MBE Advance Access originally published online on June 27, 2003
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Mol. Biol. Evol. 20(11):1767-1777. 2003
DOI: 10.1093/molbev/msg183
© 2003 by the Society for Molecular Biology and Evolution. ISSN: 0737-4038
Evolution of Trypsinogen Activation Peptides
* Institut National de la Santé et de la Recherche Médicale, Génétique Moléculaire et Génétique Epidémiologique, Université de Bretagne Occidentale, Etablissement Français du Sang–Bretagne, Brest, France
Department of Molecular and Cell Biology, Boston University Goldman School of Dental Medicine, Boston
Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary
Centre Hospitalier Universitaire de Melun, Service de Gastroenterologie, Melun, France
|| Centre Hospitalier Universitaire de Morvan, Brest, France
E-mail: claude.ferec{at}univ-brest.fr
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, activated the D22G mutant very poorly, and stimulated activation of the K23R mutant. 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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