eukaryotic translation initiation factor 2-alpha kinase 1; heme-controlled repressor; HCR; heme-regulated eukaryotic initiation factor eIF-2-alpha kinase; heme-regulated inhibitor; hemin-sensitive initiation factor 2-alpha kinase (EIF2AK1, HRI, KIAA1369, PRO1362)
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Function
- inhibits protein synthesis at the translation initiation level, in response to various stress conditions, including oxidative stress, heme deficiency, osmotic shock & heat shock
- exerts its function through the phosphorylation of EIF2S1 at Ser-48 & Ser-51, thus preventing its recycling
- binds hemin forming a 1:1 complex through a cysteine thiolate & histidine nitrogenous coordination
- this binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell
- this heme-sensing capacity, plays a role to terminating synthesis during acute heme-deficient conditions
- in erythrocytes, controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of heme & globin moieties
- role in RBC survival in anemias of iron deficiency
- in hepatocytes, role in heme-mediated translational control of CYP2B & CYP3A & possibly other hepatic P450 cytochromes
- may also contain ER stress during acute heme-deficient conditions
- induced by acute heme depletion
- increases EIF2AK1 protein levels
- stimulates kinase activity by autophosphorylation
- inhibited by the heme-degradation products biliverdin & bilirubin
- induced by oxidative stress generated by arsenite treatment
- binding of nitric oxide (NO) to the heme iron in the N-terminal heme-binding domain activates the kinase activity, while binding of carbon monoxide (CO) suppresses kinase activity (putative)
- activated by autophosphorylation; phosphorylated predominantly on Ser & Thr, but also on Tyr
- autophosphorylation at Thr-488 is required for kinase activation
- the active autophosphorylated form apparently is largely refractory to cellular heme fluctuations
- synthesized in an inactive form that binds to the N-terminal domain of CDC37
- has to be associated with a multiprotein complex containing Hsp90, CDC37 & PPP5C for maturation & activation by autophosphorylation
- the phosphatase PPP5C modulates this activation
- forms oligomers
- may be non-covalently bound homodimer, as well as a hexamer in the absence of hemin
- converted to an inactive disulfide linked homodimer in the presence of hemin (putative)
Structure
- belongs to the protein kinase superfamily, Ser/Thr protein kinase family, GCN2 subfamily
- contains 2 HRM (heme regulatory motif) repeats
- contains 1 protein kinase domain
Compartment
Alternative splicing
named isoforms=2
Expression
- expressed predominantly in erythroid cells
- expressed at much lower levels in hepatocytes (at protein level)
Notes
- can bind 1 molecules of heme per polypeptide chain