CDK-activating kinase

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CDK-activating kinase (CAK) is the enzyme that helps turn on cyclin-dependent kinases (Cdks) by adding a phosphate to threonine-160 in the Cdk activation loop. CAK belongs to the CDK family and helps activate Cdks 1 through 6.

Activation of Cdks happens in two steps: first, a cyclin binds to the Cdk, and second, CAK phosphorylates the activation segment on threonine-160. This phosphorylation is necessary for activity and is a post-translational modification. Cdks must be free of inhibitors and bound to cyclins for CAK to act, so CAK activity is indirectly regulated by cyclins.

CAK activity stays high through the cell cycle and is not controlled by a classic cell-cycle checkpoint, though it is lower in resting (G0) cells and can be higher in some cancer cells. In mammals, CAK can phosphorylate only after cyclin binding; in budding yeast, CAK can act before cyclin binding. In both humans and yeast, cyclin binding is the rate-limiting step for Cdk activation.

Beyond activating Cdks, CAK also helps regulate transcription and is highly conserved. In vertebrates and Drosophila, CAK is a three-part complex made of Cdk7, cyclin H, and Mat1. Cdk7 activates Cdks; Mat1 helps with transcription. The need for phosphorylation of Cdk7’s activation segment depends on Mat1: with Mat1 present, phosphorylation may not be essential for CAK activity; without Mat1, it is required. In vertebrates, CAK is mainly in the nucleus, linking cell-cycle control to transcription. Cdk7 also phosphorylates components of the transcription machinery.

In budding yeast, Cak1 is a lone cytoplasmic kinase that activates Cdks, while Kin28 (the Cdk7 homolog) does not have CAK activity. Fission yeast have two CAKs: Msc6–Msc2 (similar to vertebrate CAK and TFIIH) and Csk1 (like Cak1), with overlapping and specialized roles.

Structurally, cyclin binding to a Cdk causes the active site to rearrange, and CAK phosphorylation on Thr-160 stabilizes the active form and improves interaction with substrates, including those with SPXK sequences. Different cyclins induce different shapes in Cdks, but both cyclin binding and CAK phosphorylation are required for full activation.

CAK also exists in two forms: free CAK, which phosphorylates Cdks to drive the cell cycle, and TFIIH-associated CAK, which helps regulate transcription. TFIIH-associated CAK phosphorylates factors like RNA polymerase II and assists promoter clearance and transcription initiation. In vertebrates, TFIIH-associated CAK links transcription to DNA damage responses; damage can reduce CAK activity, helping to pause the cell cycle and protect genome integrity.