A NOVEL ZINC(II) BINDING-SITE MODULATES THE FUNCTION OF THE BETA-A4 AMYLOID PROTEIN-PRECURSOR OF ALZHEIMERS-DISEASE

Abnormalities of zinc metabolism occur in Alzheimer's disease (AD), a condition where pathological catabolism of the amyloid protein precursor (APP) causes cerebral betaA4 amyloidosis. An association between zinc and ApP metabolism was sought by studying the binding of Zn-65(2+) to APP. Zn-65(2+) bound in a rapid, saturable, and specific manner (K(D) = 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 ''P to heparin and has been shown to potentiate the inhibition of coagulation factor XIa by an APP isoform containing a Kunitz-type inhibitory domain (Komiyama, Y., Murakami, T., Egawa, H., Okubo, S., Yasunaga, K., and Murata, K. (1992) Thromb. Res. 66,397-408) situated near the zinc binding region. Zinc is a factor that modulates the functional properties of the substrate for betaA4 amyloidogenesis.