metabolism |
IF2alpha is phosphorylated at Ser51 by four kinases in what is collectively known as the integrated stress response (ISR) |
Homo sapiens |
additional information |
modeling of the closed conformation of eIF2alpha, the model is generated from the structure of human eIF2alpha (PDB ID 1Q8K), based on the intramolecular contact interface mapped using CSPs from the NMR deletion analysis, comparing spectra of full-length eIF2alpha with those of its individual domains, eIF2alpha-NTD and -CTD, docking analysis and comparisons with the structure of Schizosaccharomyces pombe, intramolecular interaction in eIF2alpha. Further structure modeling of eIF2alpha binding in the eIF2Breg regulatory subcomplex pocket, eIF2B complex with eIF2-GTP-Met-tRNAi ternary complex, eIF2B complex with eIF2 in an extended conformation, and eIF2B complex with eIF2 in closed conformation. eIF2alpha-NTD interactions with the eIF2Breg pocket play a role in catalysis, and not just in eIF2B inhibition by phosphorylated eIF2-GDP (eIF2(alpha-P)-GDP). The primary mechanism responsible for the increased affinity of eIF2B for eIF2(alpha-P)-GDP over unphosphorylated eIF2-GDP is the direct effect of phosphorylation on the affinity of the eIF2x02 phosphorylation loop (P-loop) for a corresponding surface on eIF2B. eIF2Balpha and eIF2Bbeta bind to adjacent surfaces on eIF2-N-terminal domain (NTD), and eIF2Balpha, eIF2Bbeta, and eIF2Breg show no significant preference for phosphomimetic over wild-type eIF2alpha-NTD, binding analysis, overview |
Homo sapiens |
physiological function |
eukaryotic translation initiation factor 2 (eIF2) is a heterotrimeric GTPase (cf. EC 3.6.5.1), which plays a critical role in protein synthesis regulation. eIF2-GTP binds MettRNAi to form the eIF2-GTP-Met-tRNAi ternary complex (TC), which is recruited to the 40S ribosomal subunit. Following GTP hydrolysis, eIF2-GDP is recycled back to TC by its guanine nucleotide exchange factor (GEF), eIF2B (i.e. eIF-2B GDP-GTP exchange factor). Mechanisms of eIF2B action and its regulation by phosphorylation of the substrate eIF2, overview. eIF2 consists of alpha, beta, and gamma subunits, with eIF2gamma being the actual GTPase, and eIF2alpha and beta serving accessory functions. eIF2B is inhibited by phosphorylated eIF2, eIF2(alpha-P)-GDP. Modeling of the structural and thermodynamic basis of the eIF2B/eIF2 and eIF2B/eIF2(alpha-P) interactions and the mechanism of catalysis, and modelling of the structural mechanism of IF2B inhibition by eIF2(alpha-P)-GDP, detailed overview |
Homo sapiens |