DOI: 10.1101/503540Dec 21, 2018Paper

Structural Basis for eIF2B Inhibition in Integrated Stress Response

BioRxiv : the Preprint Server for Biology
Kazuhiro KashiwagiTakuhiro Ito


A core event in the integrated stress response, an adaptive pathway common to all eukaryotic cells in response to various stress stimuli, is the phosphorylation of eukaryotic translation initiation factor 2 (eIF2). Normally, unphosphorylated eIF2 transfers methionylated initiator tRNA to the ribosome in a GTP-dependent manner. In contrast, phosphorylated eIF2 inhibits its specific guanine nucleotide exchange factor eIF2B, which leads to a deficiency of active eIF2 and resultant global translation repression. To unveil the mechanism by which the eIF2 phosphorylation status regulates the eIF2B nucleotide exchange activity, we determined cryo-electron microscopic and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2. Intriguingly, the unphosphorylated and phosphorylated forms of eIF2 bind to eIF2B in completely different manners: the nucleotide exchange-active 'productive' and nucleotide exchange-inactive 'nonproductive' modes, respectively. The nonproductive-mode phosphorylated eIF2, extending from one of the two eIF2B 'central cavities', not only prevents nucleotide exchange on itself, but also sterically prevents unphosphorylated eIF2 from productively binding on the other central cavi...Continue Reading

Related Concepts

Base Sequence
Guanine Nucleotide Exchange Factors
Biological Adaptation to Stress
Physiological Stress
Cryoelectron Microscopy

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