title: A novel zinc(II) binding site modulates the function of the beta A4 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 beta A4 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 (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 beta A4 amyloidogenesis.
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: A I
authors.initials: AI
authors.lastname: Bush
authors.forename: G
authors.initials: G
authors.lastname: Multhaup
authors.forename: R D
authors.initials: RD
authors.lastname: Moir
authors.forename: T G
authors.initials: TG
authors.lastname: Williamson
authors.forename: D H
authors.initials: DH
authors.lastname: Small
authors.forename: B
authors.initials: B
authors.lastname: Rumble
authors.forename: P
authors.initials: P
authors.lastname: Pollwein
authors.forename: K
authors.initials: K
authors.lastname: Beyreuther
authors.forename: C L
authors.initials: CL
authors.lastname: Masters
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001665:Binding Sites; D006801:Humans; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D015032:Zinc / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D015032:Zinc