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

Abstract

Summary 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 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 signalling 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 signalling.

Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage

“…It is also noteworthy that mice lacking S6ks only exhibit very subtle memory phenotypes (13). Seventh, whereas mice lacking 4e-bp2, the other mTORC1 downstream target, show impaired L-LTP and LTM (14), 4E-BP2 (protein) cannot be phosphorylated (and regulated) by mTORC1 in the adult brain (20). Thus, these data suggest that mTORC1 controls protein synthesis (in the brain) in a 4E-BP2-indepenent manner.…”

A recollection of mTOR signaling in learning and memory

“…Curiously, 4EBP2 is post-translationally regulated not only by phosphorylation, but also by spontaneous deamidation of asparagine residues. These residues are conserved in mammalian 4EBP2 but not in the other two isoforms or, indeed, in any organisms that possess a single copy of the Eif4ebp gene, suggesting a novel role in chordate brain function (Bidinosti et al 2010). Deamidation is a nonenzymatic process resulting in conversion of asparagine to aspartic acid and has been proposed to serve as a molecular timer regulating protein turnover (Robinson and Robinson 2001).…”

Translational Control Mechanisms in Long-lasting Synaptic Plasticity and Memory

“…post-translational modification that occurs 4 weeks postnatally only in the brain (48). Thus, how eIF4F complex formation is regulated in the brain in response to neuronal activity remains to be determined.…”