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. 2020 Apr 7;59(13):1299-1308.
doi: 10.1021/acs.biochem.0c00132. Epub 2020 Mar 26.

eIF2B and the Integrated Stress Response: A Structural and Mechanistic View

Assen Marintchev  1 , Takuhiro Ito  2
Affiliations

eIF2B and the Integrated Stress Response: A Structural and Mechanistic View

Assen Marintchev et al. Biochemistry. .

Abstract

The eukaryotic translation initiation factor eIF2 is a GTPase, which brings the initiator Met-tRNAi to the ribosome as the eIF2-GTP·Met-tRNAi ternary complex (TC). TC regeneration is catalyzed by the guanine nucleotide exchange factor (GEF) eIF2B. eIF2 phosphorylation by several stress-induced kinases converts it into a competitive inhibitor of eIF2B. Inhibition of eIF2B activity lowers cellular TC concentrations, which in turn triggers the integrated stress response (ISR). Depending on its degree of activation and duration, the ISR protects the cell from the stress or can itself induce apoptosis. ISR dysregulation is a causative factor in the pathology of multiple neurodegenerative disorders, while ISR inhibitors are neuroprotective. The realization that eIF2B is a promising therapeutic target has triggered significant interest in its structure and its mechanisms of action and regulation. Recently, four groups published the cryo-electron microscopy structures of eIF2B with its substrate eIF2 and/or its inhibitor, phosphorylated eIF2 [eIF2(α-P)]. While all three structures of the nonproductive eIF2B·eIF2(α-P) complex are similar to each other, there is a sharp disagreement between the published structures of the productive eIF2B·eIF2 complex. One group reports a structure similar to that of the nonproductive complex, whereas two others observe a vastly different eIF2B·eIF2 complex. Here, we discuss the recent reports on the structure, function, and regulation of eIF2B; the preclinical data on the use of ISR inhibitors for the treatment of neurodegenerative disorders; and how the new structural and biochemical information can inform and influence the use of eIF2B as a therapeutic target.

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Figures

Figure 1.
Figure 1.. Regulation of eIF2B and the Integrated Stress Response (ISR)
eIF2 brings the Met-tRNAi to the ribosomal translation initiation complex, in the form of the eIF2-GTP•Met-tRNAi ternary complex (TC). Upon start codon recognition, eIF2 hydrolyzes GTP, and eIF2-GDP is released. eIF2B catalyzes nucleotide exchange and Met-tRNAi binding to form a new TC. Phosphorylation of the α-subunit of eIF2 by several stress-activated kinases turns eIF2-GDP from substrate into an inhibitor of eIF2B. Inhibition of eIF2B activity triggers the ISR, which involves both pro-apoptotic and pro-survival pathways. The ultimate fate of the cell depends on the interplay between the stress, the pro-survival and pro-apoptotic branches of the ISR, and other stress responses in the cell. The stress response is usually proportional to the stress and self-contained through negative feedback. In the absence of adequate stress response, the stress factors can cause cell damage and death. At the opposite end of the spectrum, stress response that is too strong and/or prolonged can itself cause apoptosis.
Figure 2.
Figure 2.. Crystal structure of S. pombe eIF2B.
The structure of eIF2B is shown in surface representation. The individual eIF2B subunits are labeled. Sites of cross-linking to eIF2γ (left and right) and eIF2α (center) and are colored red and circled. The second eIF2α-binding pocket (not visible) is on the opposite face of the complex. The two alternative binding modes of eIF2 (shown in gold ribbon), involving the visible eIF2α-binding pocket on the front, are illustrated with dashed arrows above and below the eIF2B structure, and numbered as in the text. Note that the same two alternative eIF2 binding modes are possible on the opposite face of eIF2B, but not shown for clarity.
Figure 3.
Figure 3.. Structure of the eIF2B complexes with eIF2 and eIF2(α-P)
A. Structure of the productive eIF2B•eIF2 complex. eIF2B is in approximately the same orientation as in Figure 2. eIF2α and γ are colored gold; the visible portion of eIF2β is orange. The structure is similar to the structure of the eIF2B•eIF2 complex in reference.The alternative eIF2α- and eIF2γ-binding surfaces observed in the structure of the eIF2B•eIF2 complex from reference are circled and labeled. Note that the eIF2B•eIF2 structure in reference is similar to the structure of the nonproductive eIF2B•eIF2(α-P) complex, , (panel B). B. Structure of the nonproductive eIF2B•eIF2(α-P) complex. The orientation and coloring are the same as in panel A. The structure is similar to the structures of the eIF2B•eIF2(α-P) complex in references, , and to the structure of the eIF2B•eIF2 complex in reference.
Figure 4.
Figure 4.. eIF2α binding in the productive and nonproductive eIF2B•eIF2 complexes
eIF2B is in a similar orientation to that in Figure 2. The coloring is as in Figure 2, but with more aggressive shading, to zoom in on the eIF2α interface. More distant portions of the complex are invisible due to shading or are cut out. eIF2α-NTD from the nonproductive eIF2B•eIF2(α-P) complex (left) and from the productive eIF2B•eIF2 complex (right) are shown as gold ribbon. The rest of eIF2 is not shown. Residues in eIF2B subunits corresponding to sites of Gcd− mutations in S. cerevisiae are colored black; residues corresponding to sites of Gcn− mutations in S. cerevisiae are colored red; Q130 in human eIF2Bβ, corresponding to the site of a lethal mutation in S. cerevisiae is colored magenta. Residues discussed in the text are labeled. The residues in human eIF2α, corresponding to the sites of the Y81S and R88T Gcn− mutations in S. cerevisiae eIF2α, are shown as orange sticks (not labeled).
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