Stochastic Gate Dynamics Regulate the Catalytic Activity of Ubiquitination Enzymes
Bibliographic record
Abstract
Initiation of the DNA damage and innate immune responses is dependent upon the flow of chemical information through coupled protein-protein interaction networks and driven by the synthesis and recognition of Lys 63 linked polyubiquitin (polyUb) chains on adaptor proteins. The central chemical step in Lys 63-linked protein ubiquitination involves the reaction of a specific lysine on a target protein with Ub that is covalently attached as a thioester conjugate to the Ub conjugating enzyme (E2) Ubc13. The active site cysteine of Ubc13, and E2 enzymes in general, is buttressed by a flexible loop. The role of loop dynamics in catalysis was investigated by mutating the central and hinge residues to glycine. The loop dynamics were experimentally characterized through measurement of enzyme kinetics, main chain NMR relaxation, X-ray crystallographic studies, and in vivo studies in yeast. The experimental data were complemented by analysis of MD simulations of the dynamics and kinetics for the loop motion. The results show that fast pico- to nanosecond time scale active site loop fluctuations play a crucial role in regulating the catalytic activity of Ubc13 by functioning as a stochastic active site gate, which is characterized by precisely balanced rates of opening and closing. In vivo functional complementation assays in yeast demonstrate that defects within this regulatory mechanism can have profound biological consequences, given that Ubc13 is the only E2 dedicated to synthesizing Lys 63-linked polyUb chains.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".