title: Chymotrypsin C (caldecrin) stimulates autoactivation of human cationic trypsinogen.
abstract: 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 (Asp19-22) 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 approximately 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.
authors.affiliation: Department of Molecular and Cell Biology, Boston University, Goldman School of Dental Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Nemoda
authors.forename: Miklós
authors.initials: M
authors.lastname: Sahin-Tóth
mesh_terms: D002412:Cations / Q000737:chemistry*; D002478:Cells, Cultured; D002918:Chymotrypsin / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D007668:Kidney / Q000378:metabolism; D010189:Pancreatic Juice / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D014357:Trypsin / Q000494:pharmacology; D014362:Trypsinogen / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D002412:Cations; D010446:Peptide Fragments; D014362:Trypsinogen; D002918:Chymotrypsin; C117569:chymotrypsin C; D014357:Trypsin