Aggregation of proteins into amyloid fibrils is driven by interactions between relatively small amyloidogenic segments. The interplay between aggregation-prone and aggregation-resistant fragments within a single polypeptide chain remains obscure. Here, we examine fibrillization behavior of two chimeric peptides, ACC1-13E8 and ACC1-13E8(L/D), in which the highly amyloidogenic fragment of insulin (ACC1-13) is extended by an octaglutamate segment composed of all-L (E8), or alternating L/D residues (E8(L/D)). As separate entities, ACC1-13 readily forms fibrils with the infrared features of parallel β-sheet while E8 forms antiparallel β-sheets with the distinct infrared characteristics. This contrasts with the profoundly aggregation-resistant E8(L/D), although L/D patterns have been hypothesized as compatible with aggregated α-sheets. ACC1-13E8 and ACC1-13E8(L/D) are found to be equally prone to fibrillization at low pH, or in the presence of Ca2+ ions. Fibrillar states of both ACC1-13E8 and ACC1-13E8(L/D) reveal the infrared features of highly ordered parallel β-sheet without evidence of β2-aggregates (ACC1-13E8) or α-sheets (ACC1-13E8(L/D)). Hence, the preferred structural pattern of ACC1-13 overrides the tendency of E8 to form antiparallel β-sheets and enforces the fibrillar order in E8(L/D). We demonstrate how the powerful amyloid stretch determines the overall amyloid structure forcing non-amyloidogenic fragments to participate in its native amyloid pattern.
Keywords: Amyloid stretch; Chimeric peptide; Homopolypeptide.
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