Ferric ions inhibit proteolytic processing of progastrin

The gastrointestinal hormone gastrin is generated from an 80 amino acid precursor (progastrin) by cleavage after dibasic residues by prohormone convertase 1. Phosphorylation of Ser75 has previously been suggested, on the basis of indirect evidence, to inhibit cleavage of progastrin after Arg73Arg74. Gastrins bind two ferric ions with high affinity, and iron binding is essential for the biological activity of non-amidated gastrins in vitro and in vivo. This study directly investigated the effect of iron binding and of serine phosphorylation on the cleavage of synthetic progastrin-derived peptides. The affinity of synthetic progastrin55–80 for ferric ions, and the rate of cleavage by prohormone convertase 1, were not affected by phosphorylation of Ser75. In contrast, in the presence of ferric ions the rate of cleavage of both progastrin55–80 and phosphoSer75progastrin55–80 by prohormone convertase 1 was significantly reduced. Hence iron binding to progastrin may regulate processing and secretion in vivo, and regulation may be particularly important in diseases with altered iron homeostasis.

Research highlights
► In contrast to previous reports based on indirect evidence, serine phosphorylation does not influence cleavage of progastrin by prohormone convertase 1.
► Binding of ferric ions by progastrin significantly delays cleavage by prohormone convertase 1.
► Metal ion binding may represent a novel regulatory mechanism for prohormone processing.