title: Ferric ions inhibit proteolytic processing of progastrin.
abstract: The gastrointestinal hormone gastrin is generated from an 80 amino acid precursor (progastrin) by cleavage after dibasic residues by prohormone convertase 1. Phosphorylation of Ser(75) has previously been suggested, on the basis of indirect evidence, to inhibit cleavage of progastrin after Arg(73)Arg(74). 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 progastrin(55-80) for ferric ions, and the rate of cleavage by prohormone convertase 1, were not affected by phosphorylation of Ser(75). In contrast, in the presence of ferric ions the rate of cleavage of both progastrin(55-80) and phosphoSer(75)progastrin(55-80) 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.
authors.affiliation: The University of Melbourne, Department of Surgery, Austin Health, Heidelberg, 3084 Victoria, Australia.
authors.forename: Gianni
authors.initials: G
authors.lastname: Bramante
authors.forename: Oneel
authors.initials: O
authors.lastname: Patel
authors.forename: Arthur
authors.initials: A
authors.lastname: Shulkes
authors.forename: Graham S
authors.initials: GS
authors.lastname: Baldwin
mesh_terms: D000595:Amino Acid Sequence; D005755:Gastrins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D045664:Proprotein Convertase 1 / Q000378:metabolism; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
chemical_list: D005755:Gastrins; D011498:Protein Precursors; D010768:Phosphoserine; C013706:big gastrin; D012694:Serine; D007501:Iron; D014357:Trypsin; D045664:Proprotein Convertase 1