Cyclin Dependent Kinase (CDK)-enzyme

What are cyclin dependent kinases?

Cyclin dependent kinases (CDKs) are serine/threonine kinases whose activity is cyclin dependent. Based on the sequence similarity, cyclin dependent kinase belongs to CMGC kinase group. CDKs are name as CDK1 through to CDK20. Different eukaryotic organisms have different numbers of CDKs. Only six CDKs are found in budding yeast, which is widely used for the study of CDK function and regulation.

CDK is the catalytic subunit which must associate with a regulatory subunit, cyclin, to function as a kinase. There are approximately 29 cyclins in humans, which are clustered into 16 subfamilies and three major groups. CDKs can bind multiple cyclins to regulate cell cycle. For example, cyclin-dependent kinase 1 (CDK1) is able to form complex either with cyclin A or cyclin B. In humans, there are more than 10 CDKs and 10 cyclins involved in regulating cell division. And CDKs can also be activated by a single cyclin which is responsible for regulating transcription. Transcriptional CDKs are more conserved.

This type of activation mechanism has two major consequences. First, activation of CDKs is tightly regulated by the expression of a particular cyclin subunit. Second, substrate specificity is partially controlled by cyclins.

Activation of cyclin dependent kinases

Like other CMGC kinases, CDKs have some preference for S/T-P-X-K/R. CDKs have a two-lobe structure, an N-terminal lobe and a C-terminal lobe. The activation site is sitting in-between the two lobes.

Much we knew about how CDKs are activated is from the studies of CDk2 activation. CDK2 only has no catalytic activity and the activation of CDKs is a two-step mechanism. Conformation changes occur when CDK2 bind to cyclins, which alter positions of catalytic residues and lead to increased activity of CDK2 for about 5 orders of magnitude. Then phosphorylation of the residue on activation loop (T-loop) further increases CDK2 activity for about 100-fold. There is another regulatory domain located at the N-terminal lobe of CDKs, which phosphorylation results in inhibition of kinase activity. This phosphorylation does not make conformational change of CDKS. But it reduces the binding affinity between CDKs and their substrates. In addition activities of CDKs can be regulated by binding to some other small proteins to inhibit kinase activity. For example, INK4 proteins bind to CDK4 subfamily. The interaction between CDKs and INK4 distorts the cyclin interface and the ATP-binding pocket which prevents activation of CDKs.

Cycline Dependent Kinases and Cell Cycle

The cell division cycle of eukaryotic cells is divided into four phases. There are also three transition stages between four phases, which are G1-S, G2-M and metaphase-anaphase. The mammalian cell cycles are controlled by CDKs. CDKs are constantly expressed in each cell cycle. However, cyclins are expressed and degraded at specific time during the cell cycle. Since CDKs are completely inactive without cyclins, the function of CDKs is regulated by cyclins.

The classical model of cell cycle control is that each cell cycle is regulated by specific CDKs. For example, the complex of CDK2 and cyclin E is responsible for initiating S phase. Cyclin A with CDK1 or CDK2 is required for entry into mitosis.

However, recent genetic studies in mice has implicated that this mechanism is not that simple. Ablation of CDK4 and CDK6 in mice did not show any defects in G1 phase and cell cycle re-entry. Mice that lack CDK2 are viable and healthy, even though CDK2 is widely expressed in all dividing cells. Cell cycle is functional in embryos lacking CDK2, CDK4 and CDK6. Therefore, the clear mechanism of how CDKs regulate cell cycle is still under investigation.

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