Repair of Isoaspartate Formation Modulates the Interaction of Deamidated 4E-BP2 with mTORC1 in Brain
Bibliographic record
Abstract
In eukaryotes, a rate-limiting step of translation initiation is recognition of the mRNA 5' m(7)GpppN cap structure by the eukaryotic initiation factor 4F (eIF4F), a heterotrimeric complex consisting of the cap-binding protein, eIF4E, along with eIF4G, and eIF4A. The eIF4E-binding proteins (4E-BPs) repress translation by disrupting eIF4F formation, thereby preventing ribosome recruitment to the mRNA. Of the three 4E-BPs, 4E-BP2 is the predominant paralog expressed in the mammalian brain and plays an important role in synaptic plasticity and learning and memory. 4E-BP2 undergoes asparagine deamidation, solely in the brain, during early postnatal development. Deamidation spontaneously converts asparagines into a mixture of aspartates or isoaspartates, the latter of which may be destabilizing to proteins. The enzyme protein L-isoaspartyl methyltransferase (PIMT) prevents isoaspartate accumulation by catalyzing the conversion of isoaspartates to aspartates. PIMT exhibits high activity in the brain, relative to other tissues. We report here that 4E-BP2 is a substrate for PIMT. In vitro deamidated 4E-BP2 accrues isoapartyl residues and is methylated by recombinant PIMT. Using an antibody that recognizes 4E-BP2, which harbors isoaspartates at the deamidation sites, Asn(99) and Asn(102), we demonstrate that 4E-BP2 in PIMT-/- brain lysates contains isoaspartate residues. Further, we show that 4E-BP2 containing isoaspartates lacks the augmented association with raptor that is a feature of deamidated 4E-BP2.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".