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|Title:||Ferric ions are essential for the biological activity of the hormone glycine-extended gastrin.|
|Authors:||Pannequin, Julie;Barnham, Kevin J;Hollande, Frederic;Shulkes, Arthur;Norton, Raymond S;Baldwin, Graham S|
|Affiliation:||University of Melbourne Department of Surgery, Austin Campus, ARMC, Heidelberg, Victoria 3084, Australia.|
|Citation:||The Journal of Biological Chemistry 2002; 277(50): 48602-9|
|Abstract:||Amidated and nonamidated gastrins elicit different biological effects via distinct receptors in different tissues. Amidated gastrin 17 stimulates gastric acid secretion and the development of gastric carcinoids, whereas glycine-extended gastrin 17 stimulates proliferation of the colonic mucosa and the development of colorectal cancers. Because glycine-extended gastrin 17 binds two ferric ions with high affinity (Baldwin, G. S., Curtain, C. C., and Sawyer, W. H. (2001) Biochemistry 40, 10741-10746), we have investigated the identity of the iron ligands and the role of ferric ions in biological activity. Here we report the solution structure of glycine-extended gastrin 17, determined by NMR spectroscopy. The spectral changes observed upon the addition of ferric ions revealed that Glu(7) acted as a ligand at the first ferric binding site, and that Glu(8) and Glu(9) acted as ligands at the second ferric ion binding site. Fluorescence quenching experiments confirmed that a GglyE7A mutant bound only one ferric ion. The inability of this mutant to stimulate proliferation or migration in the IMGE-5 cell line and the observation that the iron chelator desferrioxamine selectively blocked the effects of glycine-extended gastrin 17 indicated that binding of a ferric ion to Glu(7) was essential for biological activity. This is the first report of an essential role for a metal ion in the action of a hormone.|
|Internal ID Number:||12270941|
|Subjects:||Amino Acid Sequence|
Molecular Sequence Data
Nuclear Magnetic Resonance, Biomolecular
Sequence Homology, Amino Acid
|Appears in Collections:||Journal articles|
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