Transthyretin Misfolding, A Fatal Structural Pathogenesis Mechanism

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Apr 30

PMID 33922648

Citations 13

Authors

Jin-Beom Si

Bokyung Kim

Jin Hae Kim

Affiliations

Soon will be listed here.

Abstract

Transthyretin (TTR) is an essential transporter of a thyroid hormone and a holo-retinol binding protein, found abundantly in human plasma and cerebrospinal fluid. In addition, this protein is infamous for its amyloidogenic propensity, causing various amyloidoses in humans, such as senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. It has been known for over two decades that decreased stability of the native tetrameric conformation of TTR is the main cause of these diseases. Yet, mechanistic details on the amyloidogenic transformation of TTR were not clear until recent multidisciplinary investigations on various structural states of TTR. In this review, we discuss recent advancements in the structural understanding of TTR misfolding and amyloidosis processes. Special emphasis has been laid on the observations of novel structural features in various amyloidogenic species of TTR. In addition, proteolysis-induced fragmentation of TTR, a recently proposed mechanism facilitating TTR amyloidosis, has been discussed in light of its structural consequences and relevance to acknowledge the amyloidogenicity of TTR.

Citing Articles

The conformational landscape of human transthyretin revealed by cryo-EM.

Basanta B, Nugroho K, Yan N, Kline G, Powers E, Tsai F Nat Struct Mol Biol. 2025; .

PMID: 39843982 DOI: 10.1038/s41594-024-01472-7.

Cationic Surface Charge Engineering of Recombinant Transthyretin Remarkably Increases the Inhibitory Potency Against Amyloid β-Protein Fibrillogenesis.

Lin X, Xu T, Hou W, Dong X, Sun Y Molecules. 2024; 29(21).

PMID: 39519665 PMC: 11547489. DOI: 10.3390/molecules29215023.

Tetrameric Transthyretin as a Protective Factor Against Alzheimer's Disease.

Corino C, Aimo A, Luigetti M, Ciccone L, Ferrari Chen Y, Panichella G Mol Neurobiol. 2024; 62(3):2945-2954.

PMID: 39192044 PMC: 11790689. DOI: 10.1007/s12035-024-04442-8.

Exploring Genetic Silencing: RNAi and CRISPR-Cas Potential against Drug Resistance in Malaria.

Gaona-Lopez C, Rivera G Mini Rev Med Chem. 2024; 25(2):128-137.

PMID: 38932611 DOI: 10.2174/0113895575306957240610102626.

Clinical spectrum of Transthyretin amyloidogenic mutations among diverse population origins.

De Lillo A, Pathak G, Low A, De Angelis F, Abou Alaiwi S, Miller E Hum Genomics. 2024; 18(1):31.

PMID: 38523305 PMC: 10962184. DOI: 10.1186/s40246-024-00596-7.

References

Mangione P, Verona G, Corazza A, Marcoux J, Canetti D, Giorgetti S . Plasminogen activation triggers transthyretin amyloidogenesis . J Biol Chem. 2018; 293(37):14192-14199. PMC: 6139548. DOI: 10.1074/jbc.RA118.003990. View

Ferguson R, EDELHOCH H, Saroff H, Robbins J, CAHNMANN H . Negative cooperativity in the binding of thyroxine to human serum prealbumin. Preparation of tritium-labeled 8-anilino-1-naphthalenesulfonic acid. Biochemistry. 1975; 14(2):282-9. DOI: 10.1021/bi00673a014. View

Jiang X, Smith C, Petrassi H, Hammarstrom P, White J, Sacchettini J . An engineered transthyretin monomer that is nonamyloidogenic, unless it is partially denatured. Biochemistry. 2001; 40(38):11442-52. DOI: 10.1021/bi011194d. View

Blake C, Swan I, Rerat C, Berthou J, Laurent A, RERAT B . An x-ray study of the subunit structure of prealbumin. J Mol Biol. 1971; 61(1):217-24. DOI: 10.1016/0022-2836(71)90218-x. View

Saelices L, Chung K, Lee J, Cohn W, Whitelegge J, Benson M . Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition. Proc Natl Acad Sci U S A. 2018; 115(29):E6741-E6750. PMC: 6055172. DOI: 10.1073/pnas.1805131115. View

