A metalloproteinase inhibitor domain in Alzheimer amyloid protein precursor.
Extracellular deposition of amyloid beta-protein (beta-AP), or A4 protein (M(r) 4,000), is associated with Alzheimer's disease and with Down's syndrome (trisomy for chromosome 21). The large membrane-bound precursor protein (APP) of beta-AP is normally cleaved within the beta-AP region by a putative proteinase (APP secretase) to release its extracellular portion; beta-AP is produced by an alternative proteolytic processing. Here we demonstrate that APP contains a proteinase inhibitor domain for the matrix metalloproteinase gelatinase A, which is located in the C-terminal glycosylated region of the secretory forms of APP. In addition, we show that the gelatinase has an APP secretase-like activity, which hydrolyses the Lys16-Leu17 bond in the beta-AP sequence. Our results indicate that the proteinase inhibitor domain of APP and gelatinase A may be involved in the formation of beta-AP.
Miyazaki
K
K
Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Japan.
Hasegawa
M
M
Funahashi
K
K
Umeda
M
M
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D006023:Glycoproteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2