Postnatal Deamidation of 4E-BP2 in Brain Enhances Its Association with Raptor and Alters Kinetics of Excitatory Synaptic Transmission

• Published in: Molecular cell 2010-03, Vol.37 (6), p.797-808
• Main Authors: Bidinosti, Michael, Ran, Israeli, Sanchez-Carbente, Maria R., Martineau, Yvan, Gingras, Anne-Claude, Gkogkas, Christos, Raught, Brian, Bramham, Clive R., Sossin, Wayne S., Costa-Mattioli, Mauro, DesGroseillers, Luc, Lacaille, Jean-Claude, Sonenberg, Nahum
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Animals, Newborn; Asparagine; Brain; Brain - metabolism; Cells, Cultured; Eukaryotic Initiation Factors - chemistry; Eukaryotic Initiation Factors - deficiency; Eukaryotic Initiation Factors - genetics; Eukaryotic Initiation Factors - metabolism; Humans; Initiation factor eIF-4E; Kinetics; Learning; Memory; Mice; Mice, Knockout; Molecular Sequence Data; Neurons; Organ Specificity; Phosphorylation; Plasticity (synaptic); Protein Processing, Post-Translational; Protein Transport; PROTEINS; RNA; Sequence Alignment; Sequence Homology, Amino Acid; Signal transduction; SIGNALING; Synaptic Transmission; TOR protein; Translation initiation
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2010.02.022

The eIF4E-binding proteins (4E-BPs) repress translation initiation by preventing eIF4F complex formation. Of the three mammalian 4E-BPs, only 4E-BP2 is enriched in the mammalian brain and plays an important role in synaptic plasticity and learning and memory formation. Here we describe asparagine deamidation as a brain-specific posttranslational modification of 4E-BP2. Deamidation is the spontaneous conversion of asparagines to aspartates. Two deamidation sites were mapped to an asparagine-rich sequence unique to 4E-BP2. Deamidated 4E-BP2 exhibits increased binding to the mammalian target of rapamycin (mTOR)-binding protein raptor, which effects its reduced association with eIF4E. 4E-BP2 deamidation occurs during postnatal development, concomitant with the attenuation of the activity of the PI3K-Akt-mTOR signaling pathway. Expression of deamidated 4E-BP2 in 4E-BP2−/− neurons yielded mEPSCs exhibiting increased charge transfer with slower rise and decay kinetics relative to the wild-type form. 4E-BP2 deamidation may represent a compensatory mechanism for the developmental reduction of PI3K-Akt-mTOR signaling. ► 4E-BP2 undergoes asparagine deamidation uniquely in the brain ► 4E-BP2 deamidation enhances its association with raptor and reduces eIF4E binding ► 4E-BP2 deamidation is developmentally regulated ► Deamidated 4E-BP2 slows excitatory Schaffer collateral synaptic transmission