Role of phosphorylated Thr160 for the activation of the CDK2/Cyclin A complex.
The enzymatic activity of the CDK2/Cyclin A complex increases upon the specific phosphorylation of Thr160@CDK2. In the present study, we have performed a comparative molecular dynamics (MD) study of models of the complex CDK2/Cyclin A/Substrate, which differ for the presence or absence of the phosphate group bound to Thr160. The models are based on two X-ray structures available for CDK2/CyclinA and pCDK2/CyclinA/Substrate complexes. In this way, we analyze the influence of the phosphorylated Thr160 (pThr160) on both the flexibility of CDK2 activation loop (AL) and substrate binding in CDK2. Our calculations point to a decreased flexibility of the AL in the phosphorylated model, in fairly good agreement with experimental data, and to a key role of pThr160 for substrate recognition and stability. Multiple alignments of the CDKs sequences point to the very high conservation of the AL sequence among the CDKs, thus extending our results to all CDKs.
De Vivo
Marco
M
Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy.
Cavalli
Andrea
A
Bottegoni
Giovanni
G
Carloni
Paolo
P
Recanatini
Maurizio
M
D001665:Binding Sites; D019925:Cyclin A / Q000737:chemistry* / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry* / Q000378:metabolism*; D004789:Enzyme Activation; D007700:Kinetics; D008958:Models, Molecular; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding
D019925:Cyclin A; D010769:Phosphothreonine; D051357:Cyclin-Dependent Kinase 2