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J. Biol. Chem., Vol. 281, Issue 14, 9418-9422, April 7, 2006

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ADAM12 Is a Four-leafed Clover

THE EXCISED PRODOMAIN REMAINS BOUND TO THE MATURE ENZYME^*

Ulla M. Wewer¹, Matthias Mörgelin, Peter Holck, Jonas Jacobsen, Magnus C. Lydolph, Anders H. Johnsen^¶, Marie Kveiborg, and Reidar Albrechtsen

From the Institute of Molecular Pathology, University of Copenhagen, Frederik V's vej 11, 2100 Copenhagen, Denmark, the Department of Clinical Sciences, BMC, Lund University, Tornavägen 10, SE-221 84 Lund, Sweden, and the ^¶Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, University of Copenhagen, 2100 Copenhagen, Denmark

The ADAMs (a disintegrin and metalloprotease) comprise a family of multidomain proteins with metalloprotease, cell adhesion, and signaling activities. Human ADAM12, which is implicated in diseases such as cancer, is expressed in two splice forms, the transmembrane ADAM12-L and the shorter and soluble ADAM12-S. ADAM12 is synthesized as a zymogen with the prodomain keeping the metalloprotease inactive through a cysteine-switch mechanism. Maturation and activation of the protease involves the cleavage of the prodomain in the trans-Golgi or possibly at the cell surface by a furin-peptidase. The aim of the present study was to determine the fate of the prodomain following furin cleavage. Here we demonstrate that, following cleavage of the human ADAM12-S prodomain in the trans-Golgi by a furin-peptidase, the prodomain remains non-covalently associated with the mature molecule. Accordingly, both the 68-kDa mature form of ADAM12-S and the 25-kDa prodomain could be detected using domain-specific antisera in immunoprecipitation and Western blot analyses of human serum ADAM12 and purified recombinant human ADAM12. Using electron microscopy after negative staining we have furthermore obtained the first visualization of a full-length ADAM molecule, human ADAM12-S, and report that it appears to be a compact clover composed of four globular domains, one of which is the prodomain. Finally, our data demonstrate that the presence of the metalloprotease domain appears to be sufficient for the prodomain to remain associated with the mature ADAM12-S. Thus, we conclude that the prodomain of human ADAM12-S is an integral domain of the mature molecule and as such might have specific biological functions in the extracellular space.

Received for publication, December 21, 2005 , and in revised form, January 31, 2006.

^* This work was supported by grants from the Danish Cancer Society, the Danish Medical Research Council, and the Dansk Kræftforskningsfond, Neye, Lundbeck, Novo Nordisk, Velux, Munksholm, Friis, and Haensch Foundations. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 45-3532-6056; Fax: 45-3532-6081; E-mail: ullaw{at}pai.ku.dk.

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