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Originally published In Press as doi:10.1074/jbc.M210564200 on January 17, 2003

J. Biol. Chem., Vol. 278, Issue 12, 10458-10464, March 21, 2003
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Sequential Autolytic Processing Activates the Zymogen of Arg-gingipain*

Jowita MikolajczykDagger , Kelly M. BoatrightDagger , Henning R. Stennicke§, Tamim Nazif, Jan Potempa||, Matthew Bogyo, and Guy S. SalvesenDagger **

From Dagger  The Burnham Institute, La Jolla, California 92037, the § Department of Protein Design, Novo Nordisk, DK-2880 Bagsvaerd, Denmark, the  Department of Biochemistry and Biophysics, University of California, San Francisco, California 94043, and the || Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602 and the Faculty of Biotechnology, Department of Microbiology, Jagiellonian University, Krakow 30-060, Poland

Most proteases are synthesized as inactive precursors to protect the synthetic machinery of the cell and allow timing of activation. The mechanisms used to render latency are varied but tend to be conserved within protease families. Proteases belonging to the caspase family have a unique mechanism mediated by transitions of two surface loops, and on the basis of conservation of mechanism one would expect this to be preserved by caspase relatives. We have been able to express the full-length precursor of the Arg-specific caspase relative from the bacterium Porphyromonas gingivalis, Arg-gingipain-B, and we show that it contains N- and C-terminal extensions that render a low amount of latency, meaning that the zymogen is substantially active. Three sequential autolytic processing steps at the N and C terminus are required for full activity, and the N-propeptide may serve as an intramolecular chaperone rather than an inhibitory peptide. Each step in activation requires the previous step, and an affinity probe reveals that incremental activity enhancements are achieved in a stepwise manner.

* This work was supported by National Institutes of Health Grant CA69381 (to G. S. S.), California Breast Cancer Research Program Fellowship 8GB-0137 (to K. M. B.), and National Institutes of Health Grant DE009761 and Committee of Scientific Research, Poland Grant KBN-6 P04A 047 17 (to J. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: The Burnham Inst., 10901 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3114; Fax: 858-713-6274; E-mail: gsalvesen@burnham.org.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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