Biochem. J. (1999) 343
(371–375) (Printed in Great Britain)
Membrane-anchored metalloprotease MDC9 has an a-secretase activity responsible for processing the amyloid precursor protein
Hisashi KOIKE*†, Shigeo TOMIOKA†, Hiroyuki SORIMACHI†, Takaomi C. SAIDO‡, Kei MARUYAMA§, Akira OKUYAMA¦, Atsuko FUJISAWA-SEHARA¶, Shigeo OHNO**, Koichi SUZUKI† and Shoichi ISHIURA*1
*Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan, †Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan, ‡Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan, §Department of Molecular Biology, Tokyo Metropolitan Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan, ¦Banyu Tsukuba Research Institute, Tsukuba Techno-park Oho, Okubo 3, Tshukuba-shi, Ibaraki 300-2611, Japan, ¶Department of Cell Biology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan, and **Department of Molecular Biology, Yokohama City University School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan
MDC9, also known as meltrin g, 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 a-secretory site in MDC9-expressing cells. When an artificial a-secretory site mutant was also co-expressed with MDC9 and treated with phorbol ester, APP secreted by a-secretase was not increased in conditional medium. Inhibition of MDC9 by a hydroxamate-based metalloprotease inhibitor, SI-27, enhanced b-secretase cleavage. These results suggest that MDC9 has an a-secretase-like activity and is activated by phorbol ester.
Abbreviations used: A
b, amyloid
b; ADAM, a disintegrin and metalloprotease; APP, amyloid precursor protein; MMP, matrix metalloproteinase; sAPP, secreted form of APP.
1 To whom correspondence should be addressed (e-mail cishiura@komaba.ecc.u-tokyo.ac.jp).
Key words: Alzheimer's disease, hydroxamate.
Received 7 December 1998//5 July 1999; accepted 9 August 1999
The Biochemical Society, London © 1999
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