Molecular-level examination of Cu2+ binding structure for amyloid fibrils of 40-residue Alzheimer's ? by solid-state NMR spectroscopy.
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ABSTRACT: Cu(2+) binding to Alzheimer's ? (A?) peptides in amyloid fibrils has attracted broad attention, as it was shown that Cu ion concentration elevates in Alzheimer's senile plaque and such association of A? with Cu(2+) triggers the production of neurotoxic reactive oxygen species (ROS) such as H(2)O(2). However, detailed binding sites and binding structures of Cu(2+) to A? are still largely unknown for A? fibrils or other aggregates of A?. In this work, we examined molecular details of Cu(2+) binding to amyloid fibrils by detecting paramagnetic signal quenching in 1D and 2D high-resolution (13)C solid-state NMR (SSNMR) for full-length 40-residue A?(1-40). Selective quenching observed in (13)C SSNMR of Cu(2+)-bound A?(1-40) suggested that primary Cu(2+) binding sites in A?(1-40) fibrils include N(?) in His-13 and His-14 and carboxyl groups in Val-40 as well as in Glu sidechains (Glu-3, Glu-11, and/or Glu-22). (13)C chemical shift analysis demonstrated no major structural changes upon Cu(2+) binding in the hydrophobic core regions (residues 18-25 and 30-36). Although the ROS production via oxidization of Met-35 in the presence of Cu(2+) has been long suspected, our SSNMR analysis of (13)C(?)H(3)-S- in M35 showed little changes after Cu(2+) binding, excluding the possibility of Met-35 oxidization by Cu(2+) alone. Preliminary molecular dynamics (MD) simulations on Cu(2+)-A? complex in amyloid fibrils confirmed binding sites suggested by the SSNMR results and the stabilities of such bindings. The MD simulations also indicate the coexistence of a variety of Cu(2+)-binding modes unique in A? fibril, which are realized by both intra- and intermolecular contacts and highly concentrated coordination sites due to the in-register parallel ?-sheet arrangements.
SUBMITTER: Parthasarathy S
PROVIDER: S-EPMC3074258 | biostudies-literature | 2011 Mar
REPOSITORIES: biostudies-literature
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