Structural Changes of Region 1-16 of the Alzheimer Disease Amyloid β-Peptide upon Zinc Binding and in Vitro Aging

Abstract

Amyloid deposits within the cerebral tissue constitute a characteristic lesion associated with Alzheimer disease. They mainly consist of the amyloid peptide Abeta and display an abnormal content in Zn(2+) ions, together with many truncated, isomerized, and racemized forms of Abeta. The region 1-16 of Abeta 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 Abeta 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 Abeta-(1-16)-Zn(2+) 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 Abeta-(1-16) led to the formation of truncated and isomerized species. The major isomer generated, Abeta-(1-16)-l-iso-Asp(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 Abeta fibrillogenesis and the potentiality of the region 1-16 of Abeta to be used as a therapeutic target.

Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states

“…The C-terminal domain contains E22 and D23, whereas seven potential residues (D1, E3, H6, D7, E11, H13, and H14) appear in the N-terminal domain. Experimental data indicate that Zn 2þ most likely binds to the N-terminal region in the Aβ peptide, in at least three distinct ways (18,22,23).…”

“…The C-terminal domain contains E22 and D23, whereas seven potential residues (D1, E3, H6, D7, E11, H13, and H14) appear in the N-terminal domain. Experimental data indicate that Zn 2þ most likely binds to the N-terminal region in the Aβ peptide, in at least three distinct ways (18,22,23).Based on experimental data and assuming that Zn 2þ binds to the N-terminal region also in the full-length Aβ peptide, we considered the U-turn and the two β-sheets forming C-terminal region The authors declare no conflict of interest. …”

“…1 and Figs. S1-S3) by covalently linking available experiment-based coordinate sets of Aβ fragments of the N and C termini (18,22,23,29) using molecular dynamics (MD) simulations to investigate their stabilities. Using replica exchange molecular dynamics (REMD) simulations, we further explored the relative stabilities and populations of the ordered aggregates as compared to the vast conformational ensembles.…”

Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice

“…For comparison, the MAS NMR spectra of the PEGylated and palmitoylated as well as the peptide chain alone in PBS buffer were measured. Whereas the NMR linewidth observed for the peptide alone is indicative of the formation of small aggregates in aqueous solution (31), larger complexes are formed in the presence of the linker sequences (SI Fig. 5).…”

Modeling Cu2+-Aβ complexes from computational approaches

“…In this line, a new protocol that combines homology modeling techniques with quantum mechanical calculations has been designed to explore Cu 2+ complexation with Aβ. The template used for these calculations was the metal bound amyloid Zn 2+ -Aβ(1-16) (PDB code 1ZE9), 61 obtained in similar conditions to those in which copper should bind the amyloid with a three nitrogen containing coordination sphere.…”