Cell growth and division are essential to life. In eukaryotes, the sequence of events leading to these processes is coordinated by a family of proteins called cyclin-dependent kinases (CDKs). The activity of CDKs is tightly controlled, and defects in its regulation often result in abnormal tissue growth and cancer. Thus, understanding the molecular mechanism of how CDK activity is controlled is important for understanding cancer biology.

Adapted from Song et al.

The kinase activity of a CDK is activated by binding to its effector partner protein in the cyclin family, and by phosphorylation of a conserved Thr in CDK. Deactivation requires both degradation of the cyclin molecule and dephosphorylation by a CDK-associated phosphatase. To define the structural basis of CDK dephosphorylation that leads to inactivation, Song et al. (Mol. Cell, 7, 615–626; 2001) have determined the crystal structure of phosphorylated CDK2 (pCDK2) in complex with a kinase-associated phosphatase (KAP).

The structure reveals that the active site of KAP (the catalytic residues at positions 110 and 140 are marked by spheres; KAP is cyan) interacts almost exclusively with the phosphate moiety of the phosphorylated Thr (pThr 160) in CDK2 (yellow). Specific recognition between the two proteins is mostly mediated by residues in the C-terminal lobe of CDK2 (αG helix and L14 loop) and those in the C-terminal helix (magenta) of KAP; these residues are removed from the active site of KAP. Thus, specific recognition of pCDK2 by KAP requires the native fold of the CDK2 molecule; notably, the sequence of the kinase activation segment (green) bearing the phosphorylated Thr residue does not play a significant role.

The kinase activation segment (green) is drawn away from the surface of pCDK2 in the complex. This conformation is different from that in all other determined structures of pCDK2, indicating that local unfolding may be necessary to expose the phosphate moiety for interaction with KAP. The kinase is in the active conformation, similar to that observed in the pCDK2–cyclin complex. This suggests that KAP may preferentially recognize pCDK2 in the context of the activated complex. The structure of the pCDK2–KAP complex therefore provides insights into the dephosphorylation — and inactivation — mechanism of CDKs.