Insights into the Architecture of the eIF2B伪/尾/未 Regulatory Subcomplex

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• 作者：Andrew M. Bogorad ; Bing Xia ; Dana G. Sandor ; Artem B. Mamonov ; Tanya R. Cafarella ; Stefan Jehle ; Sandor Vajda ; Dima Kozakov ; Assen Marintchev
• 刊名：Biochemistry
• 出版年：2014
• 出版时间：June 3, 2014
• 年：2014
• 卷：53
• 期：21
• 页码：3432-3445
• 全文大小：1010K
• 年卷期：v.53,no.21(June 3, 2014)
• ISSN：1520-4995

文摘

Eukaryotic translation initiation factor 2B (eIF2B), the guanine nucleotide exchange factor for the G-protein eIF2, is one of the main targets for the regulation of protein synthesis. The eIF2B activity is inhibited in response to a wide range of stress factors and diseases, including viral infections, hypoxia, nutrient starvation, and heme deficiency, collectively known as the integrated stress response. eIF2B has five subunits (伪鈥撐?. The 伪, 尾, and 未 subunits are homologous to each other and form the eIF2B regulatory subcomplex, which is believed to be a trimer consisting of monomeric 伪, 尾, and 未 subunits. Here we use a combination of biophysical methods, site-directed mutagenesis, and bioinformatics to show that the human eIF2B伪 subunit is in fact a homodimer, at odds with the current trimeric model for the eIF2B伪/尾/未 regulatory complex. eIF2B伪 dimerizes using the same interface that is found in the homodimeric archaeal eIF2B伪/尾/未 homolog aIF2B and related metabolic enzymes. We also present evidence that the eIF2B尾/未 binding interface is similar to that in the eIF2B伪₂ homodimer. Mutations at the predicted eIF2B尾/未 dimer interface cause genetic neurological disorders in humans. We propose that the eIF2B regulatory subcomplex is an 伪₂尾₂未₂ hexamer, composed of one 伪₂ homodimer and two 尾未 heterodimers. Our results offer novel insights into the architecture of eIF2B and its interactions with the G-protein eIF2.