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MBE Advance Access published online on June 27, 2003
Molecular Biology and Evolution, doi:10.1093/molbev/msg183
Molecular Biology and Evolution © Society for Molecular Biology and Evolution 2003; all rights reserved
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Accepted May 25, 2003
© 2003 Society for Molecular Biology and Evolution

Original Articles

Evolution of Trypsinogen Activation Peptides

Jian-Min Chen 1, Zoltán Kukor 2, Cedric Le Maréchal 1, Miklós Tóth 3, Laurent Tsakiris 4, Odile Raguénès 5, Claude Férec 6*, and Miklós Sahin-Tóth 2*

1 Institut National de la Santé et de la Recherche Médicale EMI 01 15, Génétique Moléculaire et Génétique Epidémiologique, Université de Bretagne Occidentale, Etablissement Français du Sang-Bretagne, Brest, France
2 Department of Molecular and Cell Biology, Boston University Goldman School of Dental Medicine, Boston, Massachusetts 02118, USA
3 Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary
4 Centre Hospitalier Universitaire de Melun, Service de Gastroenterologie, Melun, France
5 Centre Hospitalier Universitaire de Morvan, Brest, France
6 Institut National de la Santé et de la Recherche Médicale EMI 01 15, Génétique Moléculaire et Génétique Epidémiologique, Université de Bretagne Occidentale, Etablissement Français du Sang-Bretagne, Brest, France; Centre Hospitalier Universitaire de Morvan, Brest, France

* To whom correspondence should be addressed. E-mail: Claude.Ferec{at}univ-brest.fr.


  Abstract

The activation peptide of mammalian trypsinogens contains a highly conserved tetra-aspartate sequence (D19-D20-D21-D22) preceding the K23-I24 scissile peptide bond, which is hydrolyzed as the first step in the activation process. Here we examined the evolution and function of trypsinogen activation peptides through integrating functional characterization of disease-associated mutations with comparative genomic analysis. Activation properties of three chronic pancreatitis-associated activation peptide mutants (the novel D19A and the previously reported D22G and K23R) were simultaneously analyzed, for the first time, in the context of recombinant human cationic trypsinogen. A dramatic increase in autoactivation of cationic trypsinogen was observed in all three mutants, with D22G and K23R exhibiting the most marked increases. The physiological activator enteropeptidase activated the D19A mutant normally; the D22G mutant was activated very poorly, while activation of the K23R mutant was stimulated. The biochemical and structural data, taken together with a comprehensive sequence comparison, indicates that the tetra-aspartate sequence in mammalian trypsinogen activation peptides has evolved not only for optimal enteropeptidase recognition in the duodenum, but also for efficient inhibition of trypsinogen autoactivation within the pancreas. Moreover, the use of lysine instead of arginine at the P1 position of activation peptides also has an advantageous effect against trypsinogen autoactivation. Finally, fixed substitutions in the key residues of the trypsinogen activation peptide may suggest the evolution of new functions unrelated to digestion, as found in the group III trypsinogens of cold-adapted fishes.

Key Words: activation peptide, chronic pancreatitis, comparative genomic analysis, human cationic trypsinogen, molecular evolution, missense mutation


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