Structural changes of region 1-16 of the Alzheimer disease amyloid β-peptide upon zinc binding and in vitro aging

Amyloid deposits within the cerebral tissue constitute a characteristic lesion associated with Alzheimer disease. They mainly consist of the amyloid peptide A beta and display an abnormal content in Zn2+ ions, together with many truncated, isomerized, and racemized forms of A beta. The region 1-16 of A beta can be considered the minimal zinc-binding domain and contains two aspartates subject to protein aging. The influence of zinc binding and protein aging related modifications on the conformation of this region of A beta is of importance given the potentiality of this domain to constitute a therapeutic target, especially for immunization approaches. In this study, we determined from NMR data the solution structure of the A beta-(1-16)-Zn2+ complex in aqueous solution at pH 6.5. The residues His(6), His(13), and His(14) and the Glu(11) carboxylate were identified as ligands that tetrahedrally coordinate the Zn(II) cation. In vitro aging experiments on A beta-(1-16) led to the formation of truncated and isomerized species. The major isomer generated, A beta-(1-16)-L-isoAsp(7), displayed a local conformational change in the His(6)-Ser(8) region but kept a zinc binding propensity via a coordination mode involving L-iso-Asp(7). These results are discussed here with regard to A beta fibrillogenesis and the potentiality of the region 1-16 of A beta to be used as a therapeutic target.