Structural Impact of Pyroglutamylation at Glu3 in an Amyloid-β(3-42) Fibril Probed by Solid-State NMR Spectroscopy

08 June 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Extracellular 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 core region of pEAβ(3-42) fibrils including the loop 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) lead to differences in the N-terminus due to a salt bridge rearrangement from K28-D1 in Aβ(1-42) fibrils (at pH 2) to K28-A42 in pEAβ(3-42) fibrils (at pH 2 and 6.5). G37 and G38 act as highly sensitive internal sensors for the modified N-terminus, which remains rigid over ~five pH units.


Amyloid beta-peptides
NMR spectroscopy
Neurodegenerative diseases
Alzheimer’s disease
Pyroglutamate formation

Supplementary materials

Supporting Informnation
Material and Methods, Additional Data


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