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A Functional Role for Aβ in Metal Homeostasis? N‐Truncation and High‐Affinity Copper Binding
Author(s) -
Mital Mariusz,
Wezynfeld Nina E.,
Frączyk Tomasz,
Wiloch Magdalena Z.,
Wawrzyniak Urszula E.,
Bonna Arkadiusz,
Tumpach Carolin,
Barnham Kevin J.,
Haigh Cathryn L.,
Bal Wojciech,
Drew Simon C.
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201502644
Subject(s) - gene isoform , homeostasis , peptide , chemistry , copper , extracellular , biochemistry , metal , biology , endocrinology , organic chemistry , gene
Accumulation of the β‐amyloid (Aβ) peptide in extracellular senile plaques rich in copper and zinc is a defining pathological feature of Alzheimer′s disease (AD). The Aβ1– x ( x =16/28/40/42) peptides have been the primary focus of Cu II binding studies for more than 15 years; however, the N‐truncated Aβ4–42 peptide is a major Aβ isoform detected in both healthy and diseased brains, and it contains a novel N‐terminal FRH sequence. Proteins with His at the third position are known to bind Cu II avidly, with conditional log K values at pH 7.4 in the range of 11.0–14.6, which is much higher than that determined for Aβ1– x peptides. By using Aβ4–16 as a model, it was demonstrated that its FRH sequence stoichiometrically binds Cu II with a conditional K d value of 3×10 −14 M at pH 7.4, and that both Aβ4–16 and Aβ4–42 possess negligible redox activity. Combined with the predominance of Aβ4–42 in the brain, our results suggest a physiological role for this isoform in metal homeostasis within the central nervous system.