Enzyme sheds light on programmed cell death

Data on a complex enzyme that lies at the crossroad between cell suicide and tumor suppression has opened a promising front in the battle to find effective treatments for stroke and cancer.

Scientists at Vanderbilt University and Northwestern University (both US) have determined the three-dimensional structure of a critical region of death associated protein kinase (DAPK) and created a quantitative assay capable of measuring its activity.

DAPK contains a 'death domain' that can initiate a cascade of molecular events that cause a cell to commit suicide. This process, called programmed cell death or apoptosis, is programmed into all but the most primitive of cells. It causes the cell to shut down in an orderly manner so that its contents can be absorbed by surrounding cells without initiating an attack by the body's internal self-defense systems. This is particularly important in enclosed areas like the brain.

Previous research has implicated DAPK in a wide range of apoptotic systems and suggests that it is activated very early in the process, well before the cell becomes irreversibly committed to self-destruction.

Another region of DAPK has been labeled the kinase domain. Its role is to strip phosphates from adenosine triphosphate (ATP) - a molecule involved in enzyme regulation - and attach them to certain other proteins, called substrates. This process is called phosphorylation and it is a common method of turning cellular processes on and off.

Scientists have determined that DAPK's kinase domain is intimately involved in triggering the process of programmed cell death, but they do not know how. The determination of the domain's structure and the ability to evaluate DAPK's activity provide an important foundation for future investigations addressing this question.

"Currently, there is nothing that doctors can do to address the fundamental cause of neuronal death during this period," Martin Waterson, director of the Drug Discovery Program at Northwestern University, says. "So there is considerable interest in the possibility that administering a drug that inhibits DAPK activity during this period might reduce brain damage."

Before this idea can be tested, however, researchers must find small molecules that effectively inhibit DAPK activation. The determination of the structure of DAPK's kinase domain and the development of a quantitative assay now make it possible for drug researchers to develop efficient methods for identifying candidate inhibitors and to employ structure-assisted design procedures to create them from scratch.