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J. Biol. Chem., Vol. 281, Issue 11, 7271-7281, March 17, 2006

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Different Mechanisms of CDK5 and CDK2 Activation as Revealed by CDK5/p25 and CDK2/Cyclin A Dynamics^*

Michal Otyepka¹, Iveta Bártová, Zdenk Kí, and Jaroslav Koa²

From the Department of Physical Chemistry and Center for Biomolecules and Complex Molecular Systems, Palack University, tr. Svobody 26, 771 46 Olomouc and the National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 5, A-4, 625 00 Brno, Czech Republic

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 Thr¹⁶⁰ 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 NT-helix of cyclin A interacts with the 6-7 loop and the 7 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.

Received for publication, September 2, 2005 , and in revised form, January 9, 2006.

^* This work was supported by the Ministry of Education, Youth, and Sports Projects MSM0021622413 (to I. B., Z. K., and J. K.), MSM6198959216 (to M. O.), and LC512 (to M. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a figure.

¹To whom correspondence may be addressed: Dept. of Physical Chemistry and Centre for Biomolecules and Complex Molecular Systems, Palacky University, tr. Svobody 26, 771 46 Olomouc, Czech Republic. Tel.: 420-5856374756; Fax: 420-585634425; E-mail: otyepka{at}aix.upol.cz. ²To whom correspondence may be addressed: National Centre for Biomolecular Research, Masaryk University, Kamenice 5, A-4, 625 00 Brno, Czech Republic. Tel.: 420-549494947; Fax: 420-549492556; E-mail: jkoca{at}chemi.muni.cz.

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