Activation of the ciliary kinase CDKL5 is mediated by the cyclin-dependent kinase CDK20/LF2 to control flagellar length
Bibliographic record
Abstract
Variants in the protein kinase CDKL5 cause CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental condition characterized by seizures, developmental delay, and intellectual disability. The Chlamydomonas homolog of CDKL5, LF5, is a flagellar protein whose loss leads to elongated flagella. Here, we combine live-cell imaging, immunofluorescence, and biochemical approaches including mass spectrometry to define how CDKL5 activity is regulated and how its loss alters ciliary function. We find that Chlamydomonas CDKL5 is activated by LF2, a cyclin-dependent kinase, through phosphorylation of its activation loop. This activation controls CDKL5 localization in steady-state cilia, down-regulates its IFT-mediated transport as flagella reach steady-state, controls ciliary abundance of IFT proteins, and controls phosphorylation of the tubulin-binding domain of IFT74, thereby influencing flagellar length. Mouse Cdkl5 shows similar properties: it localizes within cilia, its loss leads to ciliary elongation, and its localization depends on both its kinase activity and Cdk20, the mammalian ortholog of LF2. These results extend our understanding of ciliary length control, challenge the prevailing model that CDKL5 is activated by autophosphorylation, and suggest that CDD pathogenesis arises, at least in part, from disruption of this conserved ciliary regulatory pathway.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".