Cyclin-dependent kinases (CDKs) are typical serine/threonine kinases that display the 11 subdomains shared by all kinases. The complete sequence of the Homo sapiens genome shows that among the ~30,000 predicted genes, there are 13 CDKs and 25 cyclins. Eleven CDKS and their associated cyclins have been characterized in man.
The structure of CDK2 consists of an amino-terminal lobe rich in β-sheets and a larger, mostly α-helical, carboxy-terminal lobe. The ATP binding site is located in a deep cleft between the two lobes that contain the conserved catalytic residues. Crystallographic studies have shown the importance of cyclin binding upon CDK2 as it forces the kinase subunit into an active conformation. The T-loop, which blocks substrate access in monomeric CDK2, moves to the outside of the catalytic cleft after binding cyclin A. This then permits the activating phosphorylation of Thr160 (by CDK7/cyclinH/MAT1). The second conformational change induced by cyclin binding is found within the ATP-binding site where a reorientation of the amino acid side chains induces the alignment of the triphosphate of ATP, which is necessary for phosphate transfer. The high degree of sequence homology between the catalytic domains of different CDKs suggests that their 3-dimensional structures will be similar. This has been essentially confirmed with CDK5 and CDK6.
Progression through the G1, S, G2, M phases of the cell cycle is directly controlled by CDKs. In early-mid G1, extracellular signals modulate the activation of CDK4 and CDK6, which are associated with D-type cyclins. These complexes phosphorylate and thereby inactivate the retinoblastoma protein pRb, resulting in the release of E2F and DP1 transcription factors that control the expression of genes required for the G1/S transition and S phase progression. The CDK2/cyclin E complex, which is responsible for the G1/S phase transition, also regulates centrosome duplication. During S phase, CDK2/cyclinA phosphorylates different substrates allowing DNA replication and the inactivation of G1 transcription factors. Around the S/G2 phase transition, CDK1 associates with cyclin A. Later, CDK1/cyclinB appears and triggers the G2/M phase transition by phosphorylating a large set of substrates. Phosphorylation of the anaphase promoting complex (APC) by CDK1/cyclin B is required for the transition to anaphase and completion of mitosis. These successive waves of CDK/cyclin assemblies and activations are tightly regulated by post-translational modifications and by intracellular translocations. They are coordinated and dependent on the completion of previous steps, through so-called “checkpoint” controls. Recent studies using knock out experiments performed in mice suggest that CDK2 and CDK3 may be dispensable, whereas CDK1, CDK5 and CDK11 are essential genes.
Some CDKs directly regulate transcription. CDK7/cyclin H/MAT1 is a component of the transcription factor TFIIH. Both CDK7/cyclin H and CDK8/cyclin C phosphorylate the C-terminal domain of the largest subunit of RNA polymerase II, which is required for elongation. CDK9/cyclin T is a component of the positive transcription elongation factor P-TEFb. It is responsible for the Tat-associated kinase activity involved in HIV-1 Tat transactivation.
CDK5 activity is important for outgrowth of neurites and neuronal development, for myogenesis and for somite organization in embryos. An interesting aspect of CDK5 is the nature of its associated regulatory subunits, p35 or p25, a proteolytic cleavage product. Despite their evolutionary distance from cyclins, the predicted structure of p35/p25 shows a similar fold to that of cyclins, which explains the efficient activation of CDK5. Conversion of p35 to p25 leads to constitutive activation of CDK5 and alteration of its cellular localization. CDK5/p25 expression in cultured primary neurons triggers apoptosis. A considerable amount of evidence links CDK5 activity to cytoskeletal abnormalities that can lead to neuronal death as observed in Alzheimer’s disease. CDK2, CDK5 and CDK11 have an essential function in apoptosis. CDK5 also acts as a downstream element of dopamine signaling by phosphorylating the striatum-specific DARPP-32 protein which then becomes an inhibitor of PKA.
The involvement of CDKs in many physiological functions and diseases has led to the identification of over 70 potent pharmacological inhibitors. Over 30 of these inhibitors have been co-crystallized with CDK2, CDK5 or CDK6. Pharmacological inhibitors of CDKs have been evaluated for therapeutic use against cancer, alopecia, neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke), cardiovascular disorders (restenosis), glomerulonephritis, viral infections (HCMV/HIV/HSV) and parasitic protozoa (Plasmodium).
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