Molecular mechanism of an enzyme involved in breast cancer and intellectual disability

Molecular mechanism of an enzyme involved in breast cancer and intellectual disability

In recent years, researchers have focussed on the enzyme Tousled-like kinases (TLK2) suspecting it of playing a main role in several diseases. A new study conducted now reveals that the enzyme displays lower levels of activity in intellectual disability and that it is possible to inhibit it in breast cancer, where it is overactive. The study thus suggests that the enzyme may be a target for potential therapies.

In order to maintain genome stability in the cells the enzyme TLK2 constantly strives to attach phosphate to proteins. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear.

In recent years the enzyme has been linked to various diseases. For example, researchers have discovered that the gene coding for the enzyme is overexpressed in patients suffering from ER-positive breast cancer and mutated in intellectual disability, but up until now no one has been able to outline the behavior of the enzyme.

Now researchers have taken a big step forwards and managed to outline the enzyme all the way to the molecular level using X-ray crystallography. Their study, which has just been published in the scientific journal Nature Communications, suggests that the enzyme activity diminishes in patients suffering from intellectual disability. Conversely, it seems to be possible to inhibit the enzyme in patients with breast cancer, where it is overactive.

Authors show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity.

They have also taken as their starting point previous studies showing that patients suffering from intellectual disability have a mutation in genes affecting the TLK2 enzyme. They also show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies.

In addition, they have drawn on knowledge from other studies revealing that the enzyme is overactive in so-called ER-positive breast cancer. On this basis they have tested several so-called small molecule drugs and learned that it is possible to inhibit the activity of the enzyme in material isolated from human cells.

The researchers will now seek to learn more about how the enzyme can be targeted and either be inhibited or activated in patients with these conditions.