Structural Impact of N‐terminal Pyroglutamylate in an Amyloid‐β(3‐42) Fibril Probed by Solid‐State NMR Spectroscopy

Abstract

AbstractExtracellular amyloid‐β (Aβ) plaques, primarily formed by Aβ(1‐40) and Aβ(1‐42) fibrils, are a hallmark of Alzheimer's disease. The Aβ peptide can undergo a high variety of different post‐translational modifications including formation of a pyroglutamate (pGlu, pE) at N‐terminal Glu3 or Glu11 of truncated Aβ(3‐x) or Aβ(11‐x), respectively. Here we studied structural similarities and differences between pEAβ(3‐42) and LS‐shaped Aβ(1‐42) fibrils grown under identical conditions (pH 2) using solid‐state NMR spectroscopy. We show that the central region of pEAβ(3‐42) fibrils including the turn region around V24 is almost identical to Aβ(1‐42) showing similar β‐strands also at the N‐terminus. The missing N‐terminal residues D1‐A2 along with pE3 formation in pEAβ(3‐42) preclude a salt bridge between K28‐D1' as in Aβ(1‐42) fibrils. G37 and G38 act as highly sensitive internal sensors for the modified N‐terminus, which remains rigid over ~five pH units.