Alanine-2 Carbonyl is an Oxygen Ligand in Cu2+ Coordination of Alzheimer's Disease Amyloid-β Peptide - Relevance to N-Terminally Truncated Forms

Copper interactions with the beta-amyloid peptide (A beta) are believed to play a role in Alzheimer's disease (AD), in particular due to production of reactive oxygen species and Cu2+-mediated oligomerization. To understand the role that copper might play in these processes, a detailed knowledge of the fundamental Cu2+/A beta interactions is essential. To date, the identity of the oxygen ligand(s) involved in Cu2+ coordination by A beta has remained unclear. Here, we have used site-specific C-13 and N-15 labeling in conjunction with hyperfine sublevel correlation (HYSCORE) spectroscopy to unambiguously identify the carbonyl of Alanine-2 as an oxygen ligand in one of the pH-dependent Cu2+ coordination modes of A beta. Polarization of the carbonyl moiety by Cu2+ could promote amide hydrolysis and cleavage of the peptide bond between Ala2 and Glu3, providing a chemical mechanism for the generation of truncated A beta 3-40/42 species found in AD plaques.