Two alternative processing pathways for a preprohormone: a bioactive form of secretin

Area of Science:

• Endocrinology
• Molecular Biology
• Gastroenterology

Background:

• Secretin is a gastrointestinal hormone crucial for regulating pancreatic and biliary secretion.
• The precise processing sites of the secretin precursor (preprosecretin) remain incompletely understood, particularly concerning signal peptide cleavage.
• Previous studies identified C-terminally elongated secretin variants, suggesting flexible precursor processing.

Purpose of the Study:

• To characterize an N-terminally elongated form of secretin, secretin-(-9 to 27) amide, isolated from porcine intestinal tissue.
• To elucidate the alternative processing pathways of the secretin precursor.
• To investigate the impact of N-terminal extension on secretin's bioactivity.

Main Methods:

• Isolation and characterization of secretin-(-9 to 27) amide from porcine intestinal tissue.
• Analysis of peptide structure to infer signal peptide cleavage sites.
• Comparative bioactivity assays of the isolated peptide versus native secretin on exocrine pancreatic secretion.

Main Results:

• An N-terminally extended secretin variant, secretin-(-9 to 27) amide, was successfully isolated and identified.
• The data suggest that signal peptide cleavage occurs at the C-terminal side of residue -10, differing from some predictions.
• The isolated peptide exhibited reduced bioactivity compared to native secretin, indicating the critical role of the free N-terminus.

Conclusions:

• Secretin precursor processing can occur via at least two alternative pathways: initial N-terminal or C-terminal cleavage.
• The N-terminal propeptide sequence and its subsequent removal are essential for optimal secretin receptor binding and biological function.
• This study provides new insights into the post-translational modification and functional significance of secretin.