a surface loop of human transthyretin leads to an aggressive drug-resistant amyloid disease. Proc Natl Acad Sci U S A 115, E6428-E6436 (2018). 207. Dasari, A.K.R., et al. Disruption of the CD Loop by Enzymatic Cleavage Promotes the Formation of Toxic Transthyretin Oligomers through a Common Transthyretin Misfolding Pathway. Biochemistry 59, 2319-2327 (2020). 208. Esperante, S.A., et al. Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation. J Biol Chem 297, 101039 (2021). 209. Lim, K.H., Dyson, H.J., Kelly, J.W. & Wright, P.E. Localized structural fluctuations promote amyloidogenic conformations in transthyretin. J Mol Biol 425, 977-988 (2013). 210. Takeuchi, M., et al. Destabilization of transthyretin by pathogenic mutations in the DE loop. Proteins 66, 716-725 (2007). | - |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91667 | - |
dc.description.abstract | 轉甲狀腺素蛋白 (Transthyretin or TTR) 是一種分子量大小為55 kDa的四聚體 (tetramer) 人類蛋白,其功能是在血液以及腦脊液中運輸甲狀腺素 (Thyroxine or T4)和全反式視網醇結合蛋白4 (holo-form retinol-binding protein 4)。轉甲狀腺素蛋白相關類澱粉沉積症 (ATTR) 是一群特徵為具有轉甲狀腺素變異體蛋白的澱粉樣纖維在細胞外累積所導致的疾病。在台灣,A97S是台灣的轉甲狀腺素蛋白相關類澱粉沉積症患者中鑑定出來的主要突變種。在本篇研究中,我們結合高解析度的A97S轉甲狀腺素蛋白的分子結構與生物化學和生物物理的數據,以證明97號位點的丙胺酸替換成絲胺酸會引起FG環 (FG-loop) 局部區域的波動,從而導致穩定態的四聚體不穩定化,形成單體種類的增加,進而增強纖維化的可能性。根據熱量計測的結果,A97S四聚體不穩定化在與天然穩定劑相互作用之下會發生顯著的變化,顯示出與野生型 (Wild-type或WT) 轉甲狀腺素相似結合能量模式。然而,儘管轉甲狀腺素變異體的分子內氫鍵網路 (intramolecular hydrogen-bonding interaction network) 部分重新排列,A97S轉甲狀腺素蛋白的四聚體中的FG環的靈活性 (flexibility) 仍相對較高。此外,A97S替換引起FG環的結構與動態變化,同時還輕微影響轉甲狀腺素蛋白與全反式視網醇結合蛋白4的複合體交界面,導致結合親和力減弱約五倍。此外引入的R104H變異體在熱力學上穩定了A97S/R104H雙變異體的四聚體結構,明顯抑制了澱粉樣生成級聯(cascade)。總而言之,我們的研究闡明了的澱粉樣A97S發生機制,證明了其對結構的不穩定作用,導致單體FG環的靈活性增加並調節澱粉樣纖維生成的動力學。 | zh_TW |
dc.description.abstract | Transthyretin (TTR) is a 55 kDa tetrameric human protein and functions to transport thyroxine (T4) and holo-form retinol-binding protein 4 (holo-RBP4) in human plasma and cerebrospinal fluid. Transthyretin amyloidosis or ATTR is a group of diseases characterized by the extracellular accumulation of the amyloid fibrils containing TTR variants. In Taiwan, Ala97Ser (A97S) is the predominant mutation identified in Taiwanese ATTR patients. In this study, we combine atomic-resolution structural details of A97S-TTR with biophysical and biochemical data to demonstrate that the substitution of Ala-97 with serine induces fluctuations in the local region of the FG-loops, bringing about the destabilizing native-state tetramer, the increasing monomeric species, and thus the augmented fibrillization potential. Based on the calorimetric results, the destabilization of the A97S tetramer undergoes significant changes when interacting with native-state stabilizers, displaying binding energy patterns similar to that of wild-type (WT) TTR. However, despite the partial rearrangement of the intramolecular hydrogen-bonding networks in TTR variants, the flexibility of FG-loops in tetrameric A97S-TTR is still relatively higher. Furthermore, the A97S substitution induces structural and dynamic