Vanselow S, Neumann-Arnold L, Wojciech-Moock F, Seufert W

The eukaryotic translation initiation factor 2 (eIF2) has key functions in the initiation step of protein synthesis. eIF2 guides the initiator tRNA to the ribosome, participates in scanning of the mRNA molecule, supports selection of the start codon, and modulates the translation of mRNAs in response to stress. eIF2 comprises ...

Read More

a heterotrimeric complex whose assembly depends on the ATP-grasp protein Cdc123. Mutations of the eIF2? subunit that compromise eIF2 complex formation cause severe neurological disease in humans. To this date, however, details about the assembly mechanism, step order, and the individual functions of eIF2 subunits remain unclear. Here, we quantified assembly intermediates and studied the behavior of various binding site mutants in budding yeast. Based on these data, we present a model in which a Cdc123-mediated conformational change in eIF2? exposes binding sites for eIF2? and eIF2? subunits. Contrary to an earlier hypothesis, we found that the associations of eIF2? and eIF2? with the ?-subunit are independent of each other, but the resulting heterodimers are nonfunctional and fail to bind the guanosine exchange factor eIF2B. In addition, levels of eIF2? influence the rate of eIF2 assembly. By binding to eIF2?, eIF2? displaces Cdc123 and thereby completes the assembly process. Experiments in human cell culture indicate that the mechanism of eIF2 assembly is conserved between yeast and humans. This study sheds light on an essential step in eukaryotic translation initiation, the dysfunction of which is linked to human disease.

Date: Dec. 01, 2021

View in: Pubmed Google Scholar

236713