Oral Presentation 10th Australian Peptide Conference 2013

Understanding the structure/activity relationships of the iron regulatory peptide hepcidin (#39)

Richard J Clark 1 , Johannes W.A Van Dijk 1 , Chia Chia Tan 2 , Gloria C Preza 3 , Eileen Fung 3 , Elizabeta Nemeth 3 , Tomas Ganz 3 , David J Craik 2
  1. School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  3. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
The peptide hormone hepcidin is a key homeostatic regulator of iron metabolism and involved in pathological regulation of iron in response to infection, inflammation, hypoxia and anaemia. It acts by binding to the iron exporter ferroportin, causing it to be internalised and degraded; however, little is known about the structure/activity relationships of the interaction of hepcidin with ferroportin. Here we show that there are key residues within the N-terminal region of hepcidin that influence its interaction with ferroportin, and we explore the structure/function relationships at these positions. We found that the interaction is primarily hydrophobic with critical stereochemical requirements at positions 4 and 6. In addition, a series of hepcidin mutants in which disulfide bonds had been replaced with diselenide bonds showed no change in biological activity compared to native hepcidin. We have also explored the effect of backbone cyclisation on stability and biological activity. The results provide mechanistic insight into the interaction between hepcidin and ferroportin and identify important constraints for the development of hepcidin congeners for the treatment of hereditary iron overload.