Multisite phosphorylation by Cdk1 initiates delayed negative feedback to control mitotic transcription
| Autor: | Mihkel Örd, Mart Loog, David O. Morgan, Jonathan B. Asfaha, Christopher R. Carlson, Ilona Faustova |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Saccharomyces cerevisiae Proteins
Cdk 1.1 Normal biological development and functioning Mitosis Cell Cycle Proteins Saccharomyces cerevisiae Cyclin B environment and public health Medical and Health Sciences General Biochemistry Genetics and Molecular Biology Article Feedback Clb2 03 medical and health sciences Substrate-level phosphorylation 0302 clinical medicine multisite phosphorylation Cyclin-dependent kinase Underpinning research Cyclins CDC2 Protein Kinase Genetics Ndd1 Phosphorylation Cks1 030304 developmental biology Cyclin 0303 health sciences Cyclin-dependent kinase 1 biology Kinase Chemistry Psychology and Cognitive Sciences Cell cycle Biological Sciences cyclin gene expression Cell biology enzymes and coenzymes (carbohydrates) biology.protein cell cycle phosphodegron General Agricultural and Biological Sciences 030217 neurology & neurosurgery Transcription Factors Developmental Biology |
| Zdroj: | Current biology : CB, vol 32, iss 1 Curr Biol bioRxiv |
| Popis: | SummaryCell-cycle progression is driven by the phosphorylation of cyclin-dependent kinase (Cdk) substrates1–3. The order of substrate phosphorylation depends in part on the general rise in Cdk activity during the cell cycle4–7, together with variations in substrate docking to sites on associated cyclin and Cks subunits3, 6, 8–10. Many substrates are modified at multiple sites to provide more complex regulation9, 11–14. Here, we describe an elegant regulatory circuit based on multisite phosphorylation of Ndd1, a transcriptional co-activator of genes required for mitotic progression15, 16. As cells enter mitosis, Ndd1 phosphorylation by Cdk1 is known to promote mitotic cyclin (CLB2) gene transcription, resulting in positive feedback17–20. Consistent with these findings, we show that low Cdk1 activity promotes CLB2 expression at mitotic entry. We also find, however, that CLB2 expression is inhibited by high levels of Cdk1 activity in a mitotic arrest. Inhibition is accompanied by Ndd1 degradation, and we present evidence that high mitotic Cdk1-Clb2 activity generates phosphodegrons on Ndd1, leading to its degradation. Complete Ndd1 phosphorylation by the Clb2-Cdk1-Cks1 complex requires the phosphothreonine-binding site of Cks1, as well as a novel phosphate-binding pocket on the cyclin Clb221. We therefore propose that initial phosphorylation by Cdk1 primes the protein for secondary phosphorylation at phosphodegrons, resulting in degradation only at high Cdk1 activity. Together, our results suggest that rising levels of mitotic Cdk1 activity act at multiple phosphorylation sites on Ndd1, first triggering rapid positive feedback and then promoting delayed negative feedback, resulting in a pulse of mitotic gene expression. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|