Cell cycle regulating
enzymes, CDKs, become activated upon association with their regulatory
proteins,
cyclins. The G1
cyclin,
cyclin E, is overexpressed and present in low molecular weight (LMW)
isoforms in
breast cancer cells and
tumor tissues. In vivo and in vitro studies have shown that these LMW
isoforms of
cyclin E hyperactivate CDK2 and accelerate the G1-S phase of cell division. The molecular basis of CDK2 hyperactivation due to LMW
cyclin E isoforms in
cancer cells is, however, unknown. Here, we employ a computational approach, combining homology modeling, bioinformatics analyses, molecular dynamics (MD) simulations, and principal component analyses to unravel the key structural features of CDK2-bound full-length and LMW
isoforms of
cyclin E1 and correlate those features to their differential activity. Results suggest that the missing N- and C-terminal regions of the
cyclin E LMW
isoforms constitute the Nuclear Localization Sequence (NLS) and PEST domains and are intrinsically disordered. These regions, when present in the full-length
cyclin E/CDK2 complex, weaken the
cyclin-CDK interface packing due to the loss of a large number of key interface interactions. Such weakening is manifested in the decreased contact area and increased
solvent accessibility at the interface and also by the absence of concerted motions between the two partner
proteins in the full-length complex. More effective packing and interactions between CDK2 and LMW
cyclin E isoforms, however, produce more efficient
protein-
protein complexes that accelerate the cell division processes in
cancer cells, where these
cyclin E isoforms are overexpressed.