Plasticity of Amyloid Fibrils

Abstract

In experiments designed to characterize the basis of amyloid fibril stability through mutational analysis of the Aβ(1-40) molecule, fibrils exhibit consistent, significant structural malleability. In these results, and in other properties, amyloid fibrils appear to more resemble plastic materials generated from synthetic polymers than they do globular proteins. Thus, like synthetic polymers and plastics, amyloid fibrils exhibit both polymorphism, the ability of one polypeptide to form aggregates of different morphologies, and isomorphism, the ability of different polypeptides to grow into a fibrillar amyloid morphology. This view links amyloid with the prehistorical and 20 th Century use of proteins as starting materials to make films, fibers, and plastics, and with the classic protein fiber stretching experiments of the Astbury group. Viewing amyloid from the point of view of the polymer chemist may shed new light on issues such as the role of protofibrils in the mechanism of amyloid formation, the biological potency of fibrils, and the prospects for discovering inhibitors of amyloid fibril formation.Amyloid fibrils and amyloid-related protein aggregates are associated with a variety of human diseases of the brain and the periphery (1,2). The past decade has seen significant progress in our understanding of this alternatively folded protein structural motif. At the same time, much remains to be learned about details of amyloid structure, the basis of fibrillogenesis, and the nature of protein aggregate cytotoxicity.Experimental work over the past 10-15 years has revealed the amyloid folding motif to be a nearly ubiquitous alternative folded state that can be accessed by many polypeptides. For globular proteins, the route to amyloid often depends on initial weakening of the native state; in addition, for all proteins and peptides, amyloid formation also depends on packing constraints within the fibril (3). Reviewed here are mutagenesis experiments designed to focus on understanding the nature of the packing constraints within the amyloid motif.The results show that amyloid fibrils, like globular proteins, achieve stability through a mixture of hydrophobic and electrostatic forces. At the same time, the response of amyloid to mutagenesis differs in a number of ways from the typical response of globular proteins, and suggests instead a significant resemblance to synthetic polymers and plastics. A relationship to synthetic polymers provides a comfortable context for a number important features of amyloid fibrils, including: (a) the ability of so many naturally occurring proteins to form amyloid, (b) the observation of multiple conformational states of amyloid fibrils from the same polypeptide sequence, (c) the role of protofibrillar intermediates on the amyloid assembly pathway, (d) the biological potency of amyloid prions, and (e) the mixed success of attempts to identify inhibitors of the amyloid formation process. † Supported by NIH grant R01 AG018416 (RW). ‡ Present address:

On the lack of polymorphism in Aβ‐peptide aggregates derived from patient brains

“…2,[19][20][21] Polymorphism implies different arrangements of b-sheets in amyloid fibrils and therefore differences in the network of hydrogen bonds that determines the structural characteristics and properties of amyloids. 2,22 Previous computational studies have demonstrated that because of differences in the contribution of hydrophobic interaction and hydrogen bonds 16 oligomers with two-fold are more stable than such with the three-fold symmetry.…”

Two-dimensional infrared spectra of isotopically diluted amyloid fibrils from Aβ40

“…1A). There is significant plasticity in the structural features of amyloid fibrils (8), and alternative models have been proposed (9).…”

Comparison of Alzheimer Aβ(1–40) and Aβ(1–42) amyloid fibrils reveals similar protofilament structures

“…These analyses have provided a wealth of information about specific structural details of the peptide in the fibril, for example dihedral torsional angles, protection factors or distances between specific atoms. Atomic models for A␤ peptides and their assembly in different amyloid fibrils have been constructed based on such data (6, 8-10) but these models have not been confirmed by more direct 3D imaging methods.A hallmark of A␤ amyloid fibrils is their substantial polymorphism (11)(12)(13)(14). We have recently shown by transmission electron cryomicroscopy (cryo-EM) and 3D reconstruction that A␤(1-40) fibrils form a range of morphologies with almost continuously altering structural properties (13).…”

“…A hallmark of A␤ amyloid fibrils is their substantial polymorphism (11)(12)(13)(14). We have recently shown by transmission electron cryomicroscopy (cryo-EM) and 3D reconstruction that A␤(1-40) fibrils form a range of morphologies with almost continuously altering structural properties (13).…”