Murine Aβ4-x Peptides Retain High-Affinity Redox-Silent Cu2+ Binding

β-Amyloid peptides N-truncated at Phe4 (Aβ4-x) contain an amino-terminal Cu- and Ni-binding (ATCUN) motif that can form high-affinity, redox-silent Cu2+ complexes. Human Aβ4-40/42 is present in the brains of individuals with and without Alzheimer's disease, and soluble Aβ4-9 can be generated by neprilysin proteolysis of Aβ1-40/42 in vitro. These observations led to the proposal that Aβ4-x may be functional Cu2+-binding peptides. Because amyloid precursor protein is constitutively expressed in mammals, this study assessed whether murine Aβ4-x peptides retain the properties of the human analogues. Cu2+ coordination, binding affinity, and redox activity were compared for murine and human Aβ4-9 and Aβ4-16. The murine peptides formed Cu2+ complexes with spectroscopic parameters closely matching those of the human peptides. Competitive binding against glycylglycylhistidine gave conditional Cu2+ dissociation constants at pH 7.4 of 3-4 fM for murine Aβ4-x and 8-10 fM for human Aβ4-x. All Cu(Aβ4-x) complexes were redox-silent in an aminophenyl fluorescein/ascorbate assay. Thus, murine Aβ4-x has the chemical capacity required for a Cu2+-binding role if generated in vivo. However, because endogenous murine Aβ4-x has not been detected in wild-type mice, the present findings challenge the support for a broadly conserved physiological role for Aβ4-x in mammalian Cu2+ handling.