Contract grant sponsors: Etablissement Français du Sang, Universite de Bretagne Occidentale, Inserm, CNRS; Centre Hospitalier Regional Universitaire de Brest (PHRC 2009).
Structure-Function Analysis of the Human Ferroportin Iron Exporter (SLC40A1): Effect of Hemochromatosis Type 4 Disease Mutations and Identification of Critical Residues
Article first published online: 10 SEP 2013
© 2013 WILEY PERIODICALS, INC.
Volume 34, Issue 10, pages 1371–1380, October 2013
How to Cite
Le Gac, G., Ka, C., Joubrel, R., Gourlaouen, I., Lehn, P., Mornon, J.-P., Férec, C. and Callebaut, I. (2013), Structure-Function Analysis of the Human Ferroportin Iron Exporter (SLC40A1): Effect of Hemochromatosis Type 4 Disease Mutations and Identification of Critical Residues. Hum. Mutat., 34: 1371–1380. doi: 10.1002/humu.22369
Communicated by Mauno Vihinen
- Issue published online: 18 SEP 2013
- Article first published online: 10 SEP 2013
- Accepted manuscript online: 19 JUN 2013 06:19AM EST
- Manuscript Accepted: 6 JUN 2013
- Manuscript Received: 29 MAR 2013
- Etablissement Français du Sang, Universite de Bretagne Occidentale, Inserm, CNRS; Centre Hospitalier Regional Universitaire de Brest. Grant Number: PHRC 2009
- molecular modeling;
- Major Facilitator Superfamily;
Ferroportin (SLC40A1) is the only known iron exporter in mammals and is considered a key coordinator of the iron balance between intracellular and systemic iron homeostasis. However, the structural organization of ferroportin in the lipid bilayer remains controversial and very little is known about the mechanism underlying iron egress. In the present study, we have developed an approach based on comparative modeling, which has led to the construction of a model of the three-dimensional (3D) structure of ferroportin by homology to the crystal structure of a Major Facilitator Superfamily member (EmrD). This model predicts atomic details for the organization of ferroportin transmembrane helices and is in agreement with our current understanding of the ferroportin function and its interaction with hepcidin. Using in vitro experiments, we demonstrate that this model can be used to identify novel critical amino acids. In particular, we show that the tryptophan residue 42 (p.Trp42), which is localized within the extracellular end of the ferroportin pore, is likely involved in both the iron export function and in the mechanism of inhibition by hepcidin. Thus, our 3D model provides a new perspective for understanding the molecular basis of ferroportin functions and dysfunctions.