Crystal structure of the C-terminal domain of the epsilon subunit of human translation initiation factor eIF2B

Eukaryotic translation initiation factor eIF2B, the guanine nucleotide exchange factor (GEF) for eIF2, catalyzes conversion of eIF2.GDP to eIF2.GTP. The eIF2B is composed of five subunits, alpha, beta, gamma, delta and epsilon, within which the epsilon subunit is responsible for catalyzing the guanine exchange reaction. Here we present the crystal structure of the C-terminal domain of human eIF2B epsilon (eIF2B epsilon-CTD) at 2.0-angstrom resolution. The structure resembles a HEAT motif and three charge-rich areas on its surface can be identified. When compared to yeast eIF2B epsilon-CTD, one area involves highly conserved AA boxes while the other two are only partially conserved. In addition, the previously reported mutations in human eIF2B epsilon-CTD, which are related to the loss of the GEF activity and human VWM disease, have been discussed. Based on the structure, most of such mutations tend to destabilize the HEAT motif.