Protein aggregation: more than just fibrils

Abstract

The aggregation of misfolded proteins into amyloid fibrils, and the importance of this step for various diseases, is well known. However, it is becoming apparent that the fibril is not the only structure that aggregating proteins of widely different types may adopt. Around the isoelectric point, when the net charge is essentially zero, rather monodisperse and quasi-amorphous nanoscale particles form. These particles are found to contain limited runs of beta-sheet structure, but their overall organization is random. These nanoparticles have the potential to be useful for such applications as the slow release of drugs. The amyloid fibrils form away from the isoelectric point, but over certain ranges of, e.g., pH, the fibrils themselves do not exist freely, but form suprafibrillar aggregates termed spherulites. These consist of fibrils radiating from a central nucleus, and form by new species attaching to the ends of growing fibrils, rather than by the aggregation of pre-existing fibrils. Under the polarizing light microscope, they exhibit a Maltese cross shape due to their symmetry. The rate of aggregation is determined by factors involving (at least) protein size, concentration, presence of salt and charge. The occurrence of spherulites, which have been found in vivo as well as in vitro, appears to be generic, although the factors which determine the equilibrium between free fibril and spherulite are not as yet clear.

Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits

“…For example, if fibrils become nucleated on the surface of a preexisting fibril (38), it is possible that the seed partially orients the daughter filament. Furthermore, total internal reflection fluorescence microscopy revealed the outgrowth of amyloidlike fibrils in vitro and the formation of fibril bundles due to fibril branching reactions (39) or the formation of star-like spherulites due to a radial extension of fibrils from a seed (40,41).…”

Characterising the secondary structure changes occurring in high density systems of BLG dissolved in aqueous pH 3 buffer

“…These nanoparticles have the potential to be useful for such applications as the slow release of drugs. The amyloid fibrils form away from the isoelectric point, but over certain ranges of, e.g., pH, the fibrils themselves do not exist freely, but form suprafibrillar aggregates termed spherulites (Krebs, Devlin &, Donald, 2009;Krebs, Domike, & Donald, 2009). Consequently, there is a marked structural difference between full amyloids and b-sheet runs.…”

Nonnative Aggregation of an IgG1 Antibody in Acidic Conditions: Part 1. Unfolding, Colloidal Interactions, and Formation of High-Molecular-Weight Aggregates

“…4,24,25 Recent results for non-MAb proteins and polypeptides illustrated that different aggregate states can be formed by the same protein, depending on the solution conditions of aggregate formation. [24][25][26][27][28] Conditions that provided weakly attractive colloidal interactions correlated well with amyloid 24 and/or insoluble aggregate formation; 24,27 conversely, conditions with strongly repulsive electrostatic interactions led to nonamyloid aggregates in some cases. 24 In this context, colloidal interactions denote screened electrostatic attractions and repulsions, van der Waals and hydrophobic attractions, and steric repulsions; the combination of forces may be net attractive or repulsive, but typically is not strong enough to create highly specific "binding" sites between two proteins such as might be found for a natively dimeric or multimeric protein.…”