A novel zinc(II) binding site modulates the function of the βa4 amyloid protein precursor of Alzheimer's disease

Abstract

Abnormalities of zinc metabolism occur in Alzheimer's disease (AD), a condition where pathological catabolism of the amyloid protein precursor (APP) causes cerebral βA4 amyloidosis. An association between zinc and APP metabolism was sought by studying the binding of 65Zn2+ to APP. 65Zn2+ bound in a rapid, saturable, and specific manner (KD = 764 nM). A novel zinc binding motif, strongly conserved between members of the APP family, was located between the cysteine-rich and negatively charged domains of the protein. Zinc increased binding of APP to heparin and has been shown to potentiate the inhibition of coagulation factor XIa by an APP isoform containing a Kunitz-type inhibitory domain (Kom..