Cryo-EM structure of a transthyretin-derived amyloid fibril from a patient with hereditary ATTR amyloidosis

Matthias Schmidt,Jonas Engler,Per Westermark,Marcus Fändrich,Sebastian Wiese,Günter Fritz,Shubhangi Agarwal,Volkan Adak,Martin Zacharias

doi:10.1038/s41467-019-13038-z

Abstract

ATTR amyloidosis is one of the worldwide most abundant forms of systemic amyloidosis. The disease is caused by the misfolding of transthyretin protein and the formation of amyloid deposits at different sites within the body. Here, we present a 2.97 Å cryo electron microscopy structure of a fibril purified from the tissue of a patient with hereditary Val30Met ATTR amyloidosis. The fibril consists of a single protofilament that is formed from an N-terminal and a C-terminal fragment of transthyretin. Our structure provides insights into the mechanism of misfolding and implies the formation of an early fibril state from unfolded transthyretin molecules, which upon proteolysis converts into mature ATTR amyloid fibrils.

Highlights

ATTR amyloidosis is one of the worldwide most abundant forms of systemic amyloidosis
Systemic amyloidosis of the ATTR type is a potentially lifethreatening disease that is caused by the misfolding of the circulating blood protein transthyretin (TTR)[1,2]
ATTR amyloid fibrils were isolated from the hearts of two patients with type A Val30Met ATTR amyloid fibrils

Summary

Introduction

ATTR amyloidosis is one of the worldwide most abundant forms of systemic amyloidosis. The disease is caused by the misfolding of transthyretin protein and the formation of amyloid deposits at different sites within the body. 1234567890():,; Systemic amyloidosis of the ATTR (amyloid fibril protein derived from transthyretin) type is a potentially lifethreatening disease that is caused by the misfolding of the circulating blood protein transthyretin (TTR)[1,2]. The disease arises from the extracellular deposition of amyloid fibrils in multiple organs. It represents one of the most abundant forms of systemic amyloidosis in many Western countries but shows geographical hotspots in Portugal, Brazil, Sweden and Japan[3,4]. Type A fibrils are relatively short and haphazardly arranged in ultrathin sections of amyloidotic tissue They consist of a mixture of N-terminally truncated and full-length TTR11,12. In the absence of detail structural information on ATTR amyloid fibrils, it is difficult to further resolve these issues and to develop a fundamental molecular understanding of the mechanism of disease

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Conclusion