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Amyloidogenic potential of transthyretin variants: insights from structural and computational analyses.

Cendron L, Trovato A, Seno F, Folli C, Alfieri B, Zanotti G, Berni R
J Biol Chem 284 25832-41 (2009)
Related entries: 1f41, 2g3x, 2g3z, 2g4e, 2g4g, 2noy, 3djr, 3djs, 3djt, 3djz, 3dk0

Cited: 24 times
EuropePMC logo PMID: 19602727

Abstract

Human transthyretin (TTR) is an amyloidogenic protein whose mild amyloidogenicity is enhanced by many point mutations affecting considerably the amyloid disease phenotype. To ascertain whether the high amyloidogenic potential of TTR variants may be explained on the basis of the conformational change hypothesis, an aim of this work was to determine structural alterations for five amyloidogenic TTR variants crystallized under native and/or destabilizing (moderately acidic pH) conditions. While at acidic pH structural changes may be more significant because of a higher local protein flexibility, only limited alterations, possibly representing early events associated with protein destabilization, are generally induced by mutations. This study was also aimed at establishing to what extent wild-type TTR and its amyloidogenic variants are intrinsically prone to beta-aggregation. We report the results of a computational analysis predicting that wild-type TTR possesses a very high intrinsic beta-aggregation propensity which is on average not enhanced by amyloidogenic mutations. However, when located in beta-strands, most of these mutations are predicted to destabilize the native beta-structure. The analysis also shows that rat and murine TTR have a lower intrinsic beta-aggregation propensity and a similar native beta-structure stability compared with human TTR. This result is consistent with the lack of in vitro amyloidogenicity found for both murine and rat TTR. Collectively, the results of this study support the notion that the high amyloidogenic potential of human pathogenic TTR variants is determined by the destabilization of their native structures, rather than by a higher intrinsic beta-aggregation propensity.

Articles - 3dk2 mentioned but not cited (1)

  1. Amyloidogenic potential of transthyretin variants: insights from structural and computational analyses. Cendron L, Trovato A, Seno F, Folli C, Alfieri B, Zanotti G, Berni R. J Biol Chem 284 25832-25841 (2009)


Reviews citing this publication (1)

  1. Diagnostic and Treatment Approaches Involving Transthyretin in Amyloidogenic Diseases. Park GY, Jamerlan A, Shim KH, An SSA. Int J Mol Sci 20 E2982 (2019)

Articles citing this publication (22)

