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Case Reports
. 2019 Nov 1;10(1):5008.
doi: 10.1038/s41467-019-13038-z.

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

Matthias Schmidt  1 , Sebastian Wiese  2 , Volkan Adak  1 , Jonas Engler  1 , Shubhangi Agarwal  3 , Günter Fritz  3   4 , Per Westermark  5 , Martin Zacharias  6 , Marcus Fändrich  7
Affiliations
Case Reports

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

Matthias Schmidt et al. Nat Commun. .

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.

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Conflict of interest statement

P.W. received research support for unrelated projects and consulting fees from Pfizer and Alnylam. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Cryo-EM reconstruction of the ATTR amyloid fibril. a Cryo-EM image of the extracted fibrils. Scale bar = 200 nm. b Side view of the reconstructed 3D map. N-terminal density: cyan; C-terminal density: orange. c Cross-sectional view of the reconstructed 3D map (grey), superimposed with a molecular model of the N-terminal (cyan) and C-terminal peptide segment (orange). Terminal amino acids are indicated in the figure. The internal cavity is marked with an asterisk
Fig. 2
Fig. 2
Packing and overall fold of the fibril protein. a Top: cross-sectional view of a 5-Å thick slice of the 3D map; bottom: Cα-trace of TTR residues Pro11-Lys35 (cyan) and Gly57-Thr123 (orange). Residues Ala36-His56 are modelled in an arbitrary conformation, showing the ability of this segment to connect the N- and C-terminal segment. The blue asterisks indicate the position of two density features not captured by our model. b Packing scheme of one cross-sectional layer. c Electrostatic surface profile of one molecular layer of the fibril. d The fibril protein contains arches at residues Pro11-Lys35 (black), Lys70-Leu111 (blue) and Thr106-Thr123 (red)
Fig. 3
Fig. 3
Location of the β-strand structure, mutational variants and aggregation-prone segments. a Amino acid sequence of Val30Met TTR and other mutational variants (magenta) known to give rise to type A fibrils. Background colour coding of the sequence shows the theoretic aggregation score (see c). Above the sequence are schematic representations of the secondary structure elements of native Val30Met TTR from protein data bank (PDB) entry 3DJT and of the fibril protein (PDB entry 6SDZ, this study). Arrows: β-strands; cylinders: α-helices; dotted line: residues not seen in the crystal structure or cryo-EM structure. b Ribbon diagram of a fibril stack showing six molecular layers. Rainbow colour from N- (blue) to C-terminus (red) as in a. c Location of the highly aggregation-prone segments according to the aggregation score 0–5 as indicated in a. d Schematic view of the fibril cross-section showing the position of the mutational variants of TTR that are known to form type A fibrils
Fig. 4
Fig. 4
Comparison of the fibril protein with a natively folded TTR protomer. Pairwise arrangement of ribbon diagrams of one natively folded Val30Met TTR protomer (PDB entry 3DJT) and of the fibril protein. Both structures are correspondingly rainbow coloured from N- (blue) to C-terminus (red). Light grey segments in the native structure are disordered in the fibril
Fig. 5
Fig. 5
Comparison of amyloid fibrils from systemic amyloidosis with tau-derived fibrils. a Views of the cross-sectional layers of five fibrils from systemic AA, AL, and ATTR amyloidosis and tau-derived fibrils from Alzheimer’s, chronic traumatic encephalopathy and Pick’s disease. b Radial mass distributions of one protein stack. c Surface area of one protein stack plotted against the number of amino acids in the fibril core. A linear fit was added to guide the eye. The colour coding is kept consistent in all panels. Source data are provided as a Source Data file
Fig. 6
Fig. 6
Possible mechanism of misfolding of TTR protein. The first step is the disassembly and unfolding of the native tetramer, followed by the assembly of the polypeptide chains into an early fibril state. The last step is the proteolytic cleavage of TTR in the structurally disordered segment of residues Ala36-His56 (red) and the formation of the mature ATTR amyloid fibril. The N- and C-terminal segments of the fibril are colour coded orange and cyan, respectively
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