Despite all the work so for on cell cycle control, we  don't know too much how cyclins, the specificity subunit of cyclin-dependent kinases, find their targets. Surprisingly, this is also true for cyclin D, which launches the human cell cycle, at least in part by phosphorylating the retinoblastoma protein, Rb. We should know how cyclin D recognizes Rb, and now we do... it might actually be important for human health. The cyclin D-Cdk4,6-Rb pathway is just now becoming an important cancer therapeutic pathway with a new series of drugs in clinical trials targeting the ATP binding pocket of Cdk4,6. That these Cdk4,6 inhibitors have significant off-target activites raises the possibility that a new class of drugs targeting cyclin substrate recognition based on our helix docking mechanism could improve cancer therapy (seriously).

On another note, there is something interesting about the cyclin D recognition mechanism. Other cyclins recognize short linear motifs in unstructured regions of the target proteins, while we observe a cyclin recognizing a structural element (an alpha-helix that resides within a previously reported unstructured region) in the C-terminus of Rb. This expands our understanding of structural elements responsible for determining cyclin-dependent kinase targets to drive the many facets of cell division.

Finally, much remains to be done, for example, we still don't know all the mechanisms cyclins E or A use to recognize Rb too... and we should understand that since these are interactions at the very core of the eukaryotic cell cycle.

AuthorJan Skotheim