Fail-safe control of translation initiation by dissociation of eIF2α phosphorylated ternary complexes
- The University of Manchester, United Kingdom
Abstract
Phosphorylation of eIF2α controls translation initiation by restricting the levels of active eIF2-GTP-Met-tRNAi ternary complexes (TC). This modulates the expression of all eukaryotic mRNAs and contributes to the cellular integrated stress response. Key to controlling the activity of eIF2 are translation factors eIF2B and eIF5, thought to primarily function with eIF2-GDP and TC respectively. Using a steady-state kinetics approach with purified proteins we demonstrate that eIF2B binds to eIF2 with equal affinity irrespective of the presence or absence of competing guanine nucleotides. We show that eIF2B can compete with Met-tRNAi for eIF2-GTP and can destabilize TC. When TC is formed with unphosphorylated eIF2, eIF5 can out-compete eIF2B to stabilize TC-eIF5 complexes. However when TC-eIF5 is formed with phosphorylated eIF2, eIF2B outcompetes eIF5 and destabilizes TC. These data uncover competition between eIF2B and eIF5 for TC and identify that phosphorylated eIF2-GTP translation initiation intermediate complexes can be inhibited by eIF2B.
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Funding
Biotechnology and Biological Sciences Research Council (BB/L020157/1)
- Graham D Pavitt
Biotechnology and Biological Sciences Research Council (BB/M006565/1)
- Graham D Pavitt
Biotechnology and Biological Sciences Research Council (BB/L000652/1)
- Graham D Pavitt
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Jennings et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Fail-safe control of translation initiation by dissociation of eIF2α phosphorylated ternary complexes
eLife 6:e24542.
https://doi.org/10.7554/eLife.24542
