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. 1999 Oct 15;343(Pt 2):371–375.

Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein.

H Koike 1, S Tomioka 1, H Sorimachi 1, T C Saido 1, K Maruyama 1, A Okuyama 1, A Fujisawa-Sehara 1, S Ohno 1, K Suzuki 1, S Ishiura 1
PMCID: PMC1220563  PMID: 10510302

Abstract

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.

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