VAC14 oligomerization is essential for the function of the FAB1/PIKfyve–VAC14–FIG4 complex
Bibliographic record
Abstract
The PIKfyve–VAC14–FIG4 complex synthesizes and turns over phosphatidylinositol-3,5-bisphosphate, PI(3,5)P2, an essential signaling lipid. A medium-resolution structure revealed that VAC14 forms a star-shaped pentamer scaffold. Two legs of VAC14 bind FIG4, with one leg also occupied by PIKfyve. The significance of VAC14 oligomerization was unknown. Here, using Alphafold2 and cryogenic electron microscopy maps we generated an atomic-resolution prediction, and found that some mutations linked to pediatric neurodegenerative diseases reside in the VAC14–VAC14 interfaces. A corresponding yeast mutation, along with additional mutations, demonstrates that VAC14 oligomerization is critical for Fab1/PIKfyve function. These mutations cause defects in the generation of PI(3,5)P2, in VAC14 localization, and in VAC14 oligomerization. Similarly, VAC14 patient mutations expressed in human VAC14 knockout (KO) cells, are defective in the formation of the PIKfyve–VAC14–FIG4 complex, as measured by pull-down assays, are defective in VAC14 oligomerization as measured by fluorescence-detection size-exclusion chromatography of cell lysates, and are defective in colocalization with VPS35-containing endosomes. These studies show that VAC14 oligomerization plays a crucial role in the regulation of PIKfyve/FAB1 and provide insights into selected patient mutations. Moreover, they suggest that small molecules that stabilize the VAC14 complex may provide an intervention for diseases linked to mutations in VAC14.
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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".