Structure-function analysis of the human ferroportin iron exporter (SLC40A1): effect of hemochromatosis type 4 disease mutations and identification of critical residues

Hum Mutat. 2013 Oct;34(10):1371-80. doi: 10.1002/humu.22369. Epub 2013 Sep 10.

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.

Keywords: Major Facilitator Superfamily; ferroportin; hemochromatosis; molecular modeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Binding Sites
  • Cation Transport Proteins / chemistry*
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / metabolism
  • Cell Line
  • Codon
  • Hemochromatosis / genetics*
  • Hepcidins / chemistry
  • Hepcidins / metabolism
  • Humans
  • Models, Molecular
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Reproducibility of Results
  • Structure-Activity Relationship

Substances

  • Cation Transport Proteins
  • Codon
  • Hepcidins
  • metal transporting protein 1

Supplementary concepts

  • Hemochromatosis, type 4