Amyloid peptides and proteins in review

Abstract

Amyloids are filamentous protein deposits ranging in size from nanometres to microns and composed of aggregated peptide beta-sheets formed from parallel or anti-parallel alignments of peptide beta-strands. Amyloid-forming proteins have attracted a great deal of recent attention because of their association with over 30 diseases, notably neurodegenerative conditions like Alzheimer's, Huntington's, Parkinson's, Creutzfeldt-Jacob and prion disorders, but also systemic diseases such as amyotrophic lateral sclerosis (Lou Gehrig's disease) and type II diabetes. These diseases are all thought to involve important conformational changes in proteins, sometimes termed misfolding, that usually produce beta-sheet structures with a strong tendency to aggregate into water-insoluble fibrous polymers. Reasons for such conformational changes in vivo are still unclear. Intermediate aggregated state(s), rather than precipitated insoluble polymeric aggregates, have recently been implicated in cellular toxicity and may be the source of aberrant pathology in amyloid diseases. Numerous in vitro studies of short and medium length peptides that form amyloids have provided some clues to amyloid formation, with an alpha-helix to beta-sheet folding transition sometimes implicated as an intermediary step leading to amyloid formation. More recently, quite a few non-pathological amyloidogenic proteins have also been identified and physiological properties have been ascribed, challenging previous implications that amyloids were always disease causing. This article summarises a great deal of current knowledge on the occurrence, structure, folding pathways, chemistry and biology associated with amyloidogenic peptides and proteins and highlights some key factors that have been found to influence amyloidogenesis.

Hemin as a generic and potent protein misfolding inhibitor

“…Cross-β-sheet structure conversion is closely linked with the process of amyloid fibril formation [33,34]. The cross-β structures have either parallel or anti-parallel orientations of stacked β-sheet monomers aligned perpendicular to the fibril axis [35].…”

Benzalkonium Chloride Accelerates the Formation of the Amyloid Fibrils of Corneal Dystrophy-associated Peptides

“…The results indicated that these mutations enhanced the amyloidogenicity of the wild-type peptide (R-type), which implied an underlying mechanism of R124 mutation-linked corneal dystrophies. In addition to the intrinsic amyloidogenicity determined by the amino acid sequence, various extrinsic factors such as pH, solvents, metal ions, membranes, and surfactants affect amyloidogenicity (12,13). Moreover, the exposure of amyloidogenic regions by denaturation is essential to induce their fibrillation (14 -17).…”

Folding and Aggregation of Cu, Zn-Superoxide Dismutase

“…This diversity is likely to play a significant role in the variable disease courses for fALS patients with SOD1 mutations. Ultimately, the role of SOD1 in ALS may be similar to the roles of other globular, oligomeric proteins in misfolding diseases such as: transthyretin in familial amyloidotic polyneuropathy and senile systemic amyloidosis, lysozyme in hereditary non-neuropathic systemic amyloidosis, immunoglobulin light chain in monoclonal protein systemic amyloidosis, prion protein in Kreutzfeld Jakob, and serpins in serpinopathies (Ohnishi and Takano 2004;Harrison et al 2007). In these diseases mutations are generally destabilizing, but the extent of destabilization of monomer versus subunit interfaces varies widely.…”