On the Structural Diversity and Individuality of Polymorphic Amyloid Protein Assemblies

Structural Identification of Individual Helical Amyloid Filaments by Integration of Cryo-Electron Microscopy-Derived Maps in Comparative Morphometric Atomic Force Microscopy Image Analysis

“…All amyloid fibrils share a cross-β core architecture comprised of extended stacks of β-strands that run perpendicular to the fibril axis, but which, importantly, can differ in cross-sectional folds and lateral organisation of protofilaments (Lutter et al, 2021). This diversity has been elucidated recently by the development of high-resolution structural analysis of fibrillar amyloid by cryo-electron microscopy (cryo-EM) and solid-state nuclear magnetic resonance (ssNMR) (Lutter et al, 2021;Willbold et al, 2021), as well as X-ray and electron diffraction of small amyloid peptide crystals (Sawaya et al, 2007(Sawaya et al, , 2016. Proteins with an identical sequence are able to form different core or filament arrangements (Gremer et al, 2017;Wälti et al, 2016).…”

Conformational Variability of Amyloid-β and the Morphological Diversity of Its Aggregates

“…X-ray diffraction studies have shown that amyloid fibrils share similar structural features characterized by a cross-β spine: a double β-sheet with each sheet running parallel to the fibril axis [ 53 ]. At the mesoscopic level, however, amyloid fibrils formed under the same conditions show considerable morphological diversity [ 54 , 55 ]. These molecular polymorphisms are assumed to be derived from differences in the number, relative orientation, and internal substructure of the protofilaments.…”

“…In the case of Aβ(1–40) fibrils, high-resolution cryo-EM data identified the most prevalent polymorph for fibrils in typical AD patients as I-shaped protofilament folds [ 67 ]; another cryo-EM study determined C-shaped folds in brain-derived fibrils [ 68 ] where both the N- and C-terminal ends of Aβ were folded back onto the central peptide domain. These morphological differences suggest that Aβ fibrils may adopt disease-specific molecular conformers such as prion and tau strains, depending on the differences in individual brain environments [ 50 , 55 , 69 ]. Intriguingly, significant differences have also been found in the amyloid formation kinetics and fibril morphology between microgravity-grown and ground-grown Aβ(1–40) amyloids [ 70 ].…”

Linking hIAPP misfolding and aggregation with type 2 diabetes mellitus: a structural perspective

“…Amyloid can be defined as fibrillar deposits of proteins that contain a β-sheet structure and as a result, have enhanced dye-binding capacity to Thioflavin T [ 35 ], Congo Red [ 36 ], or staining with iodine [ 37 ]. Amyloid fibrils tend to be unbranched, several micrometres in length, are usually twisted and have a ‘cross β’ three-dimensional structure being composed of β-strands arranged perpendicular to the fibril axis held together via hydrogen bonds [ 38 ].…”