Structural Impact of N-terminal Pyroglutamate in an Amyloid-ß(3-42) Fibril Probed by Solid-State NMR Spectroscopy.

ABSTRACT

Extracellular amyloid-ß (Aß) plaques, primarily formed by Aß(1-40) and Aß(1-42) fibrils, are a hallmark of Alzheimer's disease. The Aß 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 Aß(3-x) or Aß(11-x), respectively. Here we studied structural similarities and differences between pEAß(3-42) and LS-shaped Aß(1-42) fibrils grown under identical conditions (pH 2) using solid-state NMR spectroscopy. We show that the central region of pEAß(3-42) fibrils including the turn region around V24 is almost identical to Aß(1-42) showing similar ß-strands also at the N-terminus. The missing N-terminal residues D1-A2 along with pE3 formation in pEAß(3-42) preclude a salt bridge between K28-D1' as in Aß(1-42) fibrils. G37 and G38 act as highly sensitive internal sensors for the modified N-terminus, which remains rigid over ~five pH units.