Abstract
Protein synthesis in eukaryotes is controlled by signals and stresses via a common pathway, called the integrated stress response (ISR). Phosphorylation of the translation initiation factor eIF2 alpha at a conserved serine residue mediates translational control at the ISR core. To provide insight into the mechanism of translational control we have determined the structures of eIF2 both in phosphorylated and unphosphorylated forms bound with its nucleotide exchange factor eIF2B by electron cryomicroscopy. The structures reveal that eIF2 undergoes large rearrangements to promote binding of eIF2α to the regulatory core of eIF2B comprised of the eIF2B alpha, beta and delta subunits. Only minor differences are observed between eIF2 and eIF2αP binding to eIF2B, suggesting that the higher affinity of eIF2αP for eIF2B drives translational control. We present a model for controlled nucleotide exchange and initiator tRNA binding to the eIF2/eIF2B complex.
Highlights
Protein synthesis in eukaryotes is controlled by signals and stresses via a common pathway, called the integrated stress response (ISR)
Eukaryotic protein synthesis typically begins with a specialised initiator methionyl transfer RNA (Met-tRNAi) that is delivered to ribosomes by the translation factor eIF2 as part of a larger preinitiation complex (PIC) with multiple other translation initiation factors[1]
We provide a model for how changes in eIF2 and eIF2B interactions may promote both guanine nucleotide exchange factor (GEF) action and facilitate coupled recruitment of initiator tRNA to eIF2-GTP
Summary
Protein synthesis in eukaryotes is controlled by signals and stresses via a common pathway, called the integrated stress response (ISR). Met-tRNAi for eIF2 is controlled by guanine nucleotides They interact with high affinity only when eIF2 is bound to GTP2,3. By re-engaging with GTP can eIF2 participate in further rounds of Met-tRNAi binding and protein synthesis initiation[1]. EIF2B first removes eIF57 and acts as a guanine nucleotide exchange factor (GEF) to activate eIF2 and facilitate Met-tRNAi interaction and rebinding of eIF53. This last step prevents eIF2B competing and destabilising eIF2GTP/Met-tRNAi ternary complexes (TCs)[3,8].
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