title: Structure-function analysis of the human ferroportin iron exporter (SLC40A1): effect of hemochromatosis type 4 disease mutations and identification of critical residues.
abstract: 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.
authors.affiliation: Inserm UMR1078, Université de Brest, SFR SnInBioS, Centre Hospitalier Régional Universitaire - Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Etablissement Français du Sang - Bretagne, Brest, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Le Gac
authors.forename: Chandran
authors.initials: C
authors.lastname: Ka
authors.forename: Rozenn
authors.initials: R
authors.lastname: Joubrel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gourlaouen
authors.forename: Pierre
authors.initials: P
authors.lastname: Lehn
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Mornon
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000172:deficiency; D002460:Cell Line; D003062:Codon; D006432:Hemochromatosis / Q000235:genetics*; D064451:Hepcidins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D003062:Codon; D064451:Hepcidins; D000098742:Ferroportin
keywords: Major Facilitator Superfamily; ferroportin; hemochromatosis; molecular modeling