Different mechanisms of CDK5 and CDK2 activation as revealed by CDK5/p25 and CDK2/cyclin A dynamics
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
16407256
DOI
10.1074/jbc.m509699200
PII: S0021-9258(19)35348-7
Knihovny.cz E-resources
- MeSH
- Models, Chemical MeSH
- Cyclin A chemistry metabolism MeSH
- Cyclin-Dependent Kinase 2 metabolism MeSH
- Cyclin-Dependent Kinase 5 metabolism MeSH
- Phosphorylation MeSH
- Phylogeny MeSH
- Protein Kinase Inhibitors chemistry pharmacology MeSH
- Protein Conformation MeSH
- Humans MeSH
- Molecular Conformation MeSH
- Models, Molecular MeSH
- Cell Cycle Proteins chemistry MeSH
- Nerve Tissue Proteins metabolism MeSH
- Purines chemistry pharmacology MeSH
- Roscovitine MeSH
- Protein Structure, Secondary MeSH
- Stereoisomerism MeSH
- Substrate Specificity MeSH
- Protein Structure, Tertiary MeSH
- Threonine chemistry MeSH
- Tyrosine chemistry MeSH
- Hydrogen Bonding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cyclin A MeSH
- Cyclin-Dependent Kinase 2 MeSH
- Cyclin-Dependent Kinase 5 MeSH
- Protein Kinase Inhibitors MeSH
- neuronal Cdk5 activator (p25-p35) MeSH Browser
- Cell Cycle Proteins MeSH
- Nerve Tissue Proteins MeSH
- Purines MeSH
- Roscovitine MeSH
- Threonine MeSH
- Tyrosine MeSH
A detailed analysis is presented of the dynamics of human CDK5 in complexes with the protein activator p25 and the purine-like inhibitor roscovitine. These and other findings related to the activation of CDK5 are critically reviewed from a molecular perspective. In addition, the results obtained on the behavior of CDK5 are compared with data on CDK2 to assess the differences and similarities between the two kinases in terms of (i) roscovitine binding, (ii) regulatory subunit association, (iii) conformational changes in the T-loop following CDK/regulatory subunit complex formation, and (iv) specificity in CDK/regulatory subunit recognition. An energy decomposition analysis, used for these purposes, revealed why the binding of p25 alone is sufficient to stabilize the extended active T-loop conformation of CDK5, whereas the equivalent conformational change in CDK2 requires both the binding of cyclin A and phosphorylation of the Thr(160) residue. The interaction energy of the CDK5 T-loop with p25 is about 26 kcal.mol(-1) greater than that of the CDK2 T-loop with cyclin A. The binding pattern between CDK5 and p25 was compared with that of CDK2/cyclin A to find specific regions involved in CDK/regulatory subunit recognition. The analyses performed revealed that the alphaNT-helix of cyclin A interacts with the alpha6-alpha7 loop and the alpha7 helix of CDK2, but these regions do not interact in the CDK5/p25 complex. Further differences between the CDK5/p25 and CDK2/cyclin A systems studied are discussed with respect to their specific functionality.
References provided by Crossref.org
Two C-terminal ankyrin repeats form the minimal stable unit of the ankyrin repeat protein p18INK4c
Functional flexibility of human cyclin-dependent kinase-2 and its evolutionary conservation
