Subdomain VII of Cyclin-Dependent Kinase 2


Subdomain VII in Cdk2, residues 139-157, is different from that of PKA. PKA has a beta-strand-loop-beta-strand structure, whereas Cdk2 has an alpha-helix, alpha-L12, in place of the second beta-strand(beta-9). The helix runs from residues 147-151. The ATP binding site is adjacent to the short alpha-L12 helix. Because of the alpha-L12helix, the alpha-1 helix is further from the ATP molecule. Therefore the salt bridge between Glu51 and Lys33 is not present in the Cdk2 apoenzyme as it is in cAPK between Glu91 and Lys72. Cyclin A binding, however, melts the alpha-L12 helix and replaces it with the necessary beta-strand 9. This event allows the salt bridge to form, thus activating Cdk2. The conformation of the alpha-L12 helix also prevents the residues in the DGF motif at the N-terminal of the helix (Asp145, Phe146, Gly148) from interacting, as they do in cAPK. In cAPK, they hydrogen bond to form a loop between the backbone carbonyl of Asp184 and the backbone amide of Gly186. In Cdk2, the Asp145 side chain has a different orientation due to the presence of the alpha-L12 helix and the positioning of the side chain of Lys33 side chain.

Subdomain VII in Cdk2 also contains the beginning of the T-loop. The T-loop runs from residues 152-170, and contains the Thr160 phosphorylation site, discussed in the subdomain VIIIpage.