1. A cancer-derived mutation in the PSTAIRE helix of cyclin-dependent kinase 2 alters the stability of cyclin binding
- Author
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Karen McCague, Emma S. Child, Michal Otyepka, David J. Mann, Tereza Hendrychová, and Andrew Futreal
- Subjects
Models, Molecular ,p27Kip1 ,Cyclin D ,Molecular Sequence Data ,PSTAIRE ,Cyclin A ,Molecular Dynamics Simulation ,Article ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Cyclin-dependent kinase ,Neoplasms ,Cyclin E ,Animals ,Humans ,Molecular Biology ,030304 developmental biology ,Oncogene Proteins ,0303 health sciences ,Cyclin-dependent kinase 1 ,Cyclin binding ,biology ,cdk ,Circular Dichroism ,Cyclin-Dependent Kinase 2 ,Cyclin-dependent kinase 2 ,Cell Biology ,Molecular biology ,Protein Structure, Tertiary ,cdc28 ,Cell biology ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Cyclin-dependent kinase complex ,biological phenomena, cell phenomena, and immunity ,p21Cip1 ,Cyclin A2 ,Protein Binding - Abstract
Cyclin-dependent kinase 2 (cdk2) is a central regulator of the mammalian cell cycle. Here we describe the properties of a mutant form of cdk2 identified during large-scale sequencing of protein kinases from cancerous tissue. The mutation substituted a leucine for a proline in the PSTAIRE helix, the central motif in the interaction of the cdk with its regulatory cyclin subunit. We demonstrate that whilst the mutant cdk2 is considerably impaired in stable cyclin association, it is still able to generate an active kinase that can functionally complement defective cdks in vivo. Molecular dynamic simulations and biophysical measurements indicate that the observed biochemical properties likely stem from increased flexibility within the cyclin-binding helix.
- Published
- 2010
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