Insight into the Structure of Amyloid Fibrils from the Analysis of Globular Proteins

Abstract

The conversion from soluble states into cross-β fibrillar aggregates is a property shared by many different proteins and peptides and was hence conjectured to be a generic feature of polypeptide chains. Increasing evidence is now accumulating that such fibrillar assemblies are generally characterized by a parallel in-register alignment of β-strands contributed by distinct protein molecules. Here we assume a universal mechanism is responsible for β-structure formation and deduce sequence-specific interaction energies between pairs of protein fragments from a statistical analysis of the native folds of globular proteins. The derived fragment–fragment interaction was implemented within a novel algorithm, prediction of amyloid structure aggregation (PASTA), to investigate the role of sequence heterogeneity in driving specific aggregation into ordered self-propagating cross-β structures. The algorithm predicts that the parallel in-register arrangement of sequence portions that participate in the fibril cross-β core is favoured in most cases. However, the antiparallel arrangement is correctly discriminated when present in fibrils formed by short peptides. The predictions of the most aggregation-prone portions of initially unfolded polypeptide chains are also in excellent agreement with available experimental observations. These results corroborate the recent hypothesis that the amyloid structure is stabilised by the same physicochemical determinants as those operating in folded proteins. They also suggest that side chain–side chain interaction across neighbouring β-strands is a key determinant of amyloid fibril formation and of their self-propagating ability. In many fatal neurodegenerative diseases, including Alzheimer, Parkinson, and spongiform encephalopathies, proteins aggregate into specific fibrous structures to form insoluble plaques known as amyloid. The amyloid structure may also play a nonaberrant role in different organisms. Many globular proteins, folding to their biologically functional native structures in vivo, can be induced to aggregate into amyloid-like fibrils under suitable conditions in vitro. One hallmark of amyloid structure is a specific supramolecular architecture called cross-beta structure, held together by hydrogen bonds extending repeatedly along the fibril axis, but intermolecular interactions are yet unknown at the amino-acid level except for very few cases. In this study, the authors present an algorithm, called prediction of amyloid structure aggregation (PASTA), to computationally predict which portions of a given protein or peptide sequence forming amyloid fibrils are stabilizing the corresponding cross-beta structure and the specific intermolecular pattern of hydrogen-bonded amino acids. PASTA is based on the assumption that the same amino acid–specific interactions stabilizing hydrogen bond patterns in native structures of globular proteins are also employed by nature in amyloid structure. The successful comparison of the authors' prediction with available experimental data supports the existence of a unique framework to describe protein folding and aggregation.