Illustration of amyloid formation and cross-β structure. (A) Initiation of amyloid fibrillization by a partially structured conformer. An unstable amyloidogenic intermediate is formed via partial unfolding of a compact globular protein (i) or via the gain of structure by a natively unfolded polypeptide (ii). The partially ordered intermediate, which contains some β structure (depicted as a green block arrow), is stabilized by ordered self-assembly (iii) to form a nucleus enriched with β sheet. Alternatively, self-association may lead to the formation of large amorphous aggregates (iv). The amorphous aggregates may facilitate nucleation by providing a high local concentration of amyloidogenic intermediates (v). Growth of the nucleus by β-sheet extension leads to the formation of higher order oligomers (vi) and fibrils (vii). The fibril may consist of antiparallel, as well as parallel, β sheet. For details, see Rochet and Lansbury.61 (B) Amyloid cross-β structure. In amyloid fibrils, cross-β structures are stacked β sheets likely composed of flat and nontwisted β strands. This will result in a unique and flat 2-dimensional β-sheet surface, not seen in globular proteins. The inter-β strand distance of 4.7 Å that is measured using x-ray fiber diffraction is an import characteristic not seen in globular proteins.
