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Cu K-edge X-ray absorption spectroscopy reveals differential copper coordination within amyloid-? oligomers compared to amyloid-? monomers.

ABSTRACT: The fatal neurological disorder Alzheimer's disease has been linked to soluble neurotoxic oligomers of amyloid-? (A?) peptides. Herein we demonstrate that Cu(1+) ligated within A?(42) oligomers (A? sequence: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA) possesses a highly dioxygen sensitive tetrahedral coordination geometry. The biological implications of these findings are discussed.

SUBMITTER: Shearer J

PROVIDER: S-EPMC3082590 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Cu K-edge X-ray absorption spectroscopy reveals differential copper coordination within amyloid-β oligomers compared to amyloid-β monomers.

Shearer Jason J Callan Paige E PE Tran Thao T Szalai Veronika A VA

Chemical communications (Cambridge, England) 20101108 48

The fatal neurological disorder Alzheimer's disease has been linked to soluble neurotoxic oligomers of amyloid-β (Aβ) peptides. Herein we demonstrate that Cu(1+) ligated within Aβ(42) oligomers (Aβ sequence: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA) possesses a highly dioxygen sensitive tetrahedral coordination geometry. The biological implications of these findings are discussed. ...[more]

PMID: 21060917

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Project description:A series of mononuclear six-coordinate tungsten compounds spanning formal oxidation states from 0 to +VI, largely in a ligand environment of inert chloride and/or phosphine, was interrogated by tungsten L-edge X-ray absorption spectroscopy. The L-edge spectra of this compound set, comprised of [W(0)(PMe3)6], [W(II)Cl2(PMePh2)4], [W(III)Cl2(dppe)2][PF6] (dppe = 1,2-bis(diphenylphosphino)ethane), [W(IV)Cl4(PMePh2)2], [W(V)(NPh)Cl3(PMe3)2], and [W(VI)Cl6], correlate with formal oxidation state and have usefulness as references for the interpretation of the L-edge spectra of tungsten compounds with redox-active ligands and ambiguous electronic structure descriptions. The utility of these spectra arises from the combined correlation of the estimated branching ratio of the L3,2-edges and the L1 rising-edge energy with metal Zeff, thereby permitting an assessment of effective metal oxidation state. An application of these reference spectra is illustrated by their use as backdrop for the L-edge X-ray absorption spectra of [W(IV)(mdt)2(CO)2] and [W(IV)(mdt)2(CN)2](2-) (mdt(2-) = 1,2-dimethylethene-1,2-dithiolate), which shows that both compounds are effectively W(IV) species even though the mdt ligands exist at different redox levels in the two compounds. Use of metal L-edge XAS to assess a compound of uncertain formulation requires: (1) Placement of that data within the context of spectra offered by unambiguous calibrant compounds, preferably with the same coordination number and similar metal ligand distances. Such spectra assist in defining upper and/or lower limits for metal Zeff in the species of interest. (2) Evaluation of that data in conjunction with information from other physical methods, especially ligand K-edge XAS. (3) Increased care in interpretation if strong ?-acceptor ligands, particularly CO, or ?-donor ligands are present. The electron-withdrawing/donating nature of these ligand types, combined with relatively short metal-ligand distances, exaggerate the difference between formal oxidation state and metal Zeff or, as in the case of [W(IV)(mdt)2(CO)2], exert the subtle effect of modulating the redox level of other ligands in the coordination sphere.

Project description:Beta-2-microglobulin (beta2m) deposits as amyloid fibrils in the musculoskeletal system of patients undergoing long-term dialysis treatment as a result of kidney failure. Previous work has shown that Cu(II) binding causes beta2m to organize into nativelike dimers and tetramers that precede amyloid formation. Cu(II) is then released from higher-order oligomers before mature Cu(II)-free amyloid fibrils are formed. While some of the Cu(II)-induced structural changes that enable beta2m self-assembly are starting to be revealed, the details of how the Cu(II) binding site evolves from the monomer to the dimers and tetramers are not known. Here, we report results from three mass spectrometry (MS)-based methods that provide insight into the changing Cu-beta2m interactions. We find that monomeric beta2m binds Cu(II) via the N-terminal amine, the amide of Gln2, His31, and Asp59. In the dimer and tetramer, Asp59 is no longer bound to Cu(II), but the other residues still comprise a well-defined albeit weaker binding site that is better able to release Cu(II). Consistent with this is the observation that a fraction of the tetrameric species no longer binds Cu(II) at this weakened binding site, which agrees with a previous report that suggested the tetramer as the first Cu(II)-free oligomer. Our results also provide some insight into structural changes caused by Cu(II) binding that facilitate oligomer formation. Specifically, binding by Asp59 in the monomer requires significant movement of this residue, and we propose that this repositioning is important for establishing a pair of dimer-stabilizing salt bridges between this residue and Lys19. We also find evidence that Cu(II) binding in the N-terminal region of the monomer repels Arg3, which likely allows this residue to form a pair of dimer-stabilizing salt bridges with Glu16. Overall, our measurements suggest that the previously proposed conformational switch caused by Cu(II) binding includes not only a cis-trans isomerization at Pro32 but also the repositioning of residues that are critical for the formation of new electrostatic interactions.

Dataset Information

Cu K-edge X-ray absorption spectroscopy reveals differential copper coordination within amyloid-? oligomers compared to amyloid-? monomers.

Publications

Cu K-edge X-ray absorption spectroscopy reveals differential copper coordination within amyloid-β oligomers compared to amyloid-β monomers.

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