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 (Abeta) are believed to play a role in Alzheimer's disease (AD), in particular due to production of reactive oxygen species and Cu(2+)-mediated oligomerization. To understand the role that copper might play in these processes, a detailed knowledge of the fundamental Cu(2+)/Abeta interactions is essential. To date, the identity of the oxygen ligand(s) involved in Cu(2+) coordination by Abeta has remained unclear. Here, we have used site-specific (13)C and (15)N 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 Cu(2+) coordination modes of Abeta. Polarization of the carbonyl moiety by Cu(2+) could promote amide hydrolysis and cleavage of the peptide bond between Ala2 and Glu3, providing a chemical mechanism for the generation of truncated Abeta 3-40/42 species found in AD plaques.