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Allostery governs Cdk2 activation and differential recognition of CDK inhibitors.
- Source :
-
Nature chemical biology [Nat Chem Biol] 2021 Apr; Vol. 17 (4), pp. 456-464. Date of Electronic Publication: 2021 Feb 01. - Publication Year :
- 2021
-
Abstract
- Cyclin-dependent kinases (CDKs) are the master regulators of the eukaryotic cell cycle. To become activated, CDKs require both regulatory phosphorylation and binding of a cognate cyclin subunit. We studied the activation process of the G1/S kinase Cdk2 in solution and developed a thermodynamic model that describes the allosteric coupling between regulatory phosphorylation, cyclin binding and inhibitor binding. The results explain why monomeric Cdk2 lacks activity despite sampling an active-like state, reveal that regulatory phosphorylation enhances allosteric coupling with the cyclin subunit and show that this coupling underlies differential recognition of Cdk2 and Cdk4 inhibitors. We identify an allosteric hub that has diverged between Cdk2 and Cdk4 and show that this hub controls the strength of allosteric coupling. The altered allosteric wiring of Cdk4 leads to compromised activity toward generic peptide substrates and comparative specialization toward its primary substrate retinoblastoma (RB).
- Subjects :
- Allosteric Site genetics
Cell Cycle physiology
Cell Cycle Proteins metabolism
Cyclin A metabolism
Cyclin-Dependent Kinase 2 antagonists & inhibitors
Cyclin-Dependent Kinases antagonists & inhibitors
Cyclin-Dependent Kinases metabolism
Cyclins metabolism
Humans
Microtubule-Associated Proteins metabolism
Models, Biological
Phosphorylation physiology
Protein Kinase Inhibitors metabolism
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins metabolism
Tumor Suppressor Proteins metabolism
Allosteric Regulation physiology
Cyclin-Dependent Kinase 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4469
- Volume :
- 17
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Nature chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 33526892
- Full Text :
- https://doi.org/10.1038/s41589-020-00725-y