Importin-β mediates Cdc7 nuclear import by binding to Kinase Insert II, which can be antagonized by importin-α
Bibliographic record
Abstract
4899 The Cdc7-Dbf4 kinase (aka, DDK for Dbf4-dependent kinase) functions as a molecular switch connecting cell cycle engine (Cdks) and the replication machinery, and is essential for the activation of DNA replication throughout S phase. However, excessive levels of Cdc7 can elevate mutation rates or cause abnormal cell-cycle arrest, which may lead to genome instability and, eventually, to tumorigenesis. To be functional, both the catalytic Cdc7 and regulatory Dbf4 subunits must be located in the nucleus. The nuclear import of Dbf4 protein is mediated by the classical importin-α/-β pathway. However, it is currently unknown about how Cdc7 is translocated into the nucleus. Since Cdc7 does not contain any known nuclear localization sequence, it was initially suggested that Cdc7 may be imported into the nucleus by Dbf4. However, we and others subsequently found that Cdc7 is nuclear localized even when Dbf4 is not produced. Here, we report that importin-β directly binds to the Kinase insert II domain of human Cdc7, and promotes its nuclear import. Interestingly, both importin-α and -β can bind to Cdc7 through the Kinase Insert II. However, the binding affinity of Cdc7 for the importin-β is considerably higher than for importin-α at low protein concentrations. Immunodepletion of importin-β, but not importin-α, abrogates Cdc7 nuclear import in digitonin-permeabilized cells. Adding purified recombinant importin-β, but not importin-α, to the importin-depleted cytosol restores Cdc7 nuclear import. Furthermore, transduction of anti-importin-β antibodies, but not -importin-α antibodies, into live cells inhibits Cdc7 nuclear import. Most interestingly, we have found that the importin-β mediated Cdc7 nuclear import is inhibited by competitive binding of Cdc7 by importin-α. This inhibition of Cdc7 nuclear import by importin-α is independent of its ability to bind to importin-β. Thus, the role of importin-α in the Cdc7 nuclear localization regulation is exactly opposite to its role in the classical nuclear import of proteins containing a nuclear localization sequence. This paper, for the first time, reports a mechanism of how importin-α can impede importin-β-mediated protein nuclear import.
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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) | 0.002 | 0.001 |
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".