Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative

Almeida, Maria Rosário; Macedo, Bárbara; Cardoso, Isabel; Alves, Isabel; Valencia, Gregorio; Arsequell, Gemma; Planas, Antoni; Saraiva, Maria João

doi:10.1042/bj20040011

Cited by 89 publications

(107 citation statements)

References 27 publications

(31 reference statements)

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“…TTR aggregation has been a model system for this approach, because small molecules, including the nonsteroidal anti-inflammatory drug diflunisal and many of its derivatives, are reported to stabilize the native tetrameric structure (31,32,46). In this study, we directly investigated the effect of diflunisal on F-rTTR tetramer structure by analysis of the s isotherms in the presence and absence of drug.…”

Section: Discussionmentioning

confidence: 99%

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

Kingsbury

Laue

Klimtchuk

et al. 2008

Journal of Biological Chemistry

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Transthyretin (TTR) is normally a stable plasma protein.However, in cases of familial TTR-related amyloidosis and senile systemic amyloidosis (SSA), TTR is deposited as amyloid fibrils, leading to organ dysfunction and possibly death. The mechanism by which TTR undergoes the transition from stable, soluble precursor to insoluble amyloid fibril and the factors that promote this process are largely undetermined. Most models involve the dissociation of the native TTR tetramer as the initial step. It is largely accepted that the TTR gene mutations associated with TTR-related amyloidosis lead to the expression of variant proteins that are intrinsically unstable and prone to aggregation. It has been suggested that amyloidogenicity may be conferred to wild-type TTR (the form deposited in SSA) by chemical modification of the lone cysteine residue (Cys 10 ) through mixed disulfide bonds. S-Sulfonation and S-cysteinylation are prevalent TTR modifications physiologically, and studies have suggested their ability to modulate the structure of TTR under denaturing conditions. In the present study, we have used fluorescencedetected sedimentation velocity to determine the effect of S-sulfonate and S-cysteine on the quaternary structural stability of fluorophore-conjugated recombinant TTR under nondenaturing conditions. We determined that S-sulfonation stabilized TTR tetramer stability by a factor of 7, whereas S-cysteinylation enhanced dissociation by 2-fold with respect to the unmodified form. In addition, we report the direct observation of tetramer stabilization by the potential therapeutic compound diflunisal. Finally, as proof of concept, we report the sedimentation of TTR in serum and the qualitative assessment of the resulting data.

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Section: Discussionmentioning

confidence: 99%

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

Kingsbury

Laue

Klimtchuk

et al. 2008

Journal of Biological Chemistry

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“…Among those, are non-steroidal anti-inflammatory drugs (NSAIDs) and derivatives or natural compounds [8,9]. However some of the previously suggested compounds present low binding affinity or low selectivity of binding to TTR ex vivo and, in some cases, severe adverse side effects associated with their administration in vivo [10][11][12]. Recently, our group reported that (À)-epigallocatechin gallate (EGCG), the most abundant catechin in green tea, inhibits TTR aggregation in vitro [13] raising the possibility of using this polyphenol or analogs to treat FAP.…”

Section: Introductionmentioning

confidence: 99%

Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation

Ferreira¹,

Saraiva

Almeida³

2011

FEBS Letters

136

126

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Edited by Jesus AvilaKeywords: Transthyretin Amyloid inhibitor Fibril formation (À)-Epigallocatechin-3-gallate Curcumin a b s t r a c t Several natural polyphenols with potent inhibitory effects on amyloid fibril formation have been reported. Herein, we studied modulation of transthyretin (TTR) fibrillogenesis by selected polyphenols. We demonstrate that both curcumin and nordihydroguaiaretic acid (NDGA) bind to TTR and stabilize the TTR tetramer. However, while NDGA slightly reduced TTR aggregation, curcumin strongly suppressed TTR amyloid fibril formation by generating small ''off-pathway'' oligomers and EGCG maintained most of the protein in a non-aggregated soluble form. This indicates alternative mechanisms of action supported by the occurrence of different non-toxic intermediates. Moreover, EGCG and curcumin efficiently disaggregated pre-formed TTR amyloid fibrils. Our studies, together with the safe toxicological profile of these phytochemicals may guide a novel pharmacotherapy for TTR-related amyloidosis targeting different steps in fibrillogenesis. Structured summary of protein interactions:TTR binds to TTR by comigration in gel electrophoresis (View interaction) TTR binds to TTR by dynamic light scattering (View interaction) TTR binds to TTR by electron microscopy (View interaction)

