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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

Academic Article
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Overview

authors

  • Ferrao-Gonzales, A. D.
  • Palmieri, L.
  • Valory, M.
  • Silva, J. L.
  • Lashuel, H.
  • Kelly, Jeffery
  • Foguel, D.

publication date

  • May 2003

journal

  • Journal of Molecular Biology  Journal

abstract

  • 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

subject areas

  • Amyloid
  • Dose-Response Relationship, Drug
  • Glucose
  • Humans
  • Models, Chemical
  • Mutation
  • Neurodegenerative Diseases
  • Prealbumin
  • Pressure
  • Protein Conformation
  • Temperature
  • Thermodynamics
  • Water
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Research

keywords

  • amyloid
  • high hydrostatic pressure
  • packing defects
  • thermodynamic stability
  • transthyretin
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Identity

International Standard Serial Number (ISSN)

  • 0022-2836

Digital Object Identifier (DOI)

  • 10.1016/s0022-2836(03)00368-1

PubMed ID

  • 12729768
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Additional Document Info

start page

  • 963

end page

  • 974

volume

  • 328

issue

  • 4

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