?-amyloid model core peptides: Effects of hydrophobes and disulfides.

ABSTRACT: The mechanism by which a disordered peptide nucleates and forms amyloid is incompletely understood. A central domain of ?-amyloid (A?21-30) has been proposed to have intrinsic structural propensities that guide the limited formation of structure in the process of fibrillization. In order to test this hypothesis, we examine several internal fragments of A?, and variants of these either cyclized or with an N-terminal Cys. While A?21-30 and variants were always monomeric and unstructured (circular dichroism (CD) and nuclear magnetic resonance spectroscopy (NMRS)), we found that the addition of flanking hydrophobic residues in A?16-34 led to formation of typical amyloid fibrils. NMR showed no long-range nuclear overhauser effect (nOes) in A?21-30, A?16-34, or their variants, however. Serial ¹ H-¹⁵ N-heteronuclear single quantum coherence spectroscopy, ¹ H-¹ H nuclear overhauser effect spectroscopy, and ¹ H-¹ H total correlational spectroscopy spectra were used to follow aggregation of A?16-34 and Cys-A?16-34 at a site-specific level. The addition of an N-terminal Cys residue (in Cys-A?16-34) increased the rate of fibrillization which was attributable to disulfide bond formation. We propose a scheme comparing the aggregation pathways for A?16-34 and Cys-A?16-34, according to which Cys-A?16-34 dimerizes, which accelerates fibril formation. In this context, cysteine residues form a focal point that guides fibrillization, a role which, in native peptides, can be assumed by heterogeneous nucleators of aggregation.

SUBMITTER: Hawk LML 

PROVIDER: S-EPMC6954707 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature