An Enigma of N-termini dependent protein degradation
Bibliographic record
Abstract
The N-Degron rules that target proteins for degradation via their N-terminal sequences has expanded to encompass most N-terminal sequences. These destabilizing N-termini include many sequence combinations with the initiator methionine intact, including the recently reported N-terminal methionine followed by a basic residue. Despite the diverse sequences reported for N-Degron recognition and degradation system wide proteomic analysis has currently not observed these rules with endogenous proteins. Here we report on these apparent inconsistencies by validating the degradation of reporter proteins with N-terminal MK- and MR-sequences and also investigating global endogenous protein turnover by proteomics. In addition to verifying the reported degradation of proteins with MK- and MR- N-termini we have also identified an additional sequence dependency where an acidic residue following the basic residue inhibits protein degradation. Global protein degradation analysis using a metabolic labelling approach with azidohomoalanine failed to observe trends in cytoplasmic protein stability that correlates to the N-terminal sequence. Together we have been able to reproduce the apparent contradictory results reported using different methodologies. This included the use of different recombinant protein reporters to investigate MK- and MR- N-termini dependent protein degradation and an alternative proteomic method to quantify global protein degradation. This highlights the need into further investigations to complete our understanding of the mechanisms and roles of N-Degron pathways.
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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".