Structural Characterization of Cardiac ex vivo Transthyretin Amyloid: Insight into Transthyretin Misfolding Pathway in vivo

Anvesh K R Dasari, Ivan Hung, Brian Michael, Zhehong Gan, Jeffery W Kelly, Lawreen H Connors, Robert G Griffin, Kwang Hun Lim
Biochemistry 2020 April 27
Structural characterization of misfolded protein ag-gregates is essential to understanding molecular mechanism of protein aggregation associated with various protein misfolding disorders. Here, we re-port structural analyses of ex vivo transthyretin ag-gregates extracted from human cardiac tissue. Comparative structural analyses of in vitro and ex vivo transthyretin aggregates using various bio-physical techniques revealed that cardiac transthy-retin amyloid has similar structural features to those of in vitro transthyretin amyloid. Our solid-state NMR studies showed that in vitro amyloid contains extensive native-like -sheet structures, while other loop regions including helical structures are dis-rupted in the amyloid state. These results suggest that transthyretin undergoes a common misfolding and aggregation transition to native-like aggrega-tion-prone monomers that self-assemble into amy-loid precipitates in vitro as well as in vivo.

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