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Originally published In Press as doi:10.1074/jbc.M003547200 on September 19, 2000

J. Biol. Chem., Vol. 275, Issue 50, 39213-39222, December 15, 2000
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Processing and Sorting of the Prohormone Convertase 2 Propeptide*

Laurent MullerDagger §, Angus CameronDagger , Yolanda Fortenberry, Ekaterina V. Apletalina, and Iris LindbergDagger ||

From the Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, New Orleans, Louisiana 70112

The prohormone convertases (PCs) are synthesized as zymogens whose propeptides contain several multibasic sites. In this study, we investigated the processing of the PC2 propeptide and its function in the regulation of PC2 activity. By using purified pro-PC2 and directed mutagenesis, we found that the propeptide is first cleaved at the multibasic site separating it from the catalytic domain (primary cleavage site); the intact propeptide thus generated is then sequentially processed at two internal sites. Unlike the mechanism described for furin, our mutagenesis studies show that internal cleavage of the propeptide is not required for activation of pro-PC2. In addition, we identified a point mutation in the primary cleavage site that does not prevent the folding nor the processing of the zymogen but nevertheless results in the generation of an inactive PC2 species. These data suggest that the propeptide cleavage site is directly involved in the folding of the catalytic site. By using synthetic peptides, we found that a PC2 propeptide fragment inhibits PC2 activity, and we identified the inhibitory site as the peptide sequence containing basic residues at the extreme carboxyl terminus of the primary cleavage site. Finally, our study supplies information concerning the intracellular fate of a convertase propeptide by providing evidence that the PC2 propeptide is generated and is internally processed within the secretory granules. In agreement with this localization, an internally cleaved propeptide fragment could be released by stimulated secretion.

* This work was supported in part by National Institutes of Health Grants DK49703 and DA05084.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.

Dagger Both authors contributed equally to this work.

§ Present address: INSERM U36, Collège de France, 75231 Paris, France.

Supported by National Institutes of Health Predoctoral Training Grant DK49703S2.

|| Supported by a National Institute on Drug Abuse Research Scientist Development award. To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, LSU Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112. Tel.: 504-568-4799; Fax: 504-568-6598; E-mail: ilindb@LSUHSC.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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