Alanine-2 carbonyl is an oxygen ligand in Cu2+ coordination of Alzheimer's disease amyloid-beta 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.
Drew
Simon C
SC
Department of Pathology and Neuroproteomics Platform, National Neuroscience Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia. sdrew@unimelb.edu.au
Masters
Colin L
CL
Barnham
Kevin J
KJ
D000409:Alanine / Q000737:chemistry* / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D015394:Molecular Structure; D010100:Oxygen / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D008024:Ligands; D003300:Copper; D000409:Alanine; D010100:Oxygen