Hydration and packing are crucial to amyloidogenesis as revealed by pressure studies on transthyretin variants that either protect or worsen amyloid disease

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

Research output: Contribution to journalArticle

59 Citations (Scopus)

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, T4 *) 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<V30M<wtT119M. The pressure dissociation of L55P at 1°C exhibited dependence on protein concentration, allowing us to assess the volume change of association and the free-energy change. After a cycle of compression-decompression at 37°C and pH 5.6 or lower, all amyloidogenic variants underwent aggregation. Binding of bis-(8-anilinonaphthalene-1-sulfonate) (bis-ANS) revealed that the species formed under pressure retained part of its tertiary contacts (except T119M). However, at neutral pH, where aggregation did not take place after decompression, bis-ANS binding was absent. Thus, TTR has to experience this partially folded conformation to undergo aggregation after decompression. Overall, our studies provide evidence that amyloidogenesis correlates with less packed structures (larger volume changes) and high susceptibility to water infiltration. The hydration effects can be counteracted by osmolytes or by a specific mutation.

Original languageEnglish
Pages (from-to)963-974
Number of pages12
JournalJournal of Molecular Biology
Volume328
Issue number4
DOIs
Publication statusPublished - 9 May 2003
Externally publishedYes

Fingerprint

Prealbumin
Decompression
Amyloid
Pressure
Hydrostatic Pressure
Mutation
Proteins
Free Association
Genetic Suppression
Polyneuropathies
Amyloidosis
Glucose
Water

Keywords

  • Amyloid
  • High hydrostatic pressure
  • Packing defects
  • Thermodynamic stability
  • Transthyretin

ASJC Scopus subject areas

  • Virology

Cite this

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.

In: Journal of Molecular Biology, Vol. 328, No. 4, 09.05.2003, p. 963-974.

Research output: Contribution to journalArticle

Ferrão-Gonzales, Astria D. ; Palmieri, Leonardo ; Valory, Marcelo ; Silva, Jerson L. ; Lashuel, Hilal ; Kelly, Jeffery W. ; Foguel, Débora. / Hydration and packing are crucial to amyloidogenesis as revealed by pressure studies on transthyretin variants that either protect or worsen amyloid disease. In: Journal of Molecular Biology. 2003 ; Vol. 328, No. 4. pp. 963-974.
@article{0848e2de91084365a3d828e9700f30ce,
title = "Hydration and packing are crucial to amyloidogenesis as revealed by pressure studies on transthyretin variants that either protect or worsen amyloid disease",
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, T4 *) 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<V30M",
keywords = "Amyloid, High hydrostatic pressure, Packing defects, Thermodynamic stability, Transthyretin",
author = "Ferr{\~a}o-Gonzales, {Astria D.} and Leonardo Palmieri and Marcelo Valory and Silva, {Jerson L.} and Hilal Lashuel and Kelly, {Jeffery W.} and D{\'e}bora Foguel",
year = "2003",
month = "5",
day = "9",
doi = "10.1016/S0022-2836(03)00368-1",
language = "English",
volume = "328",
pages = "963--974",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "4",

}

TY - JOUR

T1 - Hydration and packing are crucial to amyloidogenesis as revealed by pressure studies on transthyretin variants that either protect or worsen amyloid disease

AU - Ferrão-Gonzales, Astria D.

AU - Palmieri, Leonardo

AU - Valory, Marcelo

AU - Silva, Jerson L.

AU - Lashuel, Hilal

AU - Kelly, Jeffery W.

AU - Foguel, Débora

PY - 2003/5/9

Y1 - 2003/5/9

N2 - 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, T4 *) 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<V30M

AB - 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, T4 *) 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<V30M

KW - Amyloid

KW - High hydrostatic pressure

KW - Packing defects

KW - Thermodynamic stability

KW - Transthyretin

UR - http://www.scopus.com/inward/record.url?scp=0043018095&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0043018095&partnerID=8YFLogxK

U2 - 10.1016/S0022-2836(03)00368-1

DO - 10.1016/S0022-2836(03)00368-1

M3 - Article

C2 - 12729768

AN - SCOPUS:0043018095

VL - 328

SP - 963

EP - 974

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 4

ER -