Current Understanding of the Structure, Stability and Dynamic Properties of Amyloid Fibrils

Abstract

Amyloid fibrils are supramolecular protein assemblies represented by a cross-β structure and fibrous morphology, whose structural architecture has been previously investigated. While amyloid fibrils are basically a main-chain-dominated structure consisting of a backbone of hydrogen bonds, side-chain interactions also play an important role in determining their detailed structures and physicochemical properties. In amyloid fibrils comprising short peptide segments, a steric zipper where a pair of β-sheets with side chains interdigitate tightly is found as a fundamental motif. In amyloid fibrils comprising longer polypeptides, each polypeptide chain folds into a planar structure composed of several β-strands linked by turns or loops, and the steric zippers are formed locally to stabilize the structure. Multiple segments capable of forming steric zippers are contained within a single protein molecule in many cases, and polymorphism appears as a result of the diverse regions and counterparts of the steric zippers. Furthermore, the β-solenoid structure, where the polypeptide chain folds in a solenoid shape with side chains packed inside, is recognized as another important amyloid motif. While side-chain interactions are primarily achieved by non-polar residues in disease-related amyloid fibrils, the participation of hydrophilic and charged residues is prominent in functional amyloids, which often leads to spatiotemporally controlled fibrillation, high reversibility, and the formation of labile amyloids with kinked backbone topology. Achieving precise control of the side-chain interactions within amyloid structures will open up a new horizon for designing useful amyloid-based nanomaterials.

Identification of a Steric Zipper Motif in the Amyloidogenic Core of Human Cystatin C and Its Use for the Design of Self-Assembling Peptides

“…The recorded fiber diffraction images provided further evidence that the designed peptides form amyloid fibrils. The presence of the characteristic meridional and equatorial reflections and the absence of buffer rings are consistent with a classic diffraction pattern of an amyloid peptide fibril [ 1 , 45 , 49 , 50 , 51 , 52 ].…”

Pathway Dependence of the Formation and Development of Prefibrillar Aggregates in Insulin B Chain

“…Furthermore, the identified variety in evolution of prefibrillar aggregates has provided insights into amyloid polymorphism. Diverse amyloid structures formed from the same protein or polypeptide have recently attracted attention since they have been proposed to be involved in different pathologies [35]. The present study has suggested that different patterns of prefibrillar aggregation accompany polymorphic pathways.…”

Structural biology of ex vivo mammalian prions

“…This steric zipper involves the tight interdigitation of the sidechains of alternating residues ( blue ), which are homologous in the hamster and mouse PrP sequences. Steric zippers have been observed in the spines of multiple amyloid fibrils ( 78 , 79 , 80 ).…”