Applications of Biophysical Methods to Studies of Amyloid Aggregation
Many devastating neurodegenerative diseases, like Parkinson’s and amyotrophic lateral sclerosis (ALS), are associated with pathological depositions composed of proteins in aggregated form, also known as amyloids. Our studies of these pathological depositions were based on the hypothesis that amyloid formation is driven by the local association of specific segments responsible for nucleation and growth of fibril-like aggregates. Using protein structure-based techniques, we were able to identify the segments that form the spine of the amyloid fibril. The structures of these fibril forming segments, solved by x-ray diffraction, revealed characteristic ‘steric zipper’ motifs with pairs of elongated b-sheets locked together by tightly interacting side-chains. The 3D structure of these segments carries a wealth of information, which is amenable to advanced structural computing. These findings provide a constructive mechanism for designing aggregation inhibitors using the intrinsic structural characteristics of different types of amyloids.