Mechanisms of amyloid fibril formation by proteins

Understanding the structural heterogeneity inherent in the process of amyloid fibril formation is an important goal of protein aggregation studies. Structural heterogeneity in amyloid fibrils formed by a protein manifests itself in fibrils varying in internal structure and external appearance, and may originate from molecular level variations in the internal structure of the cross-β motif. Amyloid fibril formation commences from partially structured conformations of a protein, and in many cases, proceeds via pre-fibrillar aggregates (spherical oligomers and/or protofibrils). It now appears that structural heterogeneity is prevalent in the partially structured conformations as well as in the pre-fibrillar aggregates of proteins. Amyloid fibril formation may therefore potentially commence from many precursor states, and amyloid fibril polymorphism might be the consequence of the utilization of distinct nucleation and elongation mechanisms. This review examines the current understanding of the structural heterogeneity seen in amyloid fibril formation reactions, and describes how an understanding of the initial and intermediate stages of amyloid fibril formation reactions can provide an insight into the structural heterogeneity seen in mature fibrils.