Structural basis for transthyretin amyloid formation in vitreous body of the eye

Amyloid transthyretin (ATTR) amyloidosis is characterized by the abnormal accumulation of ATTR fibrils in multiple organs. However, the structure of ATTR fibrils from the eye is poorly understood. Here, we used cryo-EM to structurally characterize vitreous body ATTR fibrils. These structures were distinct from previously characterized heart fibrils, even though both have the same mutation and type A pathology. Differences were observed at several structural levels: in both the number and arrangement of protofilaments, and the conformation of the protein fibril in each layer of protofilaments. Thus, our results show that ATTR protein structure and its assembly into protofilaments in the type A fibrils can vary between patients carrying the same mutation. By analyzing and matching the interfaces between the amino acids in the ATTR fibril with those in the natively folded TTR, we are able to propose a mechanism for the structural conversion of TTR into a fibrillar form. Systemic ATTR amyloidosis causes the abnormal accumulation of ATTR fibrils formed from the human plasma protein transthyretin (TTR) in multiple organs including the eye. Here, the authors present a 3.2 angstrom cryo-EM structure of an ATTR fibril isolated from the vitreous body of an ATTR patient's eye and discuss the mechanism for the structural conversion of TTR into a fibrillar form.

Automated summary

The study used cryo-EM to analyze the structure of vitreous body ATTR fibrils from an ATTR patient's eye, revealing differences from previously studied heart fibrils with the same mutation, indicating variations in ATTR protein structure and assembly in type A fibrils among patients with the same mutation. By analyzing amino acid interfaces, a mechanism for the structural conversion of TTR into fibrillar form was proposed.