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Two distinct aggregation pathways in transthyretin misfolding and amyloid formation.


ABSTRACT: Misfolding and amyloid formation of transthyretin (TTR) is implicated in numerous degenerative diseases. TTR misfolding is greatly accelerated under acidic conditions, and thus most of the mechanistic studies of TTR amyloid formation have been conducted at various acidic pH values (2-5). In this study, we report the effect of pH on TTR misfolding pathways and amyloid structures. Our combined solution and solid-state NMR studies revealed that TTR amyloid formation can proceed via at least two distinct misfolding pathways depending on the acidic conditions. Under mildly acidic conditions (pH?4.4), tetrameric native TTR appears to dissociate to monomers that maintain most of the native-like ?-sheet structures. The amyloidogenic protein undergoes a conformational transition to largely unfolded states at more acidic conditions (pH?2.4), leading to amyloid with distinct molecular structures. Aggregation kinetics is also highly dependent upon the acidic conditions. TTR quickly forms moderately ordered amyloids at pH?4.4, while the aggregation kinetics is dramatically reduced at a lower pH of 2.4. The effect of the pathogenic mutations on aggregation kinetics is also markedly different under the two different acidic conditions. Pathogenic TTR variants (V30M and L55P) aggregate more aggressively than WT TTR at pH?4.4. In contrast, the single-point mutations do not affect the aggregation kinetics at the more acidic condition of pH?2.4. Given that the pathogenic mutations lead to more aggressive forms of TTR amyloidoses, the mildly acidic condition might be more suitable for mechanistic studies of TTR misfolding and aggregation.

SUBMITTER: Dasari AKR 

PROVIDER: S-EPMC6339575 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Two distinct aggregation pathways in transthyretin misfolding and amyloid formation.

Dasari Anvesh K R AKR   Hung Ivan I   Gan Zhehong Z   Lim Kwang Hun KH  

Biochimica et biophysica acta. Proteins and proteomics 20181024 3


Misfolding and amyloid formation of transthyretin (TTR) is implicated in numerous degenerative diseases. TTR misfolding is greatly accelerated under acidic conditions, and thus most of the mechanistic studies of TTR amyloid formation have been conducted at various acidic pH values (2-5). In this study, we report the effect of pH on TTR misfolding pathways and amyloid structures. Our combined solution and solid-state NMR studies revealed that TTR amyloid formation can proceed via at least two dis  ...[more]

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