Synergistic Recruitment of UbcH7~Ub and Phosphorylated Ubl Domain Triggers Parkin Activation
Bibliographic record
Abstract
ABSTRACT The mechanism of activation and ubiquitin conjugation by the E3 ligase parkin is pivotal to understand the molecular pathology of early-onset Parkinson’s disease. Parkin is normally autoinhibited but is activated by the kinase PINK1 that phosphorylates parkin’s N-terminal ubiquitin-like (pUbl) domain and ubiquitin. How these alter the structure of parkin to allow recruitment of an E2~Ub conjugate to enhance ubiquitination is an unresolved question. We present the structure of an incoming E2~Ub conjugate with the phospho-ubiquitin bound C-terminus of parkin (R0RBR). We show the UbcH7~Ub conjugate is recruited by R0RBR parkin in the open state whereby conjugated ubiquitin binds to the RING1/IBR interface. Further, NMR experiments indicate there is re-modelling near the RING0/RING2 interface remote from the E2-binding site. This, and parkin phosphorylation lead to rapid reactivity of the RING2(Rcat) catalytic cysteine in parkin, needed for ubiquitin transfer. Parkin phosphorylation also leads to relocation and weak interaction of the pUbl domain with the RING0 domain that is enhanced upon E2~Ub recruitment indicating these events act synergistically to drive parkin activity.
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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 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".