Proteins that pack a punch

Bacteria that cause illnesses like pneumonia, sore throats and gastro release protein toxins that attack us by punching holes in our cells. Bacteria do this to feed and get nutrients from our cells.

Michael Parker is an honorary Professor of Biochemistry and Molecular Biology at the University of Melbourne’s Bio 21 Institute, and Deputy Director of St Vincent’s Institute of Medical Research. He is a world leader in the field of protein-cell membrane interactions.

The protein molecules we eat are broken down and then reformed into a diverse array of shapes and sizes to become the essential building blocks and molecular machines of our body. They can be found both inside and outside cells as well as within the membrane that encapsulates all cells. 

When the body’s normal proteins interact with molecules on cell membranes they activate the body’s normal functions. But some foreign proteins can disrupt normal function.  

Professor Parker explains that the proteins which interest him in his research are the hole-punching toxins released from bacteria, which recognise cholesterol found in cell membranes, and assemble there in donut shape. 

“These ‘donuts of death’ change shape, unfurling a physical punch to blast a hole across the cell membrane. This cell punching can often increase the severity of a bacterial infection.

“The action of proteins is dictated by their precise three-dimensional molecular structures,” he says.

“So if we can determine the protein structure, we can identify which parts of the protein interact with the cell, and how they do so. We can work out how diseases proceed at the atomic level. But more importantly it also provides the basis for the design of drugs that could thwart the punching of cells.”

Professor Parkers says that understanding 3D protein structures has enabled researchers to design ‘smart drugs’, where chemists can custom-design drugs to interact with proteins that cause disease. 

“This has the potential to shave years and millions of dollars off traditional drug-design approaches,” Professor Parker says. 

A key example of this work was a project in the late 1990s in which Professor Parker, with colleague Professor Colin Masters from the University of Melbourne, sought to determine the complete structure of amyloid precursor protein, a cell membrane-bound receptor that plays a central role in Alzheimer’s disease.

This work has led to an understanding of some of the normal roles of the protein. 

Most excitingly, using the Australian Synchrotron the team has obtained a detailed picture of how current Alzheimer’s drugs in clinical trials interact with proteins.

One of Dr Parker’s current projects is looking at a particular gangrene-causing bacterium. With his colleague Dr Mike Kuiper from the Victorian Life Sciences Computation Initiative the researchers have constructed colourful computer simulations of the 3D ‘donut of death’ protein clustering on cell surfaces and packing a punch. 

“These computer simulations are really useful as they can show you surprising new perspectives that inspire experiments both on computer and in the laboratory. Not only could we design drugs to stop the donuts of death forming but we could also make protein donuts to use as biosensors that could measure the flow of chemicals inside and outside cells.

“Bacterial toxins are exciting work. A hole-punching toxin called lectinolysin from a bacterium found in the mouth and throat recognises sugars on the surface of cancer cells. 

“Imagine if we could engineer this protein toxin to punch a hole in these cancer cells but leave normal cells alone – a so-called ‘magic bullet’. Protein structures not only allow us to ‘see’ biological processes but also imagine new useful ones,” Professor Parker says. 

www.bio21.unimelb.edu.au