Structural and functional studies of the Polo like kinase Sak/Plk4
Bibliographic record
Abstract
The four mammalian Polo like kinases (Plks), Plk1, Plk2, Plk3, and Plk4, are regulators of cell cycle progression. Plks are distinguished by the presence of an N-terminal Ser/Thr kinase domain and one or two conserved C-terminal polo box motifs. Plk4 (also known as Sak), the most distant family member, possesses one polo box motif whereas Plk1, Plk2, and Plk3 possess two. Sak plays essential roles in cell cycle regulation, namely in centriole duplication and late mitotic progression. Unlike Plk1, Plk2, and Plk3, the phosphorylation substrates of Sak are not known. Consequently, the question of how Sak regulates centriole duplication and late mitotic progression remains to be determined. The tandem polo boxes of Plk1 mediate Plk1 subcellular localization and autoinhibits its kinase domain. It is not known if the single polo box of Sak regulates kinase catalytic function or mediates localization. I have determined the x-ray crystal structure of the Sak polo box and shown that it constitutes an autonomously folding domain, which we termed the polo domain. As observed by others for Plk1, the Sak polo domain is sufficient for Sak subcellular localization to centrosomes and the cleavage furrow. I also find that the Sak polo domain does not regulate the catalytic activity of the adjacent kinase domain in the manner observed for Plk1. I have identified a novel domain present in Sak, and not in Plk1, Plk2, Plk3, or any other known protein, which I have termed the kinase interacting module (KIM). The KIM domain can mediate Sak subcellular localization to mitotic structures, can interact with the adjacent kinase domain, but does not affect catalytic efficiency in vitro. Finally, I have characterized the target phosphorylation consensus of the Sak catalytic domain to be Æ -- [Ile/Leu/Val] --Ser/Thr- phis;- phis;-x-Æ/Pro (where residues in brackets are selected against, phis; denotes a hydrophobic residue, and Æ denotes a charged residue dependent on the context of the surrounding sequence). I posit that this consensus will help in the identification of in vivo Sak substrates, which will in turn be key to understanding how Sak mediates centriole duplication and exit from mitosis.
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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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".