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| http://www.biopax.org/relea... |
Eukaryotic translation initiation factor 2-alpha kinase 1
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| http://www.biopax.org/relea... |
E2AK1_MOUSE
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| http://www.biopax.org/relea... | |
| http://www.biopax.org/relea... |
2.7.11.1,
HCR,
Heme-controlled repressor,
Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase,
Heme-regulated inhibitor,
Hemin-sensitive initiation factor 2-alpha kinase
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| http://www.biopax.org/relea... |
FUNCTION: Inhibits protein synthesis at the translation initiation level, in response to various stress conditions, including oxidative stress, heme deficiency, osmotic shock and heat shock. Exerts its function through the phosphorylation of EIF2S1 at 'Ser- 48' and 'Ser-51', thus preventing its recycling. Binds hemin forming a 1:1 complex through a cysteine thiolate and histidine nitrogenous coordination. This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell. Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions. In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties. Thus plays an essential protective role for RBC survival in anemias of iron deficiency. Similarly, in hepatocytes, involved in heme-mediated translational control of CYP2B and CYP3A and possibly other hepatic P450 cytochromes. May also contain ER stress during acute heme-deficient conditions. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Induced by acute heme depletion, that not only increases EIF2AK1 protein levels, but also stimulates kinase activity by autophosphorylation. Inhibited by the heme-degradation products biliverdin and 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. SUBUNIT: 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 and PPP5C for maturation and activation by autophosphorylation. The phosphatase PPP5C modulates this activation (By similarity). Forms oligomers. Has been reported as a homodimer, as well as a hexamer in the absence of hemin. Converted to an inactive disulfide linked homodimer in the presence of hemin. SUBCELLULAR LOCATION: Cytoplasm. TISSUE SPECIFICITY: Expressed predominantly in erythroid cells, mature reticulocytes, as well as fetal liver nucleated erythroid cells. At much lower levels, expressed in hepatocytes and bone marrow-derived macrophages (at protein level). DEVELOPMENTAL STAGE: Highly expressed in fetal liver erythroid precursor cells at 14.5 dpc (at protein level). INDUCTION: By phenobarbital. PTM: Activated by autophosphorylation; phosphorylated predominantly on serine and threonine residues, but also on tyrosine residues. Autophosphorylation at Thr-485 is required for kinase activation. The active autophosphorylated form apparently is largely refractory to cellular heme fluctuations. DISEASE: Note=Defects in Eif2ak1 are a cause of hyperchromic anemia in animals suffering from iron deficiency. The number of red blood cells is decreased due to increased apoptosis of erythroid precursor cells, probably because globins misfold and aggregate in the absence of heme. DISRUPTION PHENOTYPE: Mice are viable and fertile without gross morphological abnormalities. Dramatically altered response to diet-induced iron deficiency shifting from an adaptive decrease in RBC volume and intracellular hemoglobin content to an increased production of abnormally dense red blood cells (RBCs) with decreasing red cell counts. The decrease in RBC number is the result of increased apoptosis of erythroid precursors. Diminished levels of phosphorylated EIF2S1 in bone marrow-derived macrophages (BMDMs). Impaired maturation of BMDMs and blunted inflammatory response to LPS with a reduced cytokine production. Impaired phagocytosis of senescent RBCs by macrophages, resulting in a lower phagocytosis index and lower percentage of macrophages with ingested RBC. In hepatocytes, cytochromes P450 CYP2B6 and CYP3A induction by phenobarbital is not impaired in response to acute heme depletion and CYP2B6 and CYP3A proteins continue to accumulate to supranormal levels, irrespective of the hepatic heme pool status. These cells also exhibit a weak, albeit significant, elevation of the basal ER-stress as reflected by elevated levels of autophosphorylated EIF2AK3/PERK and EIF2AK4/GCN2, the ER-stress related chaperones HSPA5 and HSP90B1, and total hepatic protein ubiquitination. SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily. SIMILARITY: Contains 2 HRM (heme regulatory motif) repeats. SIMILARITY: Contains 1 protein kinase domain. SEQUENCE CAUTION: Sequence=BAD32438.1; Type=Erroneous initiation; Note=Translation N-terminally shortened; GENE SYNONYMS: Hri. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
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