EIF2S1 Protein, Human (His)

EIF2S1 is a member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form a 43S pre-initiation complex (43S PIC). Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF2 and release of an eIF2-GDP binary complex. For eIF2 to recycle and catalyze another round of initiation, the GDP bound to eIF2 must exchange with GTP via a reaction catalyzed by eIF2B. EIF2S1/eIF2-alpha is a key component of the integrated stress response (ISR), required for adaptation to various stresses: phosphorylation by metabolic-stress sensing protein kinases (EIF2AK1/HRI, EIF2AK2/PKR, EIF2AK3/PERK, and EIF2AK4/GCN2) in response to stress converts EIF2S1/eIF2-alpha into a global protein synthesis inhibitor, leading to attenuation of cap-dependent translation while initiating preferential translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1, enabling ATF4- and QRICH1-mediated reprogramming. EIF2S1/eIF2-alpha also acts as an activator of mitophagy in response to mitochondrial damage: phosphorylation by EIF2AK1/HRI promotes relocalization to the mitochondrial surface, thereby triggering PRKN-independent mitophagy.