Crystal structure of eukaryotic translation initiation factor 2B
| Autor: | Toshiaki Higo, Shigeyuki Yokoyama, Takashi Umehara, M. Takahashi, Kensaku Sakamoto, Kazuhiro Kashiwagi, Takuya B. Hiyama, Takuhiro Ito, Madoka Nishimoto |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Models Molecular Amino Acid Motifs macromolecular substances Crystallography X-Ray Guanosine Diphosphate 03 medical and health sciences 0302 clinical medicine GTP-binding protein regulators Protein structure Heterotrimeric G protein Eukaryotic initiation factor Schizosaccharomyces Phosphorylation Protein Structure Quaternary eIF2 Multidisciplinary Binding Sites biology biology.organism_classification Eukaryotic Initiation Factor-2B Protein Subunits 030104 developmental biology Cross-Linking Reagents Biochemistry Protein Biosynthesis eIF2B biology.protein Biophysics Biocatalysis Guanine nucleotide exchange factor Guanosine Triphosphate 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Nature. 531(7592) |
| ISSN: | 1476-4687 |
| Popis: | Eukaryotic cells restrict protein synthesis under various stress conditions, by inhibiting the eukaryotic translation initiation factor 2B (eIF2B). eIF2B is the guanine nucleotide exchange factor for eIF2, a heterotrimeric G protein consisting of α-, β- and γ-subunits. eIF2B exchanges GDP for GTP on the γ-subunit of eIF2 (eIF2γ), and is inhibited by stress-induced phosphorylation of eIF2α. eIF2B is a heterodecameric complex of two copies each of the α-, β-, γ-, δ- and e-subunits; its α-, β- and δ-subunits constitute the regulatory subcomplex, while the γ- and e-subunits form the catalytic subcomplex. The three-dimensional structure of the entire eIF2B complex has not been determined. Here we present the crystal structure of Schizosaccharomyces pombe eIF2B with an unprecedented subunit arrangement, in which the α2β2δ2 hexameric regulatory subcomplex binds two γe dimeric catalytic subcomplexes on its opposite sides. A structure-based in vitro analysis by a surface-scanning site-directed photo-cross-linking method identified the eIF2α-binding and eIF2γ-binding interfaces, located far apart on the regulatory and catalytic subcomplexes, respectively. The eIF2γ-binding interface is located close to the conserved 'NF motif', which is important for nucleotide exchange. A structural model was constructed for the complex of eIF2B with phosphorylated eIF2α, which binds to eIF2B more strongly than the unphosphorylated form. These results indicate that the eIF2α phosphorylation generates the 'nonproductive' eIF2-eIF2B complex, which prevents nucleotide exchange on eIF2γ, and thus provide a structural framework for the eIF2B-mediated mechanism of stress-induced translational control. |
| Databáze: | OpenAIRE |
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