Which factor is phosphorylated at Ser51 during stress?
Eukaryotic initiation factor eIF2 alpha subunit undergoes regulatory phosphorylation at conserved serine 51 in N-terminal OB-fold domain by four distinct stress kinases: PERK activated by unfolded proteins in endoplasmic reticulum, PKR that senses viral double-stranded RNA, GCN2 responding to uncharged tRNAs during amino acid starvation, and HRI sensing heme deficiency and oxidative stress. Phosphorylation converts eIF2 from substrate to competitive inhibitor of its guanine exchange factor eIF2B, because affinity increases dramatically, inactivating eIF2B due to limiting concentration, thereby initiating integrated stress response and reprogramming translation.
Ref: Berg et al., Biochemistry, 9th ed., Chapter 32, eIF2alpha Ser51 phosphorylation by PERK, PKR, GCN2 kinases