The Crystal Structure of Amyloidogenic Leu55→ Pro Transthyretin Variant Reveals a Possible Pathway for Transthyretin Polymerization into Amyloid Fibrils

Sebastião, Maria Paula; Saraiva, Maria João; Damas, Ana M.

doi:10.1074/jbc.273.38.24715

Cited by 120 publications

(103 citation statements)

References 26 publications

(25 reference statements)

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“…X-ray diffraction studies of L55P TTR suggested this variant as an amyloidogenic intermediate in the process of TTR fibril formation. The mutation leads to the disruption of the D strand due to the disturbance of the hydrogen bonds between strands D and A, thus residues 54-56 are part of a long surface loop that connects strands C and E [27]. This variant, the less stable and most amyloidogenic among the tested ones, showed the lowest affinity to the peptide, whereas the anti-amyloidogenic one, T119M, showed the highest affinity, indicating that conformational molecular changes are important to the binding, and therefore, the D strand region is relevant in binding to A-Beta.…”

Section: Discussionmentioning

confidence: 99%

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

Costa¹,

Gonçalves²,

Saraiva³

et al. 2008

FEBS Letters

132

145

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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.

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Section: Discussionmentioning

confidence: 99%

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

Costa¹,

Gonçalves²,

Saraiva³

et al. 2008

FEBS Letters

132

145

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“…The first model was derived from TTRL55P representing a highly amyloidogenic variant showing an interesting packing within the crystal lattice, where specific monomers form a propagating chain involving associations within the loop regions (36). Through this arrangement a superhelix of selected monomers shows a fibril with the ␤-strands arranged parallel to the fibril axis.…”

Section: Discussionmentioning

confidence: 99%

Probing Solvent Accessibility of Transthyretin Amyloid by Solution NMR Spectroscopy

Olofsson

Ippel

Wijmenga

et al. 2004

Journal of Biological Chemistry

107

117

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The human plasma protein transthyretin (TTR) may form fibrillar protein deposits that are associated with both inherited and idiopathic amyloidosis. The present study utilizes solution nuclear magnetic resonance spectroscopy, in combination with hydrogen/deuterium exchange, to determine residue-specific solvent protection factors within the fibrillar structure of the clinically relevant variant, TTRY114C. This novel approach suggests a fibril core comprised of the six ␤-strands, A-B-E-F-G-

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“…Each TTR monomer contains eight strands that form two sheets of four strands each and are arranged in a topology similar to the classic Greek key barrel. However, TTR fibrils are not likely to be made up of the native tetrameric form, and transition may occur in which monomers are modified into a pathological conformation (Quintas et al, 1999;Sebastiã o et al, 1998). Bearing in mind other described ligands for RAGE (A␤, amylin, serum amyloid A, and prion protein) and the high ␤ sheet content of TTR, this seems to indicate that this receptor is prone to recognize ␤ sheet structures, which, in the case of TTR, might be present in both the soluble and fibrillar form.…”

Section: Sousa Et Almentioning

confidence: 99%

Interaction of the Receptor for Advanced Glycation End Products (RAGE) with Transthyretin Triggers Nuclear Transcription Factor kB (NF-kB) Activation

Sousa¹,

Yan

Stern

et al. 2000

Laboratory Investigation

Self Cite

164

122

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SUMMARY:Mutated transthyretin (TTR) fibrils are associated with the pathology of familial amyloidotic polyneuropathy (FAP), in which extracellular amyloid deposits lead to degeneration of cells and tissues, in particular neurons of the peripheral nerve. Here we present evidence that the receptor for advanced glycation end products (RAGE), previously associated with Alzheimer's disease, acts as a selective cell surface acceptor site for both soluble and fibrillar TTR. Immunohistochemical studies demonstrating increased expression of RAGE in FAP tissues suggested the relevance of this receptor to TTR-induced fibrillar pathology. In vitro studies using soluble RAGE showed saturable specific interaction with soluble and fibrillar TTR with a K d of ϳ120 nM. However, no binding was observed when soluble TTR was combined with retinol-binding protein, which represents the form in which TTR normally circulates in plasma. Specific binding of TTR to RAGE-transfected Chinese hamster ovary cells (which was completely blocked by anti-RAGE) was observed, confirming that RAGE could mediate TTR binding to cellular surfaces. RAGE-dependent activation of nuclear transcription factor kB (NF-kB) by TTR fibrils was shown in PC-12 cells stably transfected to overexpress the receptor. Furthermore, FAP nerves showed up-regulation of p50, one of the NF-kB subunits, when compared with age-matched controls. From these observations we predict that, in vivo, the presence of TTR fibrils associated with cellular surfaces of FAP patients, by contributing to NF-kB activation, leads to the pathogenesis of neurodegeneration. Further insights into the consequences of the interaction of fibrillar TTR with RAGE may therefore provide a better understanding of neurodegeneration associated with FAP. (Lab Invest 2000, 80:1101-1110.F amilial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by the extracellular deposition of transthyretin (TTR) fibrils in several tissues, particularly in the peripheral nervous system (Saraiva, 1995). In the peripheral nerves, amyloid infiltrates the epineurium, the perineurium, and especially the endoneurium. Extensive amyloid deposition is also observed in the meninges, in the spinal and autonomic ganglia, throughout the connective tissue, and in a perivascular distribution. In contrast, no amyloid deposition is detected in the brain. Mutated TTR is the main component of these amyloid fibrils. Several mutations in TTR have been described, the most common being a valine (Val) for methionine (Met) substitution at position 30 of the protein (Val30Met) (Saraiva et al, 1983). Nonmutated TTR also deposits as amyloid in senile amyloidosis (Gustavsson et al, 1995). TTR is a plasma homotetrameric protein of approximately 55 kDa produced early in development and highly conserved in evolution (Blake et al, 1974). TTR functions as a carrier for thyroxine (T 4 ) and retinol (vitamin A) (Raz et al, 1970) by formation of a complex with retinol-binding protein (RBP). Under physiological conditions, TTR circu...

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The Crystal Structure of Amyloidogenic Leu55→ Pro Transthyretin Variant Reveals a Possible Pathway for Transthyretin Polymerization into Amyloid Fibrils

Cited by 120 publications

References 26 publications

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

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

Probing Solvent Accessibility of Transthyretin Amyloid by Solution NMR Spectroscopy

Interaction of the Receptor for Advanced Glycation End Products (RAGE) with Transthyretin Triggers Nuclear Transcription Factor kB (NF-kB) Activation

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