changes in the FG-loops, while also slightly affecting the complex interface of TTR and holo-form retinol-binding protein 4, resulting in an approximately five-fold decrease in the binding affinity. Besides, the introduced R104H variant thermodynamically stabilizes the quaternary structure of the A97S/R104H double mutant, significantly inhibiting the amyloidogenesis cascade. Collectively, our findings elucidate the molecular mechanism of amyloidogenic A97S, demonstrating its destabilizing effect on the TTR structure, leading to increased flexibility in the FG-loops of the monomer and modulation of the kinetics in amyloid fibrillization. | en |
dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-02-20T16:27:49Z No. of bitstreams: 0 | en |
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dc.description.tableofcontents | 口試委員會審定書 II
謝誌 III 中文摘要 IV Abstract VI Contents VIII List of Figures XV List of Tables XXI 1. Introduction 24 1.1 General introduction of transthyretin (TTR) 25 1.2 Biological functions of TTR 26 1.2.1 Biological functions of TTR: transporter 26 1.2.1.1 Transporter of thyroid hormones 26 1.2.1.2 Transporter of retinol-binding protein 4 (RBP4) 28 1.2.2 Biological functions of TTR: protease 30 1.2.3 Biological functions of TTR: nerve physiology and neuroprotection 30 1.3 Structure of TTR 31 1.3.1 Tetrameric assembly of TTR 31 1.3.2 Structure of TTR complexed with thyroxine 32 1.3.3 Structure of TTR complexed with holo-form RBP4 (holo-RBP4) 34 1.4 Transthyretin amyloidosis (ATTR) 36 1.4.1 Senile Systemic Amyloidosis (SSA) 36 1.4.2 Familial Amyloid Cardiomyopathy (FAC) 38 1.4.3 Familial Amyloid Polyneuropathy (FAP) 39 1.4.4 Ala97Ser (A97S): the most common variant in Taiwanese FAP patients 40 1.4.5 Leptomeningeal Amyloidosis (LA) 42 1.4.6 Non-amyloidogenic mutations 43 1.5 Treatments for ATTR 44 1.5.1 Inhibition of TTR protein synthesis 44 1.5.1.1 Liver transplantation 44 1.5.1.2 RNA silencing 45 1.5.1.3 Gene editing 46 1.5.2 TTR stabilizers 47 1.5.2.1 Structure-based designed drugs 47 1.5.2.2 Drug repositioning 49 1.5.2.2.1 Repositioning of existing drugs 49 1.5.2.2.2 Natural compounds 52 1.5.3 TTR amyloid clearance 53 1.5.3.1 Doxycycline / Tauroursodeoxycholic Acid (TUDCA) 53 1.5.3.2 Monoclonal antibodies 54 1.6 Specific aims 54 2. Materials and Methods 55 2.1 Materials 56 2.1.1 Escherichia coli (E. coli) strains (Table 4) 56 2.1.2 Construction of recombinant TTR and RBP4 plasmids (Table 5) 56 2.1.3 Culture media (Table 6) 56 2.1.4 Antibiotics (Table 7) 56 2.1.5 Buffers (Table 8) 57 2.2 Methods 57 2.2.1 Transformation 57 2.2.2 Site-directed mutagenesis and cloning 57 2.2.2.1 Primer design 57 2.2.2.2 Polymerase Chain Reaction (PCR) 58 2.2.2.3 DNA sequencing 59 2.2.3 Expression and purification of recombinant proteins 59 2.2.3.1 Expression and purification of recombinant TTR 59 2.2.3.2 Expression and purification of recombinant holo-RBP4 61 2.2.4 X-ray crystallography 64 2.2.4.1 Protein crystallization 64 2.2.4.1.1 Apo-form