Local structure and global patterning of Cu2+ binding in fibrillar amyloid-? [A?(1-40)] protein.

ABSTRACT: The amyloid-? (A?) protein forms fibrils and higher-order plaque aggegrates in Alzheimer's disease (AD) brain. The copper ion, Cu(2+), is found at high concentrations in plaques, but its role in AD etiology is unclear. We use high-resolution pulsed electron paramagnetic resonance spectroscopy to characterize the coordination structure of Cu(2+) in the fibrillar form of full-length A?(1-40). The results reveal a bis-cis-histidine (His) equatorial Cu(2+) coordination geometry and participation of all three N-terminal His residues in Cu(2+) binding. A model is proposed in which Cu(2+)-His6/His13 and Cu(2+)-His6/His14 sites alternate along the fibril axis on opposite sides of the ?-sheet fibril structure. The local intra-?-strand coordination structure is not conducive to Cu(2+)/Cu(+) redox-linked coordination changes, and the global arrangement of Cu sites precludes facile multielectron and bridged-metal site reactivity. This indicates that the fibrillar form of A? suppresses Cu redox cycling and reactive oxygen species production. The configuration suggests application of Cu(2+)-A? fibrils as an amyloid architecture for switchable electron charge/spin coupling and redox reactivity.

SUBMITTER: Gunderson WA 

PROVIDER: S-EPMC3722434 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature