Transthyretin fibrillogenesis entails the assembly of monomers: a molecular model for in vitro assembled transthyretin amyloid-like fibrils 1 1Edited by M. Moody

Cardoso, Isabel; Goldsbury, Claire; Müller, Shirley A.; Olivieri, Vesna; Wirtz, Sabine; Damas, Ana M.; Aebi, Ueli; Saraiva, Maria João

doi:10.1006/jmbi.2002.5441

Cited by 112 publications

(104 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While some mutants did not form amyloid, which is consistent with the idea that the monomeric species are necessary for fibril formation (4), others do form fibrils, pointing to a dimeric nature of the intermediate species (5). Recently, scanning transmission electron microscopy (STEM) clarified this question because it revealed a massper-length of the protofilaments of ϳ0.47 kDa/Å, which is consistent with the model where the monomer is the building block (3).…”

supporting

confidence: 69%

See 1 more Smart Citation

X-ray Absorption Spectroscopy Reveals a Substantial Increase of Sulfur Oxidation in Transthyretin (TTR) upon Fibrillization

Gales¹,

Cardoso²,

Fayard³

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Transthyretin (TTR) amyloid fibrils are the main component of the amyloid deposits occurring in Familial Amyloidotic Polyneuropathy patients. This is 1 of 20 human proteins leading to protein aggregation disorders such as Alzheimer's and Creutzfeldt-Jakob diseases. The structural details concerning the association of the protein molecules are essential for a better understanding of the disease and consequently the design of new strategies for diagnosis and therapeutics. Disulfide bonds are frequently considered essential for the stability of protein aggregates and since in the TTR monomers there is one cysteine residue, it is important to determine unambiguously the redox state of sulfur present in the fibrils. In this work we used x-ray spectroscopy to further characterize TTR amyloid fibrils. The sulfur K-edge absorption spectra for the wild type and some amyloidogenic TTR variants in the soluble and fibrillar forms were analyzed. Whereas in the soluble proteins the thiol group from cysteine (R-SH) and the thioether group from methionine (R-S-CH 3 ) are the most abundant forms, in the TTR fibrils there is a significant oxidation of sulfur to the sulfonate form in the cysteine residue and a partial oxidation of sulfur to sulfoxide in the methionine residues. Further interpretation of the data reveals that there are no disulfide bridges in the fibrillar samples and suggest conformational changes in the TTR molecule, namely in strand A and/or in its vicinity, upon fibril formation.

show abstract

supporting

confidence: 69%

“…Most of the proposed models refer to the dissociation of the tetrameric protein into an intermediate species that self-assembles leading to the insoluble fibril (2,3). However, some controversy remains regarding this intermediate structure and in particular regarding its monomeric or dimeric conformational nature.…”

mentioning

confidence: 99%

X-ray Absorption Spectroscopy Reveals a Substantial Increase of Sulfur Oxidation in Transthyretin (TTR) upon Fibrillization

Gales¹,

Cardoso²,

Fayard³

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…4,5 TTR Leu55Pro forms fibrils in vitro enabling detailed analyses of TTR fibrillogenesis; at physiological pH we recently proposed a model in which fibrillar TTR structures are composed of several elementary protofilaments that appear in the initial phases of fibrillogenesis, with each protofilament being a vertical stack of structurally modified TTR monomers. 29 The model presented for the molecular arrangement of TTR monomers in protofilaments within fibrils may resemble early deposition events in vivo as the ones here described for the TTR Leu55Pro transgenics.…”

Section: Discussionmentioning

confidence: 65%

Evidence for Early Cytotoxic Aggregates in Transgenic Mice for Human Transthyretin Leu55Pro

Sousa¹,

Fernandes²,

Palha³

et al. 2002

The American Journal of Pathology

100

View full text Add to dashboard Cite

show abstract

“…3, middle and left panels, respectively), indicating that TTR was inhibiting A-Beta fibrillogenesis; under the conditions of the experiment WT TTR does not aggregate [20]. Extended incubations at 37°C for at least 7 days revealed that TTR did not lose the inhibitory ability, resulting in a more pronounced effect as only small oligomers were observable under the microscope.…”

Section: Effect Of Ttr In A-beta Fibrillizationmentioning

confidence: 81%

Transthyretin binding to A‐Beta peptide – Impact on A‐Beta fibrillogenesis and toxicity

Costa¹,

Gonçalves²,

Saraiva³

et al. 2008

FEBS Letters

131

145

View full text Add to dashboard Cite

It has been suggested that transthyretin (TTR) is involved in preventing A-Beta fibrillization in AlzheimerÕs disease (AD). Here, we characterized the TTR/A-Beta interaction by competition binding assays. TTR binds to different A-Beta peptide species: soluble (Kd, 28 nM), oligomers and fibrils; diverse TTR variants bind differentially to A-Beta. Transmission electron microscopy (TEM) analysis demonstrated that TTR is capable of interfering with A-Beta fibrillization by both inhibiting and disrupting fibril formation. Co-incubation of the two molecules resulted in the abolishment of A-Beta toxicity. Our results confirmed TTR as an A-Beta ligand and indicated the inhibition/disruption of A-Beta fibrils as a possible mechanism underlying the protective role of TTR in AD.

show abstract

Transthyretin fibrillogenesis entails the assembly of monomers: a molecular model for in vitro assembled transthyretin amyloid-like fibrils 1 1Edited by M. Moody

Cited by 112 publications

References 27 publications

X-ray Absorption Spectroscopy Reveals a Substantial Increase of Sulfur Oxidation in Transthyretin (TTR) upon Fibrillization

X-ray Absorption Spectroscopy Reveals a Substantial Increase of Sulfur Oxidation in Transthyretin (TTR) upon Fibrillization

Evidence for Early Cytotoxic Aggregates in Transgenic Mice for Human Transthyretin Leu55Pro

Transthyretin binding to A‐Beta peptide – Impact on A‐Beta fibrillogenesis and toxicity

Contact Info

Product

Resources

About