Mode of action of the hemin-controlled inhibitor of protein synthesis.
Despite the finding that the hemin-controlled translational inhibitor in reticulocyte lysates is a cyclic AMP-independent protein kinase that phosphorylates the small subunit of the initiation factor eIF-2, the mechanism of inhibition of translation remained unexplained. Whereas treatment of hemin-containing lysates with inhibitor in the presence of ATP inhibited translation, the same treatment of highly purified eIF-2 did not affect its ability to form a ternary complex with initiator Met-tRNA and GTP or a 40S initiation complex. We have isolated from ribosomal salt washes a protein (eIF-2 stimulating protein) that enhances the capacity of unphosphorylated eIF-2 to form ternary or 40S initiation complexes but has no effect on the phosphorylated factor. At low concentrations, eIF-2 is virtually inactive without this stimulating protein. Therefore, the translational inhibitor acts by converting eIF-2 to a form that is not stimulated by the stimulating protein.
D006418:Heme / Q000031:analogs & derivatives*; D006427:Hemin / Q000494:pharmacology*; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects*; D010448:Peptide Initiation Factors; D011506:Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D012156:Reticulocytes / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D013439:Sulfhydryl Reagents / Q000494:pharmacology
D010448:Peptide Initiation Factors; D011506:Proteins; D013439:Sulfhydryl Reagents; D006418:Heme; D006427:Hemin
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