15. Phosphorylation of elF2 α subunits (at Ser 51) leads to
(1) inactivation of Met-tRNAi, binding activity of elF2B.
(2) sequestration of eIF2B because of tight binding between elF2 and elF2B.
(3) degradation of elF2B.
(4) enhanced guanine exchange activity of elF2B.
Introduction
Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2α) at serine 51 is a pivotal regulatory event controlling protein synthesis in response to cellular stress. This modification triggers a cascade that reduces global translation while allowing selective synthesis of stress-responsive proteins. Central to this process is the interaction between phosphorylated eIF2α and its guanine nucleotide exchange factor, eIF2B.
Mechanism of Translation Inhibition by eIF2α Phosphorylation
eIF2 is essential for delivering the initiator methionyl-tRNA to the ribosome during translation initiation. After GTP hydrolysis, eIF2 must be reactivated by eIF2B, which catalyzes the exchange of GDP for GTP.
When eIF2α is phosphorylated at Ser51:
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Phosphorylated eIF2α binds tightly to eIF2B.
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This binding sequesters eIF2B, preventing it from recycling other eIF2 molecules.
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The depletion of active eIF2-GTP reduces ternary complex formation.
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Translation initiation is globally downregulated.
Biological Significance
This regulatory mechanism is a cornerstone of the integrated stress response (ISR), enabling cells to conserve resources and adapt protein synthesis under stress conditions such as nutrient deprivation, viral infection, and ER stress.
Conclusion
Phosphorylation of eIF2α at Ser51 leads to sequestration of eIF2B by forming a tight complex, thereby inhibiting the guanine nucleotide exchange activity of eIF2B and reducing global protein synthesis. This mechanism is essential for cellular adaptation to stress.
Answer:
(2) sequestration of eIF2B because of tight binding between eIF2 and eIF2B.
This explanation aligns with current molecular biology understanding and is supported by extensive research.
