Hereditary Hemochromatosis Protein, HFE, Interaction with Transferrin Receptor 2 Suggests a Molecular Mechanism for Mammalian Iron Sensing

Tapasree Goswami,Nancy C Andrews

doi:10.1074/jbc.c600197200

Abstract

HFE and transferrin receptor 2 (TFR2) are membrane proteins integral to mammalian iron homeostasis and associated with human hereditary hemochromatosis. Here we demonstrate that HFE and TFR2 interact in cells, that this interaction is not abrogated by disease-associated mutations of HFE and TFR2, and that TFR2 competes with TFR1 for binding to HFE. We propose a new model for the mechanism of iron status sensing that results in the regulation of iron homeostasis.

Highlights

All mammalian cells have an absolute requirement for iron
Hereditary hemochromatosis in humans is linked to mutations in several genes namely HFE, transferrin receptor 2 (TFR2), hemojuvelin (HJV), and hepcidin (HAMP)
While transferrin receptor 1 (TFR1) is a key mediator of iron uptake, TFR2 is postulated to play a regulatory role in whole-body iron homeostasis

Summary

Introduction

All mammalian cells have an absolute requirement for iron. Both cellular iron deficiency and iron-overload are pathological and iron concentration in cells and body fluids is tightly regulated. Circulating Fe2-TF is likely to be an iron signal sensed by hepatocyte membrane proteins that regulate hepcidin production and TFR2 may be part of the regulatory system sensing transferrin saturation. TFR2-myc was immunoprecipitated by anti-FLAG antibody in lysates from cells expressing both

Results

Conclusion