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.

Benzalkonium Chloride Accelerates the Formation of the Amyloid Fibrils of Corneal Dystrophy-associated Peptides

“…In addition, because many amyloidogenic sequences are buried or have a non-amyloidogenic conformation, denaturation has been suggested to make these proteins amyloidogenic. Several methods have been proposed to predict the amyloidogenic or aggregative propensities of proteins and peptides, such as TANGO (40), Zyggregator (41), AGGRESCAN (42), PASTA (43), and 3D profiling (44). A recent approach to predicting the amyloidogenicity of proteins with 3D profiling has coined the term "amylome", and proposes that practically all human proteins contain an amyloidogenic sequence (16).…”

Nucleation of amyloid fibrils

“…30,32,33,[36][37][38][39][40][41][42][43][44] Experiments that investigate the physiochemical properties of the natural amino acids (such as -propensity, hydrophobicity, aromatic content and charge) have been used to substantiate phenomenological models able to predict changes in the aggregation rate upon mutation as well as to predict amino acid sequences of proteins, so-called hot spots, that are likely to belong to the fibril core. [45][46][47][48][49][50] Although both the experimental studies and the theoretical models show that the kinetic parameters of aggregation depend strongly on the specificity of the amino acid sequence of the protein, it may be expected that this specificity is a particular expression of a common fibril nucleation/growth mechanism which could be treated in the framework of existing general theories of nucleation and growth of new phases.…”

Identifying the amylome, proteins capable of forming amyloid-like fibrils

“…Zyggregator (12), an implementation of this algorithm, computes a Z agg score profile, taking into account both the intrinsic aggregation propensity computed from the protein sequence and the structural protection provided by the folded form of the protein. PASTA, the prediction of amyloid structure aggregation algorithm (13), uses a pairwise energy function that computes the propensity of two residues found within a beta sheet facing one another on neighboring strands. It is based on the key assumption that a universal mechanism is responsible for beta-sheet formation in globular proteins and fibrillar aggregates.…”