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Titolo:
Tetramer dissociation and monomer partial unfolding precedes protofibril formation in amyloidogenic transthyretin variants
Autore:
Quintas, A; Vaz, DC; Cardoso, I; Saraiva, MJM; Brito, RMM;
Indirizzi:
Univ Coimbra, Dept Quim, Fac Ciencias & Tecnol, P-3004535 Coimbra, Portugal Univ Coimbra Coimbra Portugal P-3004535 nol, P-3004535 Coimbra, Portugal Univ Coimbra, Ctr Neurociencias Coimbra, P-3004517 Coimbra, Portugal Univ Coimbra Coimbra Portugal P-3004517 bra, P-3004517 Coimbra, Portugal Inst Super Ciencias Saude Sul, P-2825 Monte De Caparica, Portugal Inst Super Ciencias Saude Sul Monte De Caparica Portugal P-2825 Portugal Univ Porto, Inst Ciencias Biomed Abel Salazar, P-4050 Porto, Portugal UnivPorto Porto Portugal P-4050 ed Abel Salazar, P-4050 Porto, Portugal Univ Porto, Inst Mol & Cellular Biol, P-4050 Porto, Portugal Univ Porto Porto Portugal P-4050 & Cellular Biol, P-4050 Porto, Portugal
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 29, volume: 276, anno: 2001,
pagine: 27207 - 27213
SICI:
0021-9258(20010720)276:29<27207:TDAMPU>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
IN-VITRO; PROTEIN TRANSTHYRETIN; POLYNEUROPATHY FAP; FIBRILS; FIBRILLOGENESIS; INTERMEDIATE; MODEL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
27
Recensione:
Indirizzi per estratti:
Indirizzo: Brito, RMM Univ Coimbra, Dept Quim, Fac Ciencias & Tecnol, P-3004535 Coimbra, Portugal Univ Coimbra Coimbra Portugal P-3004535 535 Coimbra, Portugal
Citazione:
A. Quintas et al., "Tetramer dissociation and monomer partial unfolding precedes protofibril formation in amyloidogenic transthyretin variants", J BIOL CHEM, 276(29), 2001, pp. 27207-27213

Abstract

Amyloid fibril formation and deposition is a common feature of a wide range of fatal diseases including spongiform encephalopathies, Alzheimer's disease, and familial amyloidotic polyneuropathies (FAP), among many others. Incertain forms of FAP, the amyloid fibrils are mostly constituted by variants of transthyretin (TTR), a homotetrameric plasma protein. Recently, we showed that transthyretin in solution may undergo dissociation to a non-native monomer, even under close to physiological conditions of temperature, pH,ionic strength, and protein concentration. We also showed that this non-native monomer is a compact structure, does not behave as a molten globule, and may lead to the formation of partially unfolded monomeric species and high molecular mass soluble aggregates (Quintas, A., Saraiva, M.J.M., and Brito, R.M.M. (1999) J. Biol. Chem. 274, 32943-32949), Here, based on aging experiments of tetrameric TTR and chemically induced protein unfolding experiments of the non-native monomeric forms, we show that tetramer dissociationand partial unfolding of the monomer precedes amyloid fibril formation. Wealso show that TTR variants with the least thermodynamically stable non-native monomer produce the largest amount of partially unfolded monomeric species and soluble aggregates under conditions that are close to physiological. Additionally, the soluble aggregates formed by the amyloidogenic TTR variants showed morphological and thioflavin-T fluorescence properties characteristic of amyloid. These results allowed us to conclude that amyloid fibril formation by some TTR variants might be triggered by tetramer dissociation to a compact non-native monomer with low conformational stability, which originates partially unfolded monomeric species with a high tendency for ordered aggregation into amyloid fibrils. Thus, partial unfolding and conformational fluctuations of molecular species with marginal thermodynamic stability may play a crucial role on amyloid formation in vivo.

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Documento generato il 28/03/20 alle ore 21:26:11