The Oxford Science Lecture Series

Dr Claire Naylor

Birkbeck College, University of London

"Pathogenic Proteins : how bacterial agents cause disease "

Dorothy Hodgkin Memorial Lecture 2003

University Museum, Oxford, 4th March 2003

Dr Claire Naylor is “an academic granddaughter of Dorothy Hodgkin” as her PhD supervisor had been supervised by Dorothy herself. She is a member of the Protein Toxins Structure Group at Birkbeck College and her work relates to the lethal bacterium Clostridium perfringens. She began her talk by describing the actions of this bacterium which can be found in the gut and in soil and can produce some thirteen different toxins. Dr Naylor proceeded to detail some of the ghastly effects of these toxins, starting with relatively harmless food poisoning, then moving on to nervous sheep disorder and finally to a fatal disease known as Pigbel which is prevalent in Papua New Guinea. In her research, she is particularly concerned with alpha-toxin which is responsible for gas gangrene. Although she detailed the distressing effects of this toxin, she generously refrained from inflicting on us the full glory of a gangrenous wound!

Alpha-toxin attacks wounds where the oxygen supply is compromised and was the first major toxin to be shown to be an enzyme. Dr Naylor described the activity of this enzyme as resembling that of “pacman” as it bites off (through chemical cleavage) the hydrophilic heads from the phospholipids that form the membrane of mammalian cells, leading to the destruction of the cell membrane. The hydrophilic head floats off into the surrounding solvent, leaving behind the hydrophobic tail portion which is further cleaved by proteins in the cell to give rise to a variety of hormones. These act within the cell to cause inflammation and muscle contraction, among other things, and also signal to neighbouring cells to trigger the same effects. The combination of these effects and the destruction of the cell membrane leads to rapid cell death.

The crystal structure of this enzyme has been established and so it is possible to study the active site – the teeth of the pacman which chew up the molecules of the cell membrane. Alpha toxin has been crystallised in two distinct conformations, one of which is believed to be catalytically active and so is known as the "open form". The second form, known as the "closed form", has two loops partially closing the active site and leaving the protein inactive (with the pacman mouth closed). The toxin has a part of its structure that binds calcium and Dr Naylor showed fluorescence studies into this calcium binding and explained how this helped to explain the behaviour of the toxin in the cell.

This fascinating and well illustrated talk took us from the discovery of the bacteria, through the toxins produced and their effects, to the structure of a specific toxin and its mode of action. These studies are increasing our knowledge of this unpleasant toxin and it is hoped that this understanding will ultimately lead to a cure for gas gangrene.

Carolyn Carr