Engineering Metal Ion Coordination to Regulate Amyloid Fibril Assembly And Toxicity

Journal Article · Tue Jun 02 04:00:00 EDT 2009 · Proc. Nat. Acad. Sci. 104:13313,2007

OSTI ID:953978

Dong, J; Canfield, J M; Mehta, A K; Shokes, J E; Tian, B; Childers, W S; Simmons, J A; Mao, Z; Scott, R A; Warncke, K; Lynn, D G

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 Zn{sup 2+} to modulate the assembly kinetics and morphology of congeners of the amyloid {beta} peptide (A{beta}) associated with Alzheimer's disease. We now reveal a correlation among A{beta}-Cu{sup 2+} coordination, peptide self-assembly, and neuronal viability. By using the central segment of A{beta}, HHQKLVFFA or A{beta}(13-21), which contains residues H13 and H14 implicated in A{beta}-metal ion binding, we show that Cu{sup 2+} forms complexes with A{beta}(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-A{beta}(13-21)H14A, alters metal coordination, allowing Cu{sup 2+} to accelerate assembly into neurotoxic fibrils. These results establish that the N-terminal region of A{beta} can access different metal-ion-coordination environments and that different complexes can lead to profound changes in A{beta} self-assembly kinetics, morphology, and toxicity. Related metal-ion coordination may be critical to the etiology of other neurodegenerative diseases.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 953978
• Report Number(s): SLAC-REPRINT-2009-414
• Journal Information: Proc. Nat. Acad. Sci. 104:13313,2007, Journal Name: Proc. Nat. Acad. Sci. 104:13313,2007 Journal Issue: 33 Vol. 104; ISSN 0027-8424; ISSN PNASA6
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
99 GENERAL AND MISCELLANEOUS
ACETYLATION
COMPLEXES
CORRELATIONS
DISEASES
ETIOLOGY
HUMAN POPULATIONS
IONS
KINETICS
METALS
MORPHOLOGY
MUTANTS
Other
OTHER
PEPTIDES
PROTEINS
RESIDUES
TOXICITY
VIABILITY