A cheat-sheet to β-sheet: Insights into structural motifs of β-Amyloid and analogue peptides

Amyloids are a family of proteins that tend to misfold into fibrillar elongated aggregates. Those aggregated species are related to various diseases, characterized by abnormal protein folding leading to tissue or systemic toxicity. Amyloid proteins accumulate to form fibrils and plaques which are implicated in the pathogenesis of Alzheimer, prion, diabetes type II and other diseases. Despite extensive research efforts devoted to plaque aggregates inhibition, there is yet no cure for this phenomenon.

Found in Alzheimer`s disease patients` brain tissue, β-Amyloid (Aβ) is a 42-amino acid long peptide that tends to fold into β-sheet structure. Through folding, the amyloid forms toxic oligomeric aggregates that elongate into fibrillar structures forming insoluble plaques, consisting of highly ordered β-sheet crystalline phase, found in perpendicular to the fibrils` long-axis.

Herein we study the stabilizing motifs of different peptide fragments derived from the full-length Aβ. Using systematic approach we have designed a set of peptide sequences, differ by their length, charge and location within the Aβ chain to define stabilizing regions. Likewise we characterize their structure, aggregation tendency and kinetics, and compared structural and morphological similarities within the different peptide sequences. At this work we illuminate the role of charge dependent stabilizing forces within the β-sheet core structure, together with the grammatic influence of amphiphility on aggregation tendency. This may provide better understanding of the driving and stabilizing forces which hold the β-sheet structure in Aβ, and enable better understanding of longer and more complex amyloids` aggregation.

References:

Arad, Elad, et al. "Membrane Determinants Affect Fibrillation Processes of β-Sheet Charged Peptides." Biomacromolecules 19.2 (2017): 307-314.‏

Bera, Santu; Arad, Elad et al. "Unravelling the role of amino acid sequence order in the assembly and function of the amyloid-β core." Chemical Communications 55.59 (2019): 8595-8598.‏