Transferrin (purple rhombus) binds two ferric iron atoms (orange squares) and circulates in the bloodstream until it comes into contact with transferrin receptors, which pair together to form dimers (red torpedo shapes) on the plasma membrane surface of cells. A complex of HFE (blue square) and β2-microglobulin (green square) binds to the transferrin receptor. Notably, the binding site for HFE overlaps the potential binding site of transferrin. Since it is likely that HFE associates with transferrin receptors shortly after synthesis, before the complex arrives at the plasma membrane, HFE can thus potentially prevent iron uptake through the transferrin receptor. Once transferrin binds the transferrin receptor (assuming that both potential binding sites are not blocked by HFE), the complex internalizes in an endosome, where acidification promotes release of ferric iron, and reduction by addition of an electron (e–) to ferrous or diferric iron allows transport of free iron from the endosome, using the divalent metal transporter, DMT1, to the cytosol. Upon release into the cytosol, iron can be incorporated into proteins, and its presence can be sensed by iron regulatory proteins (IRPs).