The unusual structure of the ubiquitin-like domain of the protein sacsin
Bibliographic record
Abstract
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a progressive neurodegenerative disorder that first presents in early childhood, with prominent symptoms of spasticity in limbs, gait ataxia, slower motor development, muscle wasting and slurred speech. The disease is due to mutations in the SACS gene, which codes for sacsin, a large multidomain protein found in neurons. Loss of sacsin function is associated with progressive loss of cerebellar Purkinje cells and hyperfused mitochondrial network, most likely due to loss of the mitochondrial fission efficiency. Most of sacsin is structurally and functionally uncharacterized. Sacsin is believed to play a role as a chaperone for promoting the folding of ataxia-related proteins. Bioinformatics analysis showed that sacsin contains an integral ubiquitin-like domain (UBL) domain, which was subsequently shown to weakly interact with the proteasomal subunit C-8 in the co-immunoprecipitation studies. The research work described in this thesis includes the incorporation of selenomethionine in the UBL sequence, crystallization of the selenomethionine-labeled UBL domain to produce well-diffracting crystals, and determination of the structure of the UBL domain by using the anomalous scattering signal from selenium. The UBL structure obtained is unusual as it is a swapped dimer formed by the exchange of the N-terminal portions of two molecules. The existence of dimer was confirmed in solution by PFG-NMR self-diffusion experiments. The hydrophobic patch that is usually responsible for interaction of the UBL domain with other proteins is occluded in the swapped dimer, which suggests that the sacsin UBL domain does not bind the proteasome as a dimer.
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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".