New cell movement understanding could impact malaria vaccine development

A research team consisting of researchers from the Walter and Eliza Hall Institute of Medical Research and the University of Chicago has determined that the decades-long understanding of cell movement is flawed.

The team studied the structure of actin-depolymerising factor 1, which is a key protein involved in the movement of malaria parasites and cancer cells. The scientists have gained new understanding of the protein, such as how to cut power to the cell’s “motor,” which could have impact in malaria and cancer treatments in the future.

“ADFs help the cell to recycle actin, a protein which controls critical functions such as cell motility, muscle contraction, and cell division and signaling,” Dr. Jake Baum of the institute’s Infection and Immunity division said. “Actin has unusual properties, being able to spontaneously form polymers which are used by cells to engage internal molecular motors – much like a clutch does in the engine of your car. A suite of accessory proteins control how the clutch is engaged, including those that dismantle or ‘cut’ these polymers, such as ADF1.

"For many years, research in yeast, plants and humans has suggested that the ability of ADFs to dismantle actin polymers – effectively disengaging the clutch – required a small molecular ‘finger’ to break the actin in two. However, when we looked at the malaria ADF1 protein, we were surprised to discover that it lacked this molecular ‘finger’, yet remarkably was still able to cut the polymers. We discovered that a previously overlooked part of the protein, effectively the ‘knuckle’ of the finger-like protrusion, was responsible for dismantling the actin; we then discovered this ‘hidden’ domain was present across all ADFs.”

The team used an Australian Synchrotron to provide extreme detail to pinpoint this protein “knuckle” to prove the segment of the protein responsible for cutting the actin polymers. This new knowledge may help researchers to understand how cells across all species grow, divide and move.

“Knowing that this one small segment of the protein is singularly responsible for ADF1 function means that we need to focus on an entirely new target not only for developing anti-malarial treatments, but also other diseases where potential treatments target actin, such as anti-cancer therapeutics,” Dr. Baum said. “One of the primary goals of the global fight against malaria is to develop novel drugs that prevent infection and transmission in all hosts, to break the malaria cycle. There is a very real possibility that, in the future, drugs could be developed that ‘jam’ this molecular ‘clutch’, meaning the malaria parasite cannot move and continue to infect cells in any of its conventional hosts, which would be a huge breakthrough for the field.”