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

• Published in: Nature communications 2019-11, Vol.10 (1), p.5008-9, Article 5008
• Main Authors: Schmidt, Matthias, Wiese, Sebastian, Adak, Volkan, Engler, Jonas, Agarwal, Shubhangi, Fritz, Günter, Westermark, Per, Zacharias, Martin, Fändrich, Marcus
• Format: Article
• Language: English
• Subjects: 101/28; 101/58; 631/45; 631/45/460; 631/45/470; 631/535/1258/1259; Aged; Amino acids; Amyloid; Amyloid - chemistry; Amyloid - metabolism; Amyloid Neuropathies, Familial - metabolism; Amyloid Neuropathies, Familial - pathology; Amyloidosis; Cryoelectron Microscopy; Electron microscopy; Fibrils; Humanities and Social Sciences; Humans; Male; Mass spectrometry; Models, Molecular; Morphology; multidisciplinary; Patients; Prealbumin - chemistry; Prealbumin - metabolism; Prealbumin - ultrastructure; Protein folding; Protein Unfolding; Proteins; Proteolysis; Proteostasis Deficiencies - metabolism; Science; Science (multidisciplinary); Scientific imaging; Transthyretin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13038-z

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. Systemic amyloidosis of the ATTR is one of the most abundant forms of systemic amyloidosis and caused by misfolding of the circulating blood protein transthyretin (TTR). Here the authors present the cryo-EM structure of patient-derived Val30Met ATTR amyloid fibrils which reveals that the protofilament consists of an N-terminal and a C-terminal TTR fragment and discuss implications for the mechanism of misfolding.