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Evolution of trypsinogen activation peptides
Jian-Min Chen1, Zoltán Kukor, Cédric Le Maréchal
1Institut 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.
Molecular Biology and Evolution
|July 2, 2003
Summary
The tetra-aspartate sequence in trypsinogen activation peptides prevents premature autoactivation and aids enteropeptidase recognition. Mutations in this sequence increase autoactivation, impacting trypsinogen function.
Area of Science:
- Biochemistry
- Evolutionary Biology
- Molecular Biology
Background:
- Mammalian trypsinogen activation involves cleaving a peptide bond at K23-I24.
- A conserved tetra-aspartate sequence (D19-D22) precedes this bond in trypsinogen activation peptides.
Purpose of the Study:
- To investigate the evolutionary role and functional significance of trypsinogen activation peptides.
- To analyze disease-associated mutations within the activation peptide sequence.
Main Methods:
- Functional characterization of three chronic pancreatitis-associated mutants (D19A, D22G, K23R) in recombinant human cationic trypsinogen.
- Comparative genomic analysis of trypsinogen activation peptides.
- Biochemical and structural analysis.
Main Results:
- All three mutants (D19A, D22G, K23R) showed significantly increased trypsinogen autoactivation.
- Enteropeptidase activated D19A normally, D22G poorly, and K23R variably.
- The tetra-aspartate sequence is crucial for both enteropeptidase recognition and inhibiting autoactivation.
Conclusions:
- The tetra-aspartate sequence in trypsinogen activation peptides evolved for dual roles: enteropeptidase recognition and autoactivation inhibition.
- Lysine at the P1 position, instead of arginine, further reduces autoactivation.
- Sequence variations may indicate evolution of non-digestive functions in certain trypsinogen groups.