Alzheimer's A beta Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu2+ Coordination

作者：Drew Simon C^*; Masters Colin L; Barnham Kevin J

来源：PLos One, 2010, 5(12): e15875.

DOI：10.1371/journal.pone.0015875

Background: The amyloid-beta (A beta) peptide is the primary component of the extracellular senile plaques characteristic of Alzheimer's disease (AD). The metals hypothesis implicates redox-active copper ions in the pathogenesis of AD and the Cu2+ coordination of various A beta peptides has been widely studied. A number of disease-associated modifications involving the first 3 residues are known, including isomerisation, mutation, truncation and cyclisation, but are yet to be characterised in detail. In particular, A beta in plaques contain a significant amount of truncated pyroglutamate species, which appear to correlate with disease progression.
Methodology/Principal Findings: We previously characterised three Cu2+/A beta 1-16 coordination modes in the physiological pH range that involve the first two residues. Based upon our finding that the carbonyl of Ala2 is a Cu2+ ligand, here we speculate on a hypothetical Cu2+-mediated intramolecular cleavage mechanism as a source of truncations beginning at residue 3. Using EPR spectroscopy and site-specific isotopic labelling, we have also examined four A beta peptides with biologically relevant N-terminal modifications, A beta 1[isoAsp]-16, A beta 1-16(A2V), A beta 3-16 and A beta 3[pE]-16. The recessive A2V mutation preserved the first coordination sphere of Cu2+/A beta, but altered the outer coordination sphere. Isomerisation of Asp1 produced a single dominant species involving a stable 5-membered Cu2+ chelate at the amino terminus. The A beta 3-16 and A beta 3[pE]-16 peptides both exhibited an equilibrium between two Cu2+ coordination modes between pH 6-9 with nominally the same first coordination sphere, but with a dramatically different pH dependence arising from differences in H-bonding interactions at the N-terminus.
Conclusions/Significance: N-terminal modifications significantly influence the Cu2+ coordination of A beta, which may be critical for alterations in aggregation propensity, redox-activity, resistance to degradation and the generation of the A beta 3-6 (x = 40/42) precursor of disease-associated A beta 3[pE]-x species.

• 出版日期2010-12-30