4E-BP3, a New Member of the Eukaryotic Initiation Factor 4E-binding Protein Family*

Translation initiation in eukaryotes is mediated by the cap structure (m7GpppN, where N is any nucleotide) present at the 5′ end of all cellular mRNAs, except organellar. The cap is recognized by eukaryotic initiation factor 4F (eIF4F), which consists of three polypeptides, including eIF4E, the cap-binding protein subunit. The interaction of the cap with eIF4E facilitates the binding of the ribosome to the mRNA. eIF4E activity is regulated in part by two translational repressors, 4E-BP1 and 4E-BP2, which bind to it and prevent its assembly into eIF4F. We report here the isolation of 4E-BP3, a new member of the 4E-BP family. 4E-BP3 is homologous to 4E-BP1 and 4E-BP2, exhibiting 57 and 59% identity, respectively. The homology is most striking in the middle region of the protein, which contains the eIF4E binding motif and residues that are phosphorylated in 4E-BP1. 4E-BP3 is a heat stable protein that binds to eIF4E in vitro as well as in vivo. Further, 4E-BP3 overexpression specifically reduces eIF4E-dependent translation. The overlapping function and expression of the different 4E-BP family members imply that there is redundancy in this translational control mechanism, underscoring its importance.

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