Structural analysis revealed a high similarity in transthyretin-derived amyloid (ATTR) fibrils isolated from different patients and regardless of TTR mutational status.

Therefore, fibrils’ morphology may not be determinant for the multitude of clinical symptoms and manifestations observed in ATTR.

“The small variations between fibrils from different patients point to a certain degree of freedom for some parts of fibril structure, but the overall arrangement of most amino acids and their interactions is kept intact,” the study’s authors wrote in Nature Communications.

Regardless of the origin, the fibrils were composed by a single fibril layer with a N- and C-terminal fragment of the ATTR peptide. The position 30, where the amino acid substitution responsible for the hereditary ATTR-associated V30M variant is located, did not show increased density on structural analysis.

Moreover, they all had a very similar spearhead-like shape in their cross-section and an almost identical N-terminal. The authors observed density spots between the N-terminal and the C-terminal region in heart-derived fibrils corresponding to an alternative histidine conformation. This could be could a patient-specific feature, although it requires further elucidation. An additional spot of unknown origin was also reported.

In contrast to the N-terminal, the analysis of the C-terminal revealed some differences, in particular, in the backbone path of fibrils from different organs (ie, heart vs eye). The differences in the backbone path might be a patient-specific feature and seem to have an effect on the height of the backbone path but not on the peptide arrangement. Furthermore, the C-terminal fragment from G57 to Y69 was also different resulting in decreased interaction surface between the C-terminal and the N-terminal region in fibrils from the eye. The structures of the C-terminal sidechains were similar.

In addition, heart-derived fibrils were found as one-filament fibrils, while eye-derived fibrils were described as are present as single protofilament fibrils, dimers of 2 protofilaments, and other polymeric fibrils with up to 5 protofilaments combined.

Steinebrei et al resolved the structure of wild-type transthyretin-derived amyloid fibrils from the heart of a patient with non-hereditary ATTR and compared it with previous observations from V30M variant-associated ATTR fibrils extracted from heart and vitreous body of the eye of different patients.

Reference

Steinebrei M, Gottwald J, Baur J, et al. Cryo-EM structure of an ATTRwt amyloid fibril from systemic non-hereditary transthyretin amyloidosis. Nat Commun. 2022;13(1):6398. doi:10.1038/s41467-022-33591-4