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Conformational differences between the wild type and V30M mutant transthyretin modulate its binding to genistein: implications to tetramer stability and ligand-binding.

Trivella DB, Bleicher L, Palmieri Lde C, Wiggers HJ, Montanari CA, Kelly JW, Lima LM, Foguel D, Polikarpov I
J Struct Biol 170 522-31 (2010)
Related entries: 3kgs, 3kgt

Cited: 25 times
EuropePMC logo PMID: 20211733

Abstract

Transthyretin (TTR) is a tetrameric beta-sheet-rich transporter protein directly involved in human amyloid diseases. It was recently found that the isoflavone genistein (GEN) potently inhibits TTR amyloid fibril formation (Green et al., 2005) and is therefore a promising candidate for TTR amyloidosis treatment. Here we used structural and biophysical approaches to characterize genistein binding to the wild type (TTRwt) and to its most frequent amyloidogenic variant, the V30M mutant. In a dose-dependent manner, genistein elicited considerable increases in both mutant and TTRwt stability as demonstrated by high hydrostatic pressure (HHP) and acid-mediated dissociation/denaturation assays. TTR:GEN crystal complexes and isothermal titration calorimetry (ITC) experiments showed that the binding mechanisms of genistein to the TTRwt and to V30M are different and are dependent on apoTTR structure conformations. Furthermore, we could also identify potential allosteric movements caused by genistein binding to the wild type TTR that explains, at least in part, the frequently observed negatively cooperative process between the two sites of TTRwt when binding ligands. These findings show that TTR mutants may present different ligand recognition and therefore are of value in ligand design for inhibiting TTR amyloidosis.

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  1. Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses. Galant NJ, Bugyei-Twum A, Rakhit R, Walsh P, Sharpe S, Arslan PE, Westermark P, Higaki JN, Torres R, Tapia J, Chakrabartty A. Sci Rep 6 25080 (2016)


Reviews citing this publication (6)

  1. The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. Johnson SM, Connelly S, Fearns C, Powers ET, Kelly JW. J. Mol. Biol. 421 185-203 (2012)
  2. Applications of isothermal titration calorimetry in pure and applied research--survey of the literature from 2010. Ghai R, Falconer RJ, Collins BM. J. Mol. Recognit. 25 32-52 (2012)
  3. Evolution of quantitative methods in protein secondary structure determination via deep-ultraviolet resonance Raman spectroscopy. Roach CA, Simpson JV, JiJi RD. Analyst 137 555-562 (2012)
  4. Application of isothermal titration calorimetry as a tool to study natural product interactions. Callies O, Hernández Daranas A. Nat Prod Rep 33 881-904 (2016)
  5. Natural compounds as inhibitors of transthyretin amyloidosis and neuroprotective agents: analysis of structural data for future drug design. Ciccone L, Tonali N, Nencetti S, Orlandini E. J Enzyme Inhib Med Chem 35 1145-1162 (2020)
  6. Factors affecting the physical stability (aggregation) of peptide therapeutics. Zapadka KL, Becher FJ, Gomes Dos Santos AL, Jackson SE. Interface Focus 7 20170030 (2017)

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  1. Potent kinetic stabilizers that prevent transthyretin-mediated cardiomyocyte proteotoxicity. Alhamadsheh MM, Connelly S, Cho A, Reixach N, Powers ET, Pan DW, Wilson IA, Kelly JW, Graef IA. Sci Transl Med 3 97ra81 (2011)
  2. Brain endogenous estrogen levels determine responses to estrogen replacement therapy via regulation of BACE1 and NEP in female Alzheimer's transgenic mice. Li R, He P, Cui J, Staufenbiel M, Harada N, Shen Y. Mol. Neurobiol. 47 857-867 (2013)
  3. 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)
  4. Transthyretin complexes with curcumin and bromo-estradiol: evaluation of solubilizing multicomponent mixtures. Ciccone L, Tepshi L, Nencetti S, Stura EA. N Biotechnol 32 54-64 (2015)
  5. A competition assay to identify amyloidogenesis inhibitors by monitoring the fluorescence emitted by the covalent attachment of a stilbene derivative to transthyretin. Choi S, Kelly JW. Bioorg. Med. Chem. 19 1505-1514 (2011)
  6. Stability of the transthyretin molecule as a key factor in the interaction with a-beta peptide--relevance in Alzheimer's disease. Ribeiro CA, Saraiva MJ, Cardoso I. PLoS ONE 7 e45368 (2012)
  7. Solid-State NMR Studies Reveal Native-like β-Sheet Structures in Transthyretin Amyloid. Lim KH, Dasari AK, Hung I, Gan Z, Kelly JW, Wright PE, Wemmer DE. Biochemistry 55 5272-5278 (2016)
  8. 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)
  9. 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)
  10. 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)
  11. Lignin-derived oak phenolics: a theoretical examination of additional potential health benefits of red wine. Setzer WN. J Mol Model 17 1841-1845 (2011)
  12. Fluorogenic small molecules requiring reaction with a specific protein to create a fluorescent conjugate for biological imaging--what we know and what we need to learn. Baranczak A, Connelly S, Liu Y, Choi S, Grimster NP, Powers ET, Wilson IA, Kelly JW. Biopolymers 101 484-495 (2014)
  13. Transthyretin: roles in the nervous system beyond thyroxine and retinol transport. Oliveira SM, Cardoso I, Saraiva MJ. Expert Rev Endocrinol Metab 7 181-189 (2012)
  14. X-ray crystal structure and activity of fluorenyl-based compounds as transthyretin fibrillogenesis inhibitors. Ciccone L, Nencetti S, Rossello A, Tepshi L, Stura EA, Orlandini E. J Enzyme Inhib Med Chem 31 824-833 (2016)
  15. Characteristics of human lysozyme and its disease-related mutants in their unfolded states. Sziegat F, Wirmer-Bartoschek J, Schwalbe H. Angew. Chem. Int. Ed. Engl. 50 5514-5518 (2011)
  16. Discovery of γ-Mangostin as an Amyloidogenesis Inhibitor. Yokoyama T, Ueda M, Ando Y, Mizuguchi M. Sci Rep 5 13570 (2015)
  17. Synthesis and structural analysis of halogen substituted fibril formation inhibitors of Human Transthyretin (TTR). Ciccone L, Nencetti S, Rossello A, Stura EA, Orlandini E. J Enzyme Inhib Med Chem 31 40-51 (2016)
  18. 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)


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