Dynamics of human CDK2 and CDK5 studied by computer simulations

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Authors

OTYEPKA Michal BÁRTOVÁ Iveta KŘÍŽ Zdeněk KOČA Jaroslav

Year of publication 2005
Type Article in Proceedings
Conference Cellular and Molecular Biology Letters
MU Faculty or unit

Faculty of Science

Citation
Field Physical chemistry and theoretical chemistry
Keywords Molecular Dynamics; Interaction Energy; phosphorylation; CDK2; CDK5
Description Cyclin-dependent kinases (CDKs) control progression of the cell cycle, apoptosis, transcription, and differentiation in neuronal cells. CDK consists of two subunits, a catalytic subunit kinase and regulatory protein cyclin. Several CDKs (CDK1, CDK2, CDK4 and CDK6) show a dual mechanism of activation based on cyclin binding and phosphorylation of the activation loop. This model of activation, however, does not apply to CDK5, despite 60% sequence identity to CDK2. CDK5 is a unique member of the CDK family, as it is not activated by a cyclin. Instead, CDK5 activity is triggered by p35 and p39, proteins whose expression is limited to neurons and to a few other cell types [1]. Association of CDK5 with p35 or p39 is enough to full activate CDK5. Furthermore, CDK5 seems not to be activated by phosphorylation in the activation loop, even if this contains a potential phosphorylation site (Ser159, equivalent to Thr160 of CDK2) [2, 3]. Additionally, phosphorylation of the glycine-rich loop (G-loop) is inhibitory for CDK2 or CDK1 but it seems to be stimulatory for CDK5 [4]. The phosphorylation of Thr14 and Tyr15 in the G-loop is an important element of CDK regulation machinery. Structural aspects of that were recently studied on CDK2 using molecular dynamics [6, 7]. The Tyr15-CDK5 activatory phosphorylation structural mechanism has been speculated by Mapelli et al. [3] namely in context of roscovitine binding. The simulation on phosho-Tyr15-CDK5/p25/roscovitine complex shows that Tyr15 phosphorylation leads to Tyr15 exposure to solvent and also to G-loop shift. Phoshorylated Tyr15 behaves similarly to phospho-Tyr15 in CDK2, which causes also exposure of phosphate group to the solvent but produces also notable shift of the G-loop [7]. The analysis of interaction energies between roscovitine and CDK5 and pTyr15-CDK5 documents that Tyr15 phosphorylation has negligible influence on roscovitine binding in according to experimental observations [3]. Also, the interaction pattern between CDK/regulatory unit will be discussed in detail (specifita CDK-Cyklin).
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