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Structural basis for eIF2B inhibition in integrated stress response.

Kazuhiro Kashiwagi1, Takeshi Yokoyama1, Madoka Nishimoto1

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Phosphorylation of eukaryotic translation initiation factor 2 (eIF2) regulates the integrated stress response. Structural studies reveal how phosphorylated eIF2 inhibits its guanine nucleotide exchange factor, eIF2B, by altering binding modes.

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Area of Science:

  • Molecular Biology
  • Cellular Stress Response
  • Protein Structure and Function

Background:

  • The integrated stress response is a fundamental adaptive pathway in eukaryotic cells.
  • Phosphorylation of eukaryotic translation initiation factor 2 (eIF2) is a key regulatory event in this response.
  • eIF2 normally facilitates protein synthesis by delivering initiator tRNA to ribosomes.

Purpose of the Study:

  • To elucidate the mechanism by which eIF2 phosphorylation regulates the activity of its guanine nucleotide exchange factor, eIF2B.
  • To understand how different phosphorylation states of eIF2 impact its interaction with eIF2B.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to determine the structure of eIF2B.
  • Crystallography was used to resolve the structures of eIF2B in complex with both unphosphorylated and phosphorylated eIF2.
  • Structural analysis focused on the distinct binding modes and their functional implications.

Main Results:

  • Unphosphorylated and phosphorylated eIF2 exhibit markedly different binding interactions with eIF2B.
  • The unphosphorylated form of eIF2 binds eIF2B in a manner that supports nucleotide exchange activity.
  • The phosphorylated form of eIF2 binds eIF2B differently, leading to inhibition of nucleotide exchange activity.

Conclusions:

  • The distinct binding modes of phosphorylated and unphosphorylated eIF2 to eIF2B explain the regulation of nucleotide exchange activity.
  • These findings provide a structural basis for how eIF2 phosphorylation acts as a dominant inhibitor of eIF2B.
  • Understanding this regulatory mechanism is crucial for comprehending the integrated stress response pathway.