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Title: Biological activity and ferric ion binding of fragments of glycine-extended gastrin.
Austin Authors: He, Hong ;Shehan, B Philip;Barnham, Kevin J;Norton, Raymond S;Shulkes, Arthur;Baldwin, Graham S
Affiliation: The University of Melbourne Department of Surgery, Austin Health, Heidelberg, Victoria 3084, Australia
Issue Date: 21-Sep-2004
Publication information: Biochemistry; 43(37): 11853-61
Abstract: Nonamidated gastrins such as progastrin and glycine-extended gastrin17 (Ggly) induce cell proliferation and migration in vitro and colonic mucosal proliferation in vivo. Our earlier NMR study defined the structure of Ggly and showed that ferric ions are essential to its biological activity, with the first binding to Glu7 and the second to Glu8 and Glu9 (Pannequin, J. et al. (2002) J. Biol. Chem. 277, 48602-48609). The aims of this study were to define the minimum biologically active fragment of Ggly and to determine whether ferric ions were also required for its activity. Cell-proliferation studies with Ggly fragments containing the five glutamate residues showed that the nonapeptide LE(5)AYG, the octapeptide LE(5)AY, and the heptapeptides E(5)AY and LE(5)A were fully active and that their activity was dependent on the presence of ferric ions. The activity of the hexapeptides LE(5) and E(5)A and the pentapeptide E(5) was reduced and independent of the presence of iron. The stoichiometry of ferric ion binding to LE(5)AYG, LE(5)AY, and E(5)AY, determined by absorption spectroscopy, was 2 mol/mol. NMR spectroscopy showed that the nonapeptide LE(5)AYG and shorter fragments had no defined structure and that the iron-binding sites differed from those in Ggly. We conclude that, in contrast to amidated gastrins where the C-terminal tetrapeptide is the minimum bioactive fragment, the shortest fully active fragments of Ggly are the heptapeptides LE(5)A and E(5)AY. These observations indicate that extensive proteolytic processing may not completely inactivate Ggly and that bioactive forms that are not detected by current radioimmunoassays may be present in tissues and/or plasma.
Gov't Doc #: 15362871
DOI: 10.1021/bi0495984
Type: Journal Article
Subjects: Amino Acid Sequence
Cell Division.physiology
Cell Line
Cell Movement.physiology
Gastric Mucosa.cytology
Mice, Transgenic
Molecular Sequence Data
Nuclear Magnetic Resonance, Biomolecular
Peptide Fragments.metabolism
Protein Binding
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