期刊
EMBO JOURNAL
卷 40, 期 2, 页码 -出版社
WILEY
DOI: 10.15252/embj.2020105839
关键词
cell cycle; cyclin docking; cyclin-dependent kinase; phosphorylation; short linear motifs
资金
- ERC [649124]
- Estonian Science Agency [PRG550]
- Centre of Excellence for Molecular Cell Technologies [TK143]
- European Research Council (ERC) [649124] Funding Source: European Research Council (ERC)
Cyclin-dependent kinases (CDKs) are regulated by different cyclins throughout the cell cycle, with the NLxxxL docking motif playing a crucial role in the phosphorylation-dependent degradation of the CDK inhibitor Far1 at the G1/S stage in yeast. This motif is specifically recognized by the S-phase CDK (S-CDK) Clb5/6-Cdc28, indicating its importance in controlling cell cycle events. Additionally, the NLxxxL motif governs S-cyclin-specificity in multiple yeast CDK targets, suggesting its significance in fine-tuning cell cycle processes.
Cyclin-dependent kinases (CDKs), the master regulators of cell division, are activated by different cyclins at different cell cycle stages. In addition to being activators of CDKs, cyclins recognize various linear motifs to target CDK activity to specific proteins. We uncovered a cyclin docking motif, NLxxxL, that contributes to phosphorylation-dependent degradation of the CDK inhibitor Far1 at the G1/S stage in the yeast Saccharomyces cerevisiae. This motif is recognized exclusively by S-phase CDK (S-CDK) Clb5/6-Cdc28 and is considerably more potent than the conventional RxL docking motif. The NLxxxL and RxL motifs were found to overlap in some target proteins, suggesting that cyclin docking motifs can evolve to switch from one to another for fine-tuning of cell cycle events. Using time-lapse fluorescence microscopy, we show how different docking connections temporally control phosphorylation-driven target degradation. This also revealed a differential function of the phosphoadaptor protein Cks1, as Cks1 docking potentiated degron phosphorylation of RxL-containing but not of NLxxxL-containing substrates. The NLxxxL motif was found to govern S-cyclin-specificity in multiple yeast CDK targets including Fin1, Lif1, and Slx4, suggesting its wider importance.
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