A Functional Role for Aβ in Metal Homeostasis? N‐Truncation and High‐Affinity Copper Binding1. Issue 36 (14th July 2015)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Angewandte Chemie international edition. Volume 54:Issue 36(2015)
• Page Start: 10460
• Page End: 10464
• Publication Date: 2015-07-14
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201502644
• Languages: English
• ISSNs: 1433-7851

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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–<italic>x</italic> (<italic>x</italic>=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 <italic>K</italic> values at pH 7.4 in the range of 11.0–14.6, which is much higher than that determined for Aβ1–<italic>x</italic> peptides. By using Aβ4–16 as a model, it was demonstrated that its FRH sequence stoichiometrically binds Cu^II with a conditional <italic>K</italic>_d value of 3×10⁻¹⁴ <sc>M</sc> 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.</p> </abstract>