Mechanism of Activation of the Ubiquitin E3 Ligase, Parkin
Bibliographic record
Abstract
The Parkinson disease associated proteins, Parkin and PINK1, together comprise a mitochondrial quality control system that promotes neuronal survival through autophagy of damaged mitochondria. In the pathway, PINK1 acts as a sensor of depolarized mitochondria and phosphorylates ubiquitin to recruit and activate Parkin on the mitochondrial outer membrane. Parkin ubiquitinates mitochondrial proteins, which leads to the removal of the damaged mitochondria through mitophagy. We have carried out structural and functional studies of Parkin to understand its regulation and mechanism of activation – . Parkin exhibits low basal activity as a ubiquitin ligase and requires activation both in vitro and in cells. Multiple features inhibit Parkin activity: the E2‐binding site on RING1 is blocked, the catalytic site is partially occluded, and the incoming E2~Ub linkage is far from the parkin catalytic site (Fig. ). In response to mitochondrial damage, Parkin is activated by PINK1 via a two‐step mechanism involving binding of Parkin to phosphorylated ubiquitin and a large‐scale conformational change induced by Parkin phosphorylation (Fig. ). Positive feedback in the Parkin/PINK1 pathway generates a binary, all‐or‐nothing switch for the induction of mitophagy. These structural studies are critical for understanding how Parkin and PINK1 protect neurons and provide a framework for the design of small molecules for treating Parkinson disease. Support or Funding Information Supported by the Michael J Fox Foundation, the Canadian Institutes of Health Research, and the Canada Research Chair program. Autoinhibited conformation of Parkin. The crystal structure of Parkin revealed that the catalytic and E2‐binding sites are occluded by interdomain contacts mediated by the ubiquitin‐like domain, Repressor Element of Parkin (REP) and RING0 domain . Disruption of the inhibitory contacts derepresses ligase activity. Figure 1 Active complex of Parkin with ubiquitin‐charged E2 enzyme and phospho‐ubiquitin (Ub). The crystal structure of activated Parkin showed that phosphorylation of the Parkin Ubl domain induces a large conformational change allowing the catalytic RING2 domain to interact with the bound E2~Ub . Hydrogen‐deuterium exchange experiments confirm that the RING2 domain is released and accessible upon Ubl binding to RING0. Figure 2
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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".