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Hydration and Packing are Crucial to Amyloidogenesis as Revealed by Pressure Studies on Transthyretin Variants that Either Protect or Worsen Amyloid Disease

Ferrão-Gonzales, Astria D ; Palmieri, Leonardo ; Valory, Marcelo ; Silva, Jerson L ; Lashuel, Hilal ; Kelly, Jeffery W ; Foguel, Débora

Journal of Molecular Biology, 2003, Vol.328(4), pp.963-974 [Periódico revisado por pares]

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  • Título:
    Hydration and Packing are Crucial to Amyloidogenesis as Revealed by Pressure Studies on Transthyretin Variants that Either Protect or Worsen Amyloid Disease
  • Autor: Ferrão-Gonzales, Astria D ; Palmieri, Leonardo ; Valory, Marcelo ; Silva, Jerson L ; Lashuel, Hilal ; Kelly, Jeffery W ; Foguel, Débora
  • Assuntos: Transthyretin ; Amyloid ; Thermodynamic Stability ; Packing Defects ; High Hydrostatic Pressure ; Biology ; Chemistry
  • É parte de: Journal of Molecular Biology, 2003, Vol.328(4), pp.963-974
  • Descrição: The formation of amyloid aggregates is the hallmark of the amyloidogenic diseases. Transthyretin (TTR) is involved in senile systemic amyloidosis (wild-type protein) and familial amyloidotic polyneuropathy (point mutants). Through the use of high hydrostatic pressure (HHP), we compare the stability among wild-type (wt) TTR, two disease-associated mutations (V30M and L55P) and a trans-suppressor mutation (T119M). Our data show that the amyloidogenic conformation, easily populated in the disease-associated mutant L55P, can be induced by a cycle of compression-decompression with the wt protein rendering the latter highly amyloidogenic. After decompression, the recovered wt structure has weaker subunit interactions (loosened tetramer, T(4)(*)) and presents a stability similar to L55P, suggesting that HHP induces a defective fold in the wt protein, converting it to an altered conformation already present in the aggressive mutant, L55P. On the other hand, glucose, a chemical chaperone, can mimic the trans-suppression mutation by stabilizing the native state and by decreasing the amyloidogenic potential of the wt TTR at pH 5.0. The sequence of pressure stability observed was: L55P
  • Idioma: Inglês

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