Engineering metal ion coordination to regulate amyloid fibril assembly and toxicity

*Departments of Chemistry and Biology, Center for the Analysis of Supramolecular Self-Assemblies, and
^†Department of Physics, Emory University, Atlanta, GA 30322;
^‡Department of Chemistry and Center for Metalloenzyme Studies, University of Georgia, Athens, GA 30602; and
^§Departments of Pharmacology and Neurology, Emory University School of Medicine, Atlanta, GA 30322

Edited by Harry B. Gray, California Institute of Technology, Pasadena, CA, and approved June 26, 2007 (received for review March 21, 2007)

Abstract

Protein and peptide assembly into amyloid has been implicated in functions that range from beneficial epigenetic controls to pathological etiologies. However, the exact structures of the assemblies that regulate biological activity remain poorly defined. We have previously used Zn²⁺ to modulate the assembly kinetics and morphology of congeners of the amyloid β peptide (Aβ) associated with Alzheimer's disease. We now reveal a correlation among Aβ-Cu²⁺ coordination, peptide self-assembly, and neuronal viability. By using the central segment of Aβ, HHQKLVFFA or Aβ(13–21), which contains residues H13 and H14 implicated in Aβ-metal ion binding, we show that Cu²⁺ forms complexes with Aβ(13–21) and its K16A mutant and that the complexes, which do not self-assemble into fibrils, have structures similar to those found for the human prion protein, PrP. N-terminal acetylation and H14A substitution, Ac-Aβ(13–21)H14A, alters metal coordination, allowing Cu²⁺ to accelerate assembly into neurotoxic fibrils. These results establish that the N-terminal region of Aβ can access different metal-ion-coordination environments and that different complexes can lead to profound changes in Aβ self-assembly kinetics, morphology, and toxicity. Related metal-ion coordination may be critical to the etiology of other neurodegenerative diseases.

Footnotes

^¶To whom correspondence should be addressed. E-mail: david.lynn{at}emory.edu
Author contributions: J.D., A.K.M., W.S.C., J.A.S., Z.M., R.A.S., K.W., and D.G.L. designed research; J.D., J.M.C., J.E.S., B.T., W.S.C., J.A.S., and K.W. performed research; J.D., J.M.C., A.K.M., J.E.S., B.T., W.S.C., J.A.S., Z.M., R.A.S., K.W., and D.G.L. analyzed data; and J.D., A.K.M., W.S.C., J.A.S., Z.M., K.W., and D.G.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0702669104/DC1.
Abbreviations:

Aβ(13–21)K16A,

HHQALVFFA-NH2;

Ac-Aβ(13–21)H14A,

CH3CO-HAQKLVFFA-NH2;

ESEEM,

electron spin echo envelope modulation;

shfc,

superhyperfine coupling.