Synchrotron X-ray studies suggest that the core of the transthyretin amyloid fibril is a continuous β-sheet helix

Abstract

This work suggests that amyloid fibrils have a novel molecular structure consisting of beta sheets extended in regular helical twists along the length of the fibre. This implies that the polypeptide chains in the fibres are hydrogen-bonded together along the entire length of the fibres, thereby accounting for their great stability. The proposed structure of the FAP fibril requires a TTR building block that is structurally different from the native tetramer. This is likely to be either a monomer or dimer with reorganized or truncated beta sheets, suggesting that amyloid formation may require significant structural change in precursor proteins.

Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulations

“…To test the idea that strands C and D must be displaced from the TTR monomer b-sandwich for amyloid formation to occur, [12][13][14][15][16][17] we have also inspected the variation of SASA for the side-chains belonging to residues in strands A and B, against that of the side-chains of all other residues in the TTR monomer (Fig. 4).…”

“…We have previously published a molecular model of a TTR protofilament 17 based on experimental constraints obtained by EPR and NMR. 15,16 To build a model having the continuous extended cross-b structure characteristic of amyloid, 12 full displacement of strands C and D from the TTR b-sandwich was required to expose a new interface formed by strands A and B, and allow monomer to monomer docking. 17 The positioning of strands C and D and exposure of strands A and B were followed by analysis of the variation of SASA along the MD simulation trajectories.…”

“…1) from its native position is believed to be essential in order to expose a new interface comprised by strands A and B, necessary for monomer assembly into aggregates. [12][13][14] Site-directed spin labeling combined with electron paramagnetic resonance (EPR) 15 and hydrogen/deuterium (H/D) exchange studies by nuclear magnetic resonance (NMR) spectroscopy have supported this hypothesis 16 and, recently, a computational model of an amyloid protofilament of TTR was proposed 17 where proper subunit-subunit docking was only achieved if the D-strand-loop-C-strand segment was fully displaced from the b-sandwich core of the TTR subunit.…”

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

“…Fibrils of amyloidogenic proteins formed in vitro exhibit strikingly similar morphologies despite a lack of similarity in their sequence, structure and function 4,[6][7][8][9] . They are invariably long, straight and unbranched, and consist of two or more smaller fibrils, called protofilaments (and sometimes protofibrils) which are themselves long ribbons of layered crossed β-sheets propagating along the fibril axis [10][11][12][13][14][15] .…”

Protein folding: Then and now

“…From a protein folding standpoint, the inherent properties of the polypeptide chain that allow proteins with little or no sequence or structural similarity to misfold and assemble into similar high-order structures are of vital interest. Studies of aggregate structure reveal defined characteristics such as extensive hydrogen bond networks perpendicular to the fiber axis, called a cross-β conformation [217], and an α to β transition known to occur during the oligomerization of amyloid-forming proteins with significant helical content. Evidence for domain swapping as an early step in the aggregation process has been reported for several proteins [218][219][220].…”