Fig. 4

ATF4 protein structure and translational regulation by eIF2α phosphorylation. A The ATF4 protein consists of several of regulatory and functional domains. The regulatory domains include the N-terminal domain (NTD), oxygen dependent degradation domain (ODDD) and β-transducin repeat-containing protein (βTrCP) interacting domain all of which regulate the stability of ATF4 in response to interactions with histone acetyltransferase p300, prolyl-4-hydroxylase 3 (PHD3) and βTrCP respectively. The functional domains include a basic domain (BD) involved in DNA binding and a leucine zipper (LZ) domain that facilitates dimerization. B Under normal conditions eIF2B catalyzes the transfer of eIF2-bound GDP (inactive) for GTP to produce the eIF2-GTP (active) that forms a ternary complex with Met-tRNA_i. In the presence of sufficient ternary complex 5’ cap dependent translation proceeds resulting in inefficient translation of ATF4 mRNA due to the presence of inhibitory upstream open reading frames (uORF) in the 5’ untranslated region. Presence of cellular stress causes eIF2α kinases to phosphorylate eIF2 causing it to act as an inhibitor of eIF2B thus preventing further regeneration of eIF2-GTP. This leads to the depletion of the ternary complex which favors ribosome re-initiation at the ATF4 coding sequence (CDS) and enhanced synthesis of ATF4 protein. Created with BioRender.com