Covalently attached fatty acyl chains alter the aggregation behavior of an amyloidogenic peptide derived from human...

Aggregation of a polypeptide chain into highly ordered amyloid aggregates is a complex process. Various factors, both extrinsic and intrinsic to the polypeptide chain, have been shown to perturb this process, leading to a drastic change in the amyloidogenic behavior, which is reflected in the polymorphism of amyloid aggregates at various levels of self-assembly. In this paper, we have investigated the ability of covalently linked long-chain fatty acids in modulating the self-assembly of an aromatic amino acid-rich highly amyloidogenic sequence derived from the amino acid region 59-71 of human β2-microglobulin by thioflavin T (ThT) fluorescence microscopy, circular dichroism, and fluorescence spectroscopy. Our results indicate that under identical conditions of dissolution and concentration, each peptide enhances the fluorescence of ThT. However, the aggregates are morphologically distinct. For the same peptide, the aggregate morphologies are dependent on peptide concentration. Further, an optimum concentration, which varies with solution ionic strength, is required for the formation of fibrillar aggregates. We show that covalent modification of this amyloidogenic sequence, with long-chain fatty acids, affects the way the higher order amyloid structures assemble from the cross-β units, in fatty acyl chain-dependent and position-dependent manner. Our data indicate that noncovalent interactions leading to amyloid fibril formation can be modulated by the hydrophobicity of covalently attached long-chain fatty acids resulting in self-assembly of the peptide chain to form nonfibrillar aggregates.