Journal Article

Allostery governs Cdk2 activation and differential recognition of CDK inhibitors

Rasmussen, Damien M., Subrahmanian, Manu V., Engel, Tiffany A., Veglia, Gianluigi, Thomas, David D., Muretta, Joseph M., Levinson, Nicholas M., Thompson, Andrew R., Majumdar, Abir, Burban, David J.

2021

Overview

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). Dissection of the allosteric coupling in the cyclin-dependent kinase Cdk2 shows that this allostery explains how the kinase is activated by cyclin binding and phosphorylation and how it differentiates between Cdk2 and Cdk4 inhibitors.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/45/56 / 631/92/275 / 631/92/458 / 631/92/613 / Allosteric properties / Allosteric Regulation - physiology / Allosteric Site - genetics / Binding / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cancer / Cell Biology / Cell cycle / Cell Cycle - physiology / Cell Cycle Proteins - metabolism / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Coupling / Cyclin A - metabolism / Cyclin-dependent kinase 2 / Cyclin-Dependent Kinase 2 - antagonists & inhibitors / Cyclin-Dependent Kinase 2 - metabolism / Cyclin-dependent kinase 4 / Cyclin-dependent kinases / Cyclin-Dependent Kinases - antagonists & inhibitors / Cyclin-Dependent Kinases - metabolism / Cyclins - metabolism / Humans / Inhibitors / Kinases / Microtubule-Associated Proteins - metabolism / Models, Biological / Phosphorylation / Phosphorylation - physiology / Protein Kinase Inhibitors - metabolism / Protein Kinase Inhibitors - pharmacology / Proto-Oncogene Proteins - metabolism / Recognition / Retina / Retinoblastoma / Substrates / Thermodynamic models / Tumor Suppressor Proteins - metabolism / Wiring