Ferric ions inhibit proteolytic processing of progastrin

Area of Science:

• Biochemistry
• Endocrinology
• Gastroenterology

Background:

• Gastrin, a gastrointestinal hormone, is processed from progastrin by prohormone convertase 1.
• Progastrin cleavage at Arg(73)Arg(74) is potentially regulated by Ser(75) phosphorylation.
• Iron binding is crucial for gastrin's biological activity.

Purpose of the Study:

• To directly investigate the impact of iron binding and Ser(75) phosphorylation on progastrin peptide cleavage.
• To elucidate the role of iron in gastrin processing and secretion.

Main Methods:

• Synthesis of progastrin-derived peptides, including a phosphorylated version.
• Assays to determine ferric ion affinity and prohormone convertase 1 cleavage rates.
• Comparative analysis of cleavage rates with and without iron, and with/without phosphorylation.

Main Results:

• Serine phosphorylation at Ser(75) did not affect progastrin peptide affinity for ferric ions or cleavage rates.
• Ferric ion binding significantly reduced the cleavage rate of both non-phosphorylated and phosphorylated progastrin peptides.
• Phosphorylation did not alter the inhibitory effect of iron on cleavage.

Conclusions:

• Iron binding to progastrin, rather than Ser(75) phosphorylation, significantly regulates its processing by prohormone convertase 1.
• Iron-mediated regulation of progastrin processing may be vital in vivo, particularly in conditions with disturbed iron homeostasis.