The amyloid beta-protein precursor and its mammalian homologues. Evidence for a zinc-modulated heparin-binding superfamily.
The Alzheimer beta-amyloid precursor protein (APP) contains an ectodomain zinc binding site that has been reported to modulate the heparin affinity and protease-inhibitory properties of the molecule. This motif, GVEFVCCP, is highly conserved in amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2), as well as in the Drosophila and Caenorhabditis 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 APLP2 bound heparin-Sepharose and had NaCl elution profiles similar to that 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. Additionally, APP, APLP1, and APLP2 migrate at higher molecular sizes (approximately 40 kDa) on SDS-polyacrylamide gel electrophoresis than their predicted molecular sizes. We report data that compare the physicochemical properties of APP to its novel APLP homologues and indicate that these molecules behave as a family of zinc-modulated, heparin-binding proteins.
Bush
A I
AI
Laboratory of Genetics and Aging, Massachusetts General Hospital, Harvard Medical School, Boston 02129.
Pettingell
W H
WH
de Paradis
M
M
Tanzi
R E
RE
Wasco
W
W
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins; D002845:Chromatography; D017124:Conserved Sequence; D004330:Drosophila; D029721:Drosophila Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D015801:Helminth Proteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D012685:Sepharose / Q000031:analogs & derivatives / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015032:Zinc / Q000378:metabolism*
C084891:APL-1 protein, C elegans; D016564:Amyloid beta-Protein Precursor; C066839:Appl protein, Drosophila; D029742:Caenorhabditis elegans Proteins; D029721:Drosophila Proteins; D015801:Helminth Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C037405:heparin-sepharose; D012685:Sepharose; D015032:Zinc