An N-terminal ATTR Fibril Segment Promotes Transthyretin Amyloid Nucleation and Polymorphism

ATTR amyloidosis, a condition characterized by the deposition of transthyretin (TTR) amyloid, is caused by the misfolding of the protein. The sequence of TTR plays a crucial role in the transition from fibril formation to nucleation and structural polymorphism. In this study, researchers examined two components of the pathological core: an N-terminal beta-hairpin (N-TTR) and a C-terminal fragment (C-TTR).

Both fragments can independently form beta-rich amyloid fibrils, as confirmed by electron microscopy, circular dichroism, and fluorescence spectroscopy. However, their abilities differ significantly. The N-TTR fibrils are capable of promoting full-length TTR aggregation and initiating the process, while the C-TTR aggregates do not show any templating activity.

Through cryo-electron microscopy, the researchers identified two N-TTR polymorphs that retain features of disease-derived structures. Additionally, energetic profiling indicates that N-TTR acts as a stabilizing hotspot within ex vivo structures, highlighting its role as a templating agent. These discoveries shed light on the hierarchical nature of amyloidogenic segments in TTR, demonstrating that specific regions can form fibrils independently, but only those with compatible structures can effectively seed the parent protein.

Consequently, N-TTR emerges as an autonomous amyloidogenic segment that connects local sequence propensity to TTR nucleation, templating, and fibril polymorphism.