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The C terminus of initiation factor 4E-binding protein 1 contains multiple regulatory features that influence its function and phosphorylation.

http://www.ncbi.nlm.nih.gov/pubmed/12588975

Eukaryotic initiation factor 4E (eIF4E) binds the mRNA cap structure and forms eIF4F complexes that recruit 40S subunits to the mRNA. Formation of eIF4F is blocked by eIF4E-binding proteins such as 4E-BP1, which interacts with eIF4E via a motif in the center of its 118-residue sequence. 4E-BP1 plays key roles in cell proliferation, growth, and survival. Binding of 4E-BP1 to eIF4E is regulated by hierarchical multisite phosphorylation. Here we demonstrate that three different features in the C terminus of 4E-BP1 play distinct roles in regulating its phosphorylation and function. Firstly, we identify a new phosphorylation site in its C terminus (S101). A serine or glutamate at this position is required for efficient phosphorylation at Ser65. A second C-terminal site, S112, directly affects binding of 4E-BP1 to eIF4E without influencing phosphorylation of other sites. Thirdly, a conserved C-terminal motif influences phosphorylation of multiple residues, including rapamycin-insensitive sites. These relatively long-range effects are surprising given the reportedly unstructured nature of 4E-BP1 and may imply that phosphorylation of 4E-BP1 and/or binding to eIF4E induces a more-ordered structure. 4E-BP2 and -3 lack phosphorylatable residues corresponding to both S101 and S112. However, in 4E-BP3, replacement of the alanine at the position corresponding to S112 by serine or glutamate did not confer the ability to be released from eIF4E in response to insulin.

Pubmed ID: 12588975 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Amino Acid Motifs | Amino Acid Sequence | Binding Sites | Carrier Proteins | Cell Division | Cell Line | Cell Survival | Enzyme Inhibitors | Eukaryotic Initiation Factor-4E | Genetic Vectors | Glutamic Acid | Glutamine | Humans | Immunoblotting | Insulin | Models, Genetic | Molecular Sequence Data | Mutation | Peptides | Phosphoproteins | Phosphorylation | Protein Binding | Protein Isoforms | Protein Structure, Tertiary | Sequence Homology, Amino Acid | Serine | Time Factors | Transfection