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12 The eIF2α Kinases

Thomas E. Dever, Arvin C. Dar, Frank Sicheri


Perhaps the best-characterized mechanism of translational control in eukaryotic cells involves phosphorylation of eukaryotic translation initiation factor eIF2. As described in Chapters 4 and 9, eIF2, consisting of three subunits, α, β, and γ, specifically binds the initiator methionyl-tRNA (Met-tRNAiMet) in a GTP-dependent manner and delivers this essential component of translation initiation to the small ribosomal subunit. The γ-subunit of eIF2 is responsible for GTP binding, and like other GTP-binding proteins, eIF2 cycles between its GTP-bound state and its GDP-bound state. The recycling of inactive eIF2•GDP to active eIF2•GTP is catalyzed by the guanine nucleotide exchange factor eIF2B. It is this recycling reaction that is regulated by phosphorylation of eIF2. Phosphorylation of Ser-51 in mature eIF2α converts eIF2 from a substrate to a competitive inhibitor of eIF2B. (It is noteworthy that according to the DNA sequence, the phosphorylation site in eIF2α is Ser-52. However, because the initiating Met of eIF2α is posttranslationally cleaved, the phosphorylated residue is Ser-51 in the mature protein.) This phosphorylation of eIF2α enhances its interaction with a trimeric regulatory eIF2Bαβδ subcomplex that can be biochemically separated from the pentameric eIF2B complex (Chapter 9). In all cells examined, the amount of eIF2B is limiting compared to the amount of eIF2. As a consequence, phosphorylation of a small percentage of eIF2α results in the apparent sequestration of eIF2B in inactive phosphorylated eIF2•eIF2B complexes and in the inhibition of protein synthesis.

Initially, eIF2 phosphorylation was linked to the shut-off of protein synthesis in heme-deprived or double-stranded RNA (dsRNA)-treated rabbit...

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