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Published online before print November 27, 2007
Protein Science, DOI: 10.1110/ps.072951208
 Copyright © 2007 The Protein Society
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Functional flexibility of human cyclin-dependent kinase-2 and its evolutionary conservation

Iveta Bártová1,2,3, Jaroslav Koca3, and Michal Otyepka1,2

1 Department of Physical Chemistry, Palacky University, 771 46 Olomouc, Czech Republic
2 Center for Biomolecular and Complex Molecular Systems, Palacky University, 771 46 Olomouc, Czech Republic
3 National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic

(RECEIVED April 16, 2007; FINAL REVISION September 18, 2007; ACCEPTED September 22, 2007)

Cyclin-dependent kinase 2 (CDK2) is the most thoroughly studied of the cyclin-dependent kinases that regulate essential cellular processes, including the cell cycle, and it has become a model for studies of regulatory mechanisms at the molecular level. This contribution identifies flexible and rigid regions of CDK2 based on temperature B-factors acquired from both X-ray data and molecular dynamics simulations. In addition, the biological relevance of the identified flexible regions and their motions is explored using information from the essential dynamics analysis related to conformational changes of CDK2 and knowledge of its biological function(s). The conserved regions of CMGC protein kinases' primary sequences are located in the most rigid regions identified in our analyses, with the sole exception of the absolutely conserved G13 in the tip of the glycine-rich loop. The conserved rigid regions are important for nucleotide binding, catalysis, and substrate recognition. In contrast, the most flexible regions correlate with those where large conformational changes occur during CDK2 regulation processes. The rigid regions flank and form a rigid skeleton for the flexible regions, which appear to provide the plasticity required for CDK2 regulation. Unlike the rigid regions (which as mentioned are highly conserved) no evidence of evolutionary conservation was found for the flexible regions.

Keywords: protein; dynamics; evolutionary conservation; cell cycle; protein kinase

Reprint requests to: Michal Otyepka, Department of Physical Chemistry and Center for Biomolecular and Complex Molecular Systems, Palacky University, trída Svobody 26, 771 46 Olomouc, Czech Republic; e-mail: otyepka{at}aix.upol.cz; fax: +420-58-5634756.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.072951208.


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