The structural basis of translational control by eIF2 phosphorylation.

Area of Science:

• Molecular Biology
• Structural Biology
• Cellular Stress Response

Background:

• Protein synthesis regulation is crucial for eukaryotic cells, particularly under stress.
• The integrated stress response (ISR) pathway modulates translation initiation via the eIF2 alpha (eIF2α) protein.
• Phosphorylation of eIF2α is a key event in controlling translation during the ISR.

Purpose of the Study:

• To elucidate the structural mechanism of translational control mediated by eIF2α phosphorylation.
• To understand the interaction between the nucleotide exchange factor eIF2B and its substrate eIF2 in both phosphorylated and unphosphorylated states.

Main Methods:

• Electron cryomicroscopy (cryo-EM) was employed to determine high-resolution structures.
• Structures of eIF2 complexed with eIF2B were solved for both unphosphorylated and phosphorylated eIF2 forms.

Main Results:

• Cryo-EM structures reveal significant conformational rearrangements in eIF2 upon binding to eIF2B.
• eIF2α binds to the core subunits (alpha, beta, delta) of eIF2B.
• Minimal structural differences were observed between eIF2 and phosphorylated eIF2 (eIF2αP) bound to eIF2B.
• The higher binding affinity of eIF2αP for eIF2B is proposed as the driver of translational control.

Conclusions:

• The study provides atomic-level insights into the mechanism of ISR-mediated translational control.
• A model for regulated nucleotide exchange and initiator tRNA binding to the eIF2/eIF2B complex is proposed.
• These findings advance our understanding of how cells manage protein synthesis under stress conditions.