  1. AGGRESCAN3D (A3D): server for prediction of aggregation properties of protein structures. Zambrano R, Jamroz M, Szczasiuk A, Pujols J, Kmiecik S, Ventura S. Nucleic Acids Res 43 W306-13 (2015)
  2. Cryo-EM structure of a transthyretin-derived amyloid fibril from a patient with hereditary ATTR amyloidosis. Schmidt M, Wiese S, Adak V, Engler J, Agarwal S, Fritz G, Westermark P, Zacharias M, Fändrich M. Nat Commun 10 5008 (2019)
  3. Localized structural fluctuations promote amyloidogenic conformations in transthyretin. Lim KH, Dyson HJ, Kelly JW, Wright PE. J Mol Biol 425 977-988 (2013)
  4. Transthyretin is a metallopeptidase with an inducible active site. Liz MA, Leite SC, Juliano L, Saraiva MJ, Damas AM, Bur D, Sousa MM. Biochem J 443 769-778 (2012)
  5. Transthyretin Binding Heterogeneity and Anti-amyloidogenic Activity of Natural Polyphenols and Their Metabolites. Florio P, Folli C, Cianci M, Del Rio D, Zanotti G, Berni R. J Biol Chem 290 29769-29780 (2015)
  6. NMR Measurements Reveal the Structural Basis of Transthyretin Destabilization by Pathogenic Mutations. Leach BI, Zhang X, Kelly JW, Dyson HJ, Wright PE. Biochemistry 57 4421-4430 (2018)
  7. Conformational flexibility tunes the propensity of transthyretin to form fibrils through non-native intermediate states. Das JK, Mall SS, Bej A, Mukherjee S. Angew Chem Int Ed Engl 53 12781-12784 (2014)
  8. A new crystal form of human transthyretin obtained with a curcumin derived ligand. Polsinelli I, Nencetti S, Shepard W, Ciccone L, Orlandini E, Stura EA. J Struct Biol 194 8-17 (2016)
  9. Disruption of the CD Loop by Enzymatic Cleavage Promotes the Formation of Toxic Transthyretin Oligomers through a Common Transthyretin Misfolding Pathway. Dasari AKR, Arreola J, Michael B, Griffin RG, Kelly JW, Lim KH. Biochemistry 59 2319-2327 (2020)
  10. Functional variation of the transthyretin gene among human populations and its correlation with amyloidosis phenotypes. Polimanti R, Di Girolamo M, Manfellotto D, Fuciarelli M. Amyloid 20 256-262 (2013)
  11. Human TTR conformation altered by rhenium tris-carbonyl derivatives. Ciccone L, Policar C, Stura EA, Shepard W. J Struct Biol 195 353-364 (2016)
  12. Optimal identification of semi-rigid domains in macromolecules from molecular dynamics simulation. Bernhard S, Noé F. PLoS One 5 e10491 (2010)
  13. Structural evidence for asymmetric ligand binding to transthyretin. Cianci M, Folli C, Zonta F, Florio P, Berni R, Zanotti G. Acta Crystallogr D Biol Crystallogr 71 1582-1592 (2015)
  14. Structural evidence for native state stabilization of a conformationally labile amyloidogenic transthyretin variant by fibrillogenesis inhibitors. Zanotti G, Cendron L, Folli C, Florio P, Imbimbo BP, Berni R. FEBS Lett 587 2325-2331 (2013)
  15. In silico analysis of TTR gene (coding and non-coding regions, and interactive network) and its implications in transthyretin-related amyloidosis. Polimanti R, Di Girolamo M, Manfellotto D, Fuciarelli M. Amyloid 21 154-162 (2014)
  16. Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics. Saldaño TE, Zanotti G, Parisi G, Fernandez-Alberti S. PLoS One 12 e0181019 (2017)
  17. Biophysical characterization and modulation of Transthyretin Ala97Ser. Liu YT, Yen YJ, Ricardo F, Chang Y, Wu PH, Huang SJ, Lin KP, Yu TY. Ann Clin Transl Neurol 6 1961-1970 (2019)
  18. Disease-associated mutations impacting BC-loop flexibility trigger long-range transthyretin tetramer destabilization and aggregation. Esperante SA, Varejāo N, Pinheiro F, Sant'Anna R, Luque-Ortega JR, Alfonso C, Sora V, Papaleo E, Rivas G, Reverter D, Ventura S. J Biol Chem 297 101039 (2021)
  19. Sequence-Based Prediction of Protein Phase Separation: The Role of Beta-Pairing Propensity. Mullick P, Trovato A. Biomolecules 12 1771 (2022)
  20. The Transthyretin/Oleuropein Aglycone Complex: A New Tool against TTR Amyloidosis. Bemporad F, Leri M, Ramazzotti M, Stefani M, Bucciantini M. Pharmaceuticals (Basel) 15 277 (2022)
  21. 3-O-Methyltolcapone and Its Lipophilic Analogues Are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity. Poonsiri T, Dell'Accantera D, Loconte V, Casnati A, Cervoni L, Arcovito A, Benini S, Ferrari A, Cipolloni M, Cacioni E, De Franco F, Giacchè N, Rinaldo S, Folli C, Sansone F, Berni R, Cianci M. Int J Mol Sci 25 479 (2023)
  22. Hypertrophic cardiomyopathy caused by a heterozygous variant in TTR gene: A case report. Yuan H, Lin Y, Wang J, Li J, Chen X, Guo Y, Tang J. Medicine (Baltimore) 102 e33752 (2023)


Related citations provided by authors (2)

  1. Acidic pH-induced conformational changes in amyloidogenic mutant transthyretin.. Pasquato N, Berni R, Folli C, Alfieri B, Cendron L, Zanotti G J Mol Biol 366 711-9 (2007)
  2. A comparative analysis of 23 structures of the amyloidogenic protein transthyretin.. Hörnberg A, Eneqvist T, Olofsson A, Lundgren E, Sauer-Eriksson AE J Mol Biol 302 649-69 (2000)

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