Characterization of the high affinity heparin binding site of the Alzheimer's disease beta A4 amyloid precursor protein (APP) and its enhancement by zinc(II)

Journal of Molecular Recognition : JMR
G MulthaupC L Masters

Abstract

The Alzheimer's disease beta A4 amyloid precursor protein (APP) has been shown to be involved in a diverse set of biological activities including regulation of cell growth, neurite outgrowth and adhesiveness. The APP and amyloid protein precursor-like proteins (APLP1 and APLP2) belong to a superfamily of proteins that are probably functionally related. In order to characterize the cell adhesion properties of APP the brain specific isoform APP695 was purified and used to assess the binding to heparin, a structural and functional analogue of the glycosaminoglycan heparan sulfate. We show that APP binds in a time dependent and saturable manner to heparin. The salt concentration of 620 mM at which APP elutes from heparin Sepharose is greater than physiological. The apparent equilibrium constant for dissociation was determined to be 300 pM for APP binding to heparin Sepharose. A high affinity heparin binding site was identified within a region conserved in rodent and human APP, APLP1 and APLP2. This binding site was located between residues 316-337 of APP695 which is within the carbohydrate domain of APP. We also demonstrate an interaction between this heparin binding site and the zinc(II) binding site which is conserved in all memb...Continue Reading

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