THE AMYLOID BETA-PROTEIN PRECURSOR AND ITS MAMMALIAN HOMOLOGS - EVIDENCE FOR A ZINC-MODULATED HEPARIN-BINDING SUPERFAMILY

The Alzheimer beta-amyloid precursor protein (APP) contains an ectodom ain zinc binding site that has been reported to modulate the heparin a ffinity and protease-inhibitory properties of the molecule. This motif , GVEFVCCP, is highly conserved in amyloid precursor-like proteins 1 a nd 2 (APLP1 and APLP2), as well as in the Drosophila and Caenorhabditi s elegans APP-like proteins (APPL and APL-1). To determine whether the function of this domain is preserved in the human APP-like proteins, the effect of zinc in modulating the elution profile of these proteins upon heparin-Sepharose chromatography was studied. Both APLP1 and APL P2 bound heparin-Sepharose and had NaCl elution profiles similar to th at of APP. As previously reported for APP, zinc increased the recovery of APLP1 and APLP2 upon heparin-Sepharose chromatography. APP, APLP1, and APLP2 all bind zinc-chelating Sepharose, indicating that the zinc binding motif may be functionally conserved in these proteins. Additi onally, APP, APLP1, and APLP2 migrate at higher molecular sizes (appro ximate to 40 kDa) on SDS-polyacrylamide gel electrophoresis than their predicted molecular sizes. We report data that compare the physicoche mical properties of APP to its novel APLP homologues and indicate that these molecules behave as a family of zinc-modulated, heparin-binding proteins.