The Structure and Function of Iron Regulatory Factor

Abstract

The discovery of iron regulatory factor (IRF), a soluble cytoplasmic protein also referred to as iron-responsive element-binding protein (IRE-BP) or ferritin repressor protein (FRP), has led to the characterization of a coordinate post-transcriptional regulation of key proteins in cellular iron metabolism. 1-3 The control integrates cellular iron absorption by receptor-mediated endocytosis of transferrin, iron storage in ferritin and specific pathways of iron utilization (Fig.l). Most remarkably, iron appears to regulate its own intra-cellular homeostasis through mechanisms that act as feedback loops: IRF is active as a mRNA-binding protein only after iron deprivation. Under these conditions, it associates with the iron responsive elements (IRE) in the 5’ or 3’ untranslated mRNA-regions and thereby inhibits ferritin synthesis as well as transferrin receptor (TfR) mRNA degradation (Fig.l). As a result ferritin is less expressed and iron storage diminished, while TfR expression and iron uptake is increased. Both effects tend to compensate for the unavailability of cellular iron. Once the free iron pool has increased to higher levels, IRF becomes inactivated and presumably dissociates from the IREs. This permits a shift in the regulatory balance and results in facilitated iron deposition and reduced iron uptake. IRF can therefore be considered as both a sensor and regulator of intra-cellular iron.KeywordsTransferrin ReceptorSulfur ClusterCellular IronIron Responsive ElementAconitase ActivityThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.