Aβ40-lactam(D23/K28) models a conformation highly favorable for nucleation of amyloid

Abstract

Recent solid-state NMR data (1) demonstrate that Aβ1-40 adopts a conformation in amyloid fibrils with two in-register, parallel β-sheets, connected by a bend structure encompassing residues D 23VGSNKG29, with a close contact between the side chains of Asp23 and Lys28. We hypothesized that forming this bend structure might be rate-limiting in fibril formation, as indicated by the lag period typically observed in the kinetics of Aβ1-40 fibrillogenesis. We synthesized Aβ1-40-Lactam(D23/K28), a congener Aβ1-40 peptide that contains a lactam bridge between the side chains of Asp23 and Lys28. Aβ1-40-Lactam-(D23/K28) forms fibrils similar to those formed by Aβ1-40. The kinetics of fibrillogenesis, however, occur without the typical lag period, and at a rate ≈1000-fold greater than is seen with Aβ1-40 fibrillogenesis. The strong tendency toward self-association is also shown by size exclusion chromatography in which Aβ1-40-Lactam(D23/K28) forms oligomers even at concentrations of ≈1-5 μM. Under the same conditions, Aβ1-40 shows no detectable oligomers by size exclusion chromatography. Our data suggest that Aβ1-40-Lactam(D23/K28) could bypass an unfavorable folding step in fibrillogenesis, because the lactam linkage "preforms" a bendlike structure in the peptide. Consistent with this view Aβ1-40 growth is efficiently nucleated by Aβ1-40-Lactam(D23/K28) fibril seeds. © 2005 American Chemical Society.