eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response

Area of Science:

• Molecular Biology
• Cellular Biology
• Biochemistry

Background:

• The integrated stress response (ISR) is a critical cellular pathway controlling protein synthesis.
• The general translation initiation factor eIF2 is a key regulator, modulated by phosphorylation.
• eIF2B acts as the dedicated nucleotide exchange factor for eIF2, essential for its activation.

Purpose of the Study:

• To elucidate the structural basis of eIF2 activation by its nucleotide exchange factor, eIF2B.
• To understand how phosphorylation of eIF2 alters its interaction with eIF2B.
• To provide insights into the regulatory mechanism of the integrated stress response.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to determine the structures.
• High-resolution structural analysis of eIF2 bound to eIF2B in its dephosphorylated state.
• Comparative structural analysis to infer the mechanism of inhibition upon phosphorylation.

Main Results:

• The heterodecameric eIF2B complex serves as a static platform for eIF2 binding.
• One or two flexible eIF2 trimers bind to eIF2B, aligning with catalytic centers for nucleotide exchange.
• Phosphorylation of eIF2α induces a conformational change, leading to a distinct interaction with eIF2B, likely inhibiting its function.

Conclusions:

• The study reveals the structural dynamics of eIF2-eIF2B interaction during nucleotide exchange.
• Phosphorylation of eIF2α is a key event that repurposes the eIF2-eIF2B complex into an inhibitory state.
• These findings offer a molecular understanding of ISR regulation and potential therapeutic targets.