HRI (encoded in humans by the gene EIF2AK1) also dimerizes in order to autophosphorylate and activate. This activation is dependent on the presence of heme. HRI has two domains that heme may bind to, including one on the N-terminus and one on the kinase insertion domain. The presence of heme causes a disulfide bond to form between the monomers of HRI, resulting in the structure of an inactive dimer. However, when heme is absent, HRI monomers form an active dimer through non-covalent interactions. Therefore, the activation of this kinase is dependent on heme deficiency. HRI activation can also occur due to other stressors such as heat shock, osmotic stress and proteasome inhibition. Activation of HRI in response to these stressors does not depend on heme, but rather relies on the help of two heat shock proteins (HSP90 and HSP70). HRI is mainly found in the precursors of red blood cells, and has been observed to increase during erythropoiesis.