CommunicationCrystal Structure of the C-terminal Domain of Human eIF2D and Its Implications on Eukaryotic Translation Initiation

- eIF2D regulates the initiation of protein synthesis under a stress condition.
- The structure of the C-terminal part of eIF2D was determined at 1.4-Å resolution.
- eIF2D has an eIF1-like domain, crucial for scanning and the fidelity of AUG recognition.
- Extensive atomic interaction between the domains imparts rigidity to the structure.

Protein synthesis is a key process in all living organisms. In eukaryotes, initiation factor 2 (eIF2) plays an important role in translation initiation as it selects and delivers the initiator tRNA to the small ribosomal subunit. Under stress conditions, phosphorylation of the α-subunit of eIF2 downregulates cellular protein synthesis. However, translation of certain mRNAs continues via the eIF2D-dependent non-canonical initiation pathway. The molecular mechanism of this process remains elusive. In addition, eIF2D plays a role in translation re-initiation and ribosome recycling. Currently, there has been no structural information of eIF2D. We have now determined the crystal structure of the C-terminal domains of eIF2D at 1.4-Å resolution. One domain has the fold similar to that of eIF1, which is crucial for the scanning and initiation codon selection. The second domain has a known SWIB/MDM2 fold, which was not observed before in other translation initiation factors. Our structure reveals atomic details of inter-domain interactions in the C-terminal part of eIF2D and sheds light on the possible role of these domains in eIF2D during translation.

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