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J Biol Chem, Vol. 274, Issue 19, 13427-13433, May 7, 1999

Regulation of Human ADAM 12 Protease by the Prodomain
EVIDENCE FOR A FUNCTIONAL CYSTEINE SWITCH

Frosty Loechel, Michael T. Overgaard^¶, Claus Oxvig^¶, Reidar Albrechtsen, and Ulla M. Wewer

From the  Institute of Molecular Pathology, University of Copenhagen, Copenhagen DK-2100, and the ^¶ Department of Molecular and Structural Biology, University of Aarhus, Aarhus, Denmark DK-8000

The ADAMs (a disintegrin and metalloprotease) are a family of multidomain proteins that are believed to play key roles in cell-cell and cell-matrix interactions. We have shown recently that human ADAM 12-S (meltrin ) is an active metalloprotease. It is synthesized as a zymogen, with the prodomain maintaining the protease in a latent form. We now provide evidence that the latency mechanism of ADAM 12 can be explained by the cysteine switch model, in which coordination of Zn²⁺ in the active site of the catalytic domain by a cysteine residue in the prodomain is critical for inhibition of the protease. Replacing Cys¹⁷⁹ with other amino acids results in an ADAM 12 proform that is proteolytically active, but latency can be restored by placing cysteine at other positions in the propeptide. None of the amino acids adjacent to the crucial cysteine residue is essential for blocking activity of the protease domain. In addition to its latency function, the prodomain is required for exit of ADAM 12 protease from the endoplasmic reticulum. Tissue inhibitor of metalloprotease-1, -2, and -3 were not found to block proteolytic activity of ADAM 12, hence a physiological inhibitor of ADAM 12 protease in the extracellular environment remains to be identified.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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