Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein.
MDC9, also known as meltrin gamma, is a membrane-anchored metalloprotease. MDC9 contains several distinct protein domains: a signal sequence followed by a prodomain and a domain showing sequence similarity to snake venom metalloproteases, a disintegrin-like domain, a cysteine-rich region, an epidermal-growth-factor-like repeat, a transmembrane domain and a cytoplasmic domain. Here we demonstrate that MDC9 expressed in COS cells is cleaved between the prodomain and the metalloprotease domain. Further, when MDC9 was co-expressed in COS cells with amyloid precursor protein (APP695) and treated with phorbol ester, APP695 was digested exclusively at the alpha-secretory site in MDC9-expressing cells. When an artificial alpha-secretory site mutant was also co-expressed with MDC9 and treated with phorbol ester, APP secreted by alpha-secretase was not increased in conditional medium. Inhibition of MDC9 by a hydroxamate-based metalloprotease inhibitor, SI-27, enhanced beta-secretase cleavage. These results suggest that MDC9 has an alpha-secretase-like activity and is activated by phorbol ester.
Koike
H
H
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.
Tomioka
S
S
Sorimachi
H
H
Saido
T C
TC
Maruyama
K
K
Okuyama
A
A
Fujisawa-Sehara
A
A
Ohno
S
S
Suzuki
K
K
Ishiura
S
S
D051722:ADAM Proteins; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D019556:COS Cells; D017077:Culture Media, Conditioned / Q000378:metabolism; D019483:Disintegrins; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020539:Sequence Analysis, Protein; D017384:Sequence Deletion; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned; D019483:Disintegrins; D008565:Membrane Proteins; D009124:Muscle Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D051722:ADAM Proteins; C098339:ADAM9 protein, human; C498316:Adam9 protein, mouse; D008666:Metalloendopeptidases; D013755:Tetradecanoylphorbol Acetate