FAP Mutations Destabilize Transthyretin Facilitating Conformational Changes Required for Amyloid Formation

Colón, Wilfredo; Lai, Zhihong; McCutchen, Sandra L.; Miroy, Greta J.; Strang, Candace

doi:10.1002/9780470514924.ch14

Cited by 19 publications

(16 citation statements)

References 38 publications

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“…1). Some mutations described for the human lysozyme and transthyretin are also known to destabilize the proteins and facilitate the conversion to amyloid fibrils (Dumoulin et al 2005;Colon et al 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, in the conformational diseases involving globular proteins, pathogenic mutations destabilizing the native folded conformation result in increased levels of aggregated protein. This is the case of human lysozyme and transthyretin, two proteins involved in systemic amyloidosis (Dumoulin et al 2005;Colon et al 1996). In both cases, natural occurring mutations destabilize the native fold, promoting the population of partially unfolded intermediates able to experiment large conformational rearrangements towards the formation of an aggregated cross β-sheet conformation.…”

Section: Introductionmentioning

confidence: 97%

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Aggregation of the neuroblastoma-associated mutant (S120G) of the human nucleoside diphosphate kinase-A/NM23-H1 into amyloid fibrils

Georgescauld

Sabaté

Espargaró

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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The human nucleoside diphosphate (NDP) kinase A, product of the NME1 gene also named NM23-H1, is known as a metastasis suppressor protein. A naturally occurring variant, S120G, identified in neuroblastomas, possesses native three-dimensional structure and enzymatic activity but displays reduced conformational stability and a folding defect with the accumulation of a "molten globule" folding intermediate during refolding in vitro. As such intermediate has been postulated to be involved in amyloid formation, NDP kinase A may serve as a model protein for studying the relationship between folding intermediates and amyloid fibrils. The NDP kinase A S120G was heated in phosphate buffer (pH 7.0). The protein precipitated as amyloid fibrils, as demonstrated by electron microscopy, Congo red, and thioflavin T binding and FTIR spectroscopy. The NDP kinase A S120G, at neutral pH and at moderate temperature experiences a transition towards amyloid fibrils. The aggregation process was faster if seeded by preformed fibrils. The fibrils presented a large proteinase K-resistant core not including residue Gly 120, as shown by mass spectrometry. This suggests that the aggregation process is triggered by the reduced stability of the S120G variant and not by a specific increase in the kinase domain intrinsic aggregation propensity at the place of mutation. This constitutes one of the few reports on a protein involved in cancer biology able to aggregate into amyloid structures under mild conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Aggregation of the neuroblastoma-associated mutant (S120G) of the human nucleoside diphosphate kinase-A/NM23-H1 into amyloid fibrils

Georgescauld

Sabaté

Espargaró

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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“…TTR amyloid fibrils arise from the monomeric, but not the tetrameric, configuration. Amyloidogenic TTR mutations appear to destabilize the tetrameric configuration and facilitate monomer formation [64]. In contrast, binding of thyroid hormones and their derivatives stabilizes the tetrameric form of TTR.…”

Section: Treatment Targetsmentioning

confidence: 98%

Emerging treatment approaches for the systemic amyloidoses

Dember

2005

Kidney International

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“…FAP is caused by mutations in the gene encoding transthyretin (TTR) (17,18). Many FAP mutations destabilize the native TTR tetramer, facilitating its dissociation, partial unfolding, and aggregation (17,19).…”

mentioning

confidence: 99%

Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation

Ray

Nowak²,

Brown³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

144

120

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Familial amyotrophic lateral sclerosis (FALS) is a fatal motor neuron disease that is caused by mutations in the gene encoding superoxide dismutase-type 1 (SOD1). The affected regions of the FALS brain are characterized by aggregated SOD1, and the mutations that destabilize SOD1 appear to promote its aggregation in vitro. Because dissociation of the native SOD1 dimer is required for its in vitro aggregation, we initiated an in silico screening program to find drug-like molecules that would stabilize the SOD1 dimer. A potential binding site for such molecules at the SOD1 dimer interface was identified, and its importance was validated by mutagenesis. About 1.5 million molecules from commercial databases were docked at the dimer interface. Of the 100 molecules with the highest predicted binding affinity, 15 significantly inhibited in vitro aggregation and denaturation of A4V, a FALS-linked variant of SOD1. In the presence of several of these molecules, A4V and other FALS-linked SOD1 mutants such as G93A and G85R behaved similarly to wild-type SOD1, suggesting that these compounds could be leads toward effective therapeutics against FALS.drug discovery ͉ in silico screening ͉ docking ͉ thermopeutics ͉ thermodynamics

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FAP Mutations Destabilize Transthyretin Facilitating Conformational Changes Required for Amyloid Formation

Cited by 19 publications

References 38 publications

Aggregation of the neuroblastoma-associated mutant (S120G) of the human nucleoside diphosphate kinase-A/NM23-H1 into amyloid fibrils

Aggregation of the neuroblastoma-associated mutant (S120G) of the human nucleoside diphosphate kinase-A/NM23-H1 into amyloid fibrils

Emerging treatment approaches for the systemic amyloidoses

Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation

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