title: A Functional Role for Aβ in Metal Homeostasis? N-Truncation and High-Affinity Copper Binding.
abstract: 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 Kd 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.
authors.affiliation: Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010 (Australia).|Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw (Poland).
authors.forename: Mariusz
authors.initials: M
authors.lastname: Mital
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw (Poland).
authors.forename: Nina E
authors.initials: NE
authors.lastname: Wezynfeld
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw (Poland).
authors.forename: Tomasz
authors.initials: T
authors.lastname: Frączyk
authors.affiliation: Department of Microbioanalytics, Faculty of Chemistry, Warsaw University of Technology (Poland).
authors.forename: Magdalena Z
authors.initials: MZ
authors.lastname: Wiloch
authors.affiliation: Department of Microbioanalytics, Faculty of Chemistry, Warsaw University of Technology (Poland).
authors.forename: Urszula E
authors.initials: UE
authors.lastname: Wawrzyniak
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw (Poland).
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Bonna
authors.affiliation: Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010 (Australia).
authors.forename: Carolin
authors.initials: C
authors.lastname: Tumpach
authors.affiliation: Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010 (Australia).|Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, 3010 (Australia).
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Victoria, 3010 (Australia).
authors.forename: Cathryn L
authors.initials: CL
authors.lastname: Haigh
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw (Poland). wbal@ibb.waw.pl.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Bal
authors.affiliation: Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010 (Australia). sdrew@unimelb.edu.au.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Drew
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000502:physiology*; D003300:Copper / Q000378:metabolism*; D006706:Homeostasis
chemical_list: D016229:Amyloid beta-Peptides; D003300:Copper
keywords: Alzheimer's disease; amyloid; bioinorganic chemistry; copper; peptides