Stabilini R, Vergani C, AGOSTONI A, Agostoni R . Influence of age and sex on prealbumin levels. Clin Chim Acta. 1968; 20(2):358-9. DOI: 10.1016/0009-8981(68)90173-3. View

Ingbar S . Observations concerning the binding of thyroid hormones by human serum prealbumin. J Clin Invest. 1963; 42:143-60. PMC: 289263. DOI: 10.1172/JCI104701. View

Kingsbury J, Theberge R, Karbassi J, Lim A, Costello C, Connors L . Detailed structural analysis of amyloidogenic wild-type transthyretin using a novel purification strategy and mass spectrometry. Anal Chem. 2007; 79(5):1990-8. DOI: 10.1021/ac061546s. View

Dasari A, Hughes R, Wi S, Hung I, Gan Z, Kelly J . Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers. Sci Rep. 2019; 9(1):33. PMC: 6328637. DOI: 10.1038/s41598-018-37230-1. View

10.

Shirzadeh M, Boone C, Laganowsky A, Russell D . Topological Analysis of Transthyretin Disassembly Mechanism: Surface-Induced Dissociation Reveals Hidden Reaction Pathways. Anal Chem. 2019; 91(3):2345-2351. PMC: 6464633. DOI: 10.1021/acs.analchem.8b05066. View

11.

Faria T, Almeida Z, Cruz P, Jesus C, Castanheira P, Brito R . A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model. Phys Chem Chem Phys. 2015; 17(11):7255-63. DOI: 10.1039/c4cp04549a. View

12.

Lai Z, Colon W, Kelly J . The acid-mediated denaturation pathway of transthyretin yields a conformational intermediate that can self-assemble into amyloid. Biochemistry. 1996; 35(20):6470-82. DOI: 10.1021/bi952501g. View

13.

Mizuguchi M, Yokoyama T, Nabeshima Y, Kawano K, Tanaka I, Niimura N . Quaternary structure, aggregation and cytotoxicity of transthyretin. Amyloid. 2012; 19 Suppl 1:5-7. DOI: 10.3109/13506129.2012.666510. View

14.

Costa P, Figueira A, Bravo F . Amyloid fibril protein related to prealbumin in familial amyloidotic polyneuropathy. Proc Natl Acad Sci U S A. 1978; 75(9):4499-503. PMC: 336143. DOI: 10.1073/pnas.75.9.4499. View

15.

Oroz J, Kim J, Chang B, Zweckstetter M . Mechanistic basis for the recognition of a misfolded protein by the molecular chaperone Hsp90. Nat Struct Mol Biol. 2017; 24(4):407-413. DOI: 10.1038/nsmb.3380. View

16.

Yee A, Aldeghi M, Blakeley M, Ostermann A, Mas P, Moulin M . A molecular mechanism for transthyretin amyloidogenesis. Nat Commun. 2019; 10(1):925. PMC: 6390107. DOI: 10.1038/s41467-019-08609-z. View

17.

Schreiber G, Aldred A, Jaworowski A, Nilsson C, Achen M, Segal M . Thyroxine transport from blood to brain via transthyretin synthesis in choroid plexus. Am J Physiol. 1990; 258(2 Pt 2):R338-45. DOI: 10.1152/ajpregu.1990.258.2.R338. View

18.

Hammarstrom P, Schneider F, Kelly J . Trans-suppression of misfolding in an amyloid disease. Science. 2001; 293(5539):2459-62. DOI: 10.1126/science.1062245. View

19.

Pires R, Saraiva M, Damas A, Kellermayer M . Structure and assembly-disassembly properties of wild-type transthyretin amyloid protofibrils observed with atomic force microscopy. J Mol Recognit. 2011; 24(3):467-76. DOI: 10.1002/jmr.1112. View

20.

Akinboboye O, Shah K, Warner A, Damy T, Taylor H, Gollob J . DISCOVERY: prevalence of transthyretin () mutations in a US-centric patient population suspected of having cardiac amyloidosis. Amyloid. 2020; 27(4):223-230. DOI: 10.1080/13506129.2020.1764928. View