Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 33, Pages 13313-13318Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0702669104
Keywords
copper-binding; neurotoxicity s; self-assembly
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Funding
- NIA NIH HHS [AG023695, P50 AG025688, R01 AG023695] Funding Source: Medline
- NIGMS NIH HHS [R01 GM042025, GM42025] Funding Source: Medline
- NINDS NIH HHS [R01 NS048254, NS048254] Funding Source: Medline
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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 13 peptide (A beta) associated with Alzheimer's disease. We now reveal a correlation among A beta-CU2+ 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 CU2+ forms complexes with A)3(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 Cu2+ 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 neuroclegenerative diseases.
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