crystals 64 2.2.4.1.1.1 A97S crystals 64 2.2.4.1.1.2 A97S/R104H crystals 65 2.2.4.1.2 Complex crystals 65 2.2.4.1.2.1 A97S/tolcapone 65 2.2.4.1.2.2 A97S/diflunisal 65 2.2.4.2 X-ray data collection and processing 66 2.2.4.3 Structure determination 66 2.2.4.4 Structure analysis 67 2.2.5 Acid-induced aggregation assay 68 2.2.6 Congo-red binding assay 69 2.2.7 Transmission electron microscopy (TEM) 69 2.2.8 Turbidity assay 70 2.2.9 Probing the pH-mediated quaternary structural changes 70 2.2.10 pH-jump assay 71 2.2.11 SDS-trapping (S-Trap) assay 72 2.2.12 Evaluating calcium-mediated quaternary structural changes 73 2.2.13 Isothermal Titration Calorimetry (ITC) 73 2.2.14 Nuclear magnetic resonance (NMR) 74 2.2.14.1 Preparation of isotopically labeled proteins 74 2.2.14.2 Acquisition of NMR spectra 75 2.2.14.2.1 NMR spectra of TTR 75 2.2.14.2.2 NMR spectra of holo-RBP4 76 2.2.14.2.3 NMR spectra of TTR/holo-RBP4 complex 77 2.2.15 Surface Plasmon Resonance (SPR) 77 2.2.15.1 The binding of holo-RBP4 onto TTR 77 2.2.15.2 The binding of TTR onto holo-RBP4 79 3. Results 81 3.1 Structure and amyloidogenicity of A97S 82 3.1.1 Structure flexibility of A97S 82 3.1.2 Conformational stability of A97S 86 3.1.2.1 Tetramer destabilization of A97S under acid environments 86 3.1.2.2 pH effect on amyloidogenicity and conformation of A97S 87 3.1.2.2.1 pH-mediated amyloidogenicity of A97S 87 3.1.2.2.2 pH-mediated conformational changes on A97S 88 3.1.2.3 The effect of chemical treatments on the A97S conformation 90 3.2 The interactions of A97S with stabilizers 91 3.2.1 Characterization of the binding energetics of stabilizers to A97S 91 3.2.2 The complex structures of A97S with stabilizers 92 3.2.2.1 The binding patterns of stabilizers to A97S 92 3.2.2.2 The hydrogen bonding networks of FG-loops in the complex structures 94 3.3 The interactions of A97S with holo-RBP4 97 3.4 The stabilizing effect of introduced R104H on the A97S-TTR structure 99 4. Discussion 102 5. Figures 110 6. Tables 203 7. References 230 8. Declaration 244 | - |
dc.language.iso | en | - |
dc.title | 人類轉甲狀腺素蛋白A97S突變之結構與生物物理研究 | zh_TW |
dc.title | Structural and Biophysical Studies of Human Transthyretin A97S Variant | en |
dc.type | Thesis | - |
dc.date.schoolyear | 112-1 | - |
dc.description.degree | 博士 | - |
dc.contributor.oralexamcommittee | 詹迺立;謝松蒼;楊瑞彬;徐駿森;楊啓伸;黃駿翔 | zh_TW |
dc.contributor.oralexamcommittee | Nei-Li Chan;Sung-Tsang Hsieh;Ruey-Bing Yang;Chun-Hua Hsu;Chii-Shen Yang;Chun-Hsiang Huang | en |
dc.subject.keyword | 轉甲狀腺素蛋白,類澱粉沉積,神經退化,A97S,小分子藥物, | zh_TW |
dc.subject.keyword | Transthyretin,Amyloidosis,Neurodegeneration,A97S,small-molecule drug, | en |
dc.relation.page | 245 | - |
dc.identifier.doi | 10.6342/NTU202400294 | - |
dc.rights.note | 同意授權(限校園內公開) | - |
dc.date.accepted | 2024-02-06 | - |
dc.contributor.author-college | 醫學院 | - |
dc.contributor.author-dept | 生物化學暨分子生物學研究所 | - |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
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