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Review
. 2014;13(17):2660-5.
doi: 10.4161/15384101.2014.948797.

A new function and complexity for protein translation initiation factor eIF2B

Martin D Jennings  1 , Graham D Pavitt
Affiliations
Review

A new function and complexity for protein translation initiation factor eIF2B

Martin D Jennings et al. Cell Cycle. 2014.

Abstract

eIF2B is a multisubunit protein that is critical for protein synthesis initiation and its control. It is a guanine nucleotide exchange factor (GEF) for its GTP-binding protein partner eIF2. eIF2 binds initiator tRNA to ribosomes and promotes mRNA AUG codon recognition. eIF2B is critical for regulation of protein synthesis via a conserved mechanism of phosphorylation of eIF2, which converts eIF2 from a substrate to an inhibitor of eIF2B GEF. In addition, inherited mutations affecting eIF2B subunits cause the fatal disorder leukoencephalopathy with Vanishing White Matter (VWM), also called Childhood Ataxia with Central nervous system Hypomyelination (CACH). Here we review findings which reveal that eIF2B is a decameric protein and also define a new function for the eIF2B. Our results demonstrate that the eIF2Bγ subunit is required for eIF2B to gain access to eIF2•GDP. Specifically it displaces a third translation factor eIF5 (a dual function GAP and GDI) from eIF2•GDP/eIF5 complexes. Thus eIF2B is a GDI displacement factor (or GDF) in addition to its role as a GEF, prompting the redrawing of the eIF2 cycling pathway to incorporate the new steps. In structural studies using mass spectrometry and cross-linking it is shown that eIF2B is a dimer of pentamers and so is twice as large as previously thought. A binding site for GTP on eIF2B was also found, raising further questions concerning the mechanism of nucleotide exchange. The implications of these findings for eIF2B function and for VWM/CACH disease are discussed.

Keywords: G protein; GAP; GDF; GDI; GEF; eIF2B; translation initiation.

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Figures

Figure 1.
Figure 1.
Models for eIF2B functions in protein synthesis initiation. (A) Original model depicting eIF2-GTP-Met-tRNAi recruitment to the ribosome and its release following GTP hydrolysis to eIF2-GDP upon mRNA AUG start codon recognition. Here eIF2B perfoms a single GEF step to reactivate eIF2. (B) Revised model for eIF2 recycling accounting for eIF5 GDI and eIF2B GDF functions. (C) New model showing the impact of eIF2α phosphorylation on eIF2B and eIF5. For further explanations, including step numbering, refer to the main text.
See this image and copyright information in PMC

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