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“…Thus, new strategies are clearly required. Several non-steroidal anti-inflammatory compounds and molecules derived from them have been shown to be very effective in inhibiting aggregation of TTR in vitro (43,44). These molecules are not currently available to be administered to FAP patients, however.…”

Section: Discussionmentioning

confidence: 99%

Trapping the Monomer of a Non-amyloidogenic Variant of Transthyretin

Palhano

Leme

Busnardo

et al. 2009

Journal of Biological Chemistry

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Transthyretin (TTR) is a 127-residue homotetrameric ␤-sheetrich protein that transports thyroxine in the blood and cerebrospinal fluid. The deposition of fibrils and amorphous aggregates of TTR in patients' tissues is a hallmark of TTR amyloid disease. Familial amyloidotic polyneuropathy is a hereditary form of TTR amyloidosis that is associated with one among 80 different variants of TTR. The most aggressive variants of TTR are V30M, L55P, and A25T, and the propensity to undergo aggregation seems to be linked to tetramer stability. T119M is a very stable, non-amyloidogenic variant of TTR. Here we show that the combination of high hydrostatic pressure with subdenaturing concentrations of urea (4 M) at 1°C irreversibly dissociates T119M into monomers in less than 30 min in a concentration-dependent fashion. After pressure and urea removal, long lived monomers are the only species present in solution. We took advantage of the slow reassociation kinetics of these monomers into tetramers to produce heterotetramers by mixing the T119M monomers with the tetramers of the aggressive mutants of TTR. Our data show that T119M monomers can be successfully incorporated into all of these tetramers even when the exchange is performed in a more physiological environment such as human plasma; these monomers render the resultant heterotetramers less amyloidogenic. The data presented here are relevant for the understanding of T119M folding and association reactions and provide a protocol for producing T119M monomers that function as inhibitors of TTR aggregation when incorporated into tetramers. This protocol may provide a new strategy for treating TTR diseases for which there is no therapy available other than liver transplantation. Transthyretin (TTR)2 is a 55-kDa homotetrameric protein composed of identical 127-residue subunits with a predominantly ␤-sheet structure (1). TTR is found in human plasma (0.1-0.4 mg/ml) and cerebral spinal fluid (0.017 mg/ml). The plasma form serves as a secondary carrier for thyroxine (T4) and binds to retinol-binding protein (1), whereas the form that resides in the cerebral spinal fluid is the primary T4 transporter (2).Wild-type TTR is responsible for senile systemic amyloidosis, a disease that affects 10% of people over 80 years old and is characterized by heavy amyloid deposits in the heart (3). Around 80 point mutants of TTR have been described thus far that are involved in familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy, and central nervous system amyloidosis (4). In general, patients with the familial form of the disease experience the first symptoms by the time they reach their second or third decade with peripheral neuropathy, cardiomyopathy, and leptomeningeal deposition (5).Among the variants of TTR identified worldwide, V30M and L55P are the most important because of their high frequency of occurrence and the aggressiveness of the symptoms they evoke. A25T is one of the most unstable known tetramer of TTR that is involved in central nervous system amyloid...

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Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative

Cited by 89 publications

References 27 publications

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation

Trapping the Monomer of a Non-amyloidogenic Variant of Transthyretin

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