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J. Biol. Chem., Vol. 281, Issue 17, 11879-11886, April 28, 2006

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Chymotrypsin C (Caldecrin) Stimulates Autoactivation of Human Cationic Trypsinogen^*

From the Department of Molecular and Cell Biology, Boston University, Goldman School of Dental Medicine, Boston, Massachusetts 02118

Trypsin-mediated trypsinogen activation (autoactivation) facilitates digestive zymogen activation in the duodenum but may precipitate pancreatitis if it occurs prematurely in the pancreas. Autoactivation of human cationic trypsinogen is inhibited by a repulsive electrostatic interaction between the unique Asp²¹⁸ on the surface of cationic trypsin and the conserved tetra-aspartate (Asp^19-22) motif in the trypsinogen activation peptide (Nemoda, Z., and Sahin-Tóth, M. (2005) J. Biol. Chem. 280, 29645-29652). Here we describe that this interaction is regulated by chymotrypsin C (caldecrin), which can specifically cleave the Phe¹⁸-Asp¹⁹ peptide bond in the trypsinogen activation peptide and remove the N-terminal tripeptide. In contrast, chymotrypsin B, elastase 2A, or elastase 3A (proteinase E) are ineffective. Autoactivation of N-terminally truncated cationic trypsinogen is stimulated 3-fold, and this effect is dependent on the presence of Asp²¹⁸. Because chymotrypsinogen C is activated by trypsin, and chymotrypsin C stimulates trypsinogen activation, these reactions establish a positive feedback mechanism in the digestive enzyme cascade of humans. Furthermore, inappropriate activation of chymotrypsinogen C in the pancreas may contribute to the development of pancreatitis. Consistent with this notion, the pancreatitis-associated mutation A16V in cationic trypsinogen increases the rate of chymotrypsin C-mediated processing of the activation peptide 4-fold and causes accelerated trypsinogen activation in vitro.

Received for publication, January 5, 2006 , and in revised form, February 27, 2006.

^* This work was supported by National Institutes of Health Grant DK058088 (to M. S.-T.). 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: 715 Albany St., Evans-433, Boston, MA 02118. Tel.: 617-414-1070; Fax: 617-414-1041; E-mail: miklos{at}bu.edu.

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