Vanselow, Sven and Neumann-Arnold, Lea and Wojciech-Moock, Franziska and Seufert, Wolfgang (2022) Stepwise assembly of the eukaryotic translation initiation factor 2 complex. JOURNAL OF BIOLOGICAL CHEMISTRY, 298 (2): 101583. ISSN , 1083-351X
Full text not available from this repository. (Request a copy)Abstract
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 a heterotrimeric complex whose assembly depends on the ATP-grasp protein Cdc123. Mutations of the eIF2 gamma 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 gamma exposes binding sites for eIF2 alpha and eIF2 beta subunits. Contrary to an earlier hypothesis, we found that the associations of eIF2 alpha and eIF2 beta with the gamma-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 alpha influence the rate of eIF2 assembly. By binding to eIF2 gamma, eIF2 alpha 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SACCHAROMYCES-CEREVISIAE; INTELLECTUAL DISABILITY; BETA-SUBUNIT; TRANSFER-RNA; CELL-CYCLE; PROTEIN; EIF2-GAMMA; MECHANISM; GENES; IDENTIFICATION; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie > Cell Cycle Control > Prof. Dr. Wolfgang Seufert |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Oct 2023 13:52 |
| Last Modified: | 17 Oct 2023 13:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/56